glucagon-like-peptide-1 and Cardiovascular-Diseases

Patients with type 2 diabetes (T2DM) are more likely to have cardiovascular disease (CVD). Glucose-lowering drugs with cardiovascular benefits represented by Glucagon-like peptide 1 receptor agonists (GLP1RAs) were discovered and gained more and more attention. Data from 1985 to the 2021 were downloaded in the Web of Science Core Collection (WoSCC) database. CiteSpaceV was used for bibliometric analysis to find research hotspots and frontiers. The 2088 papers were published by 74 countries (regions), 876 institutions, and 2203 authors. The annual publications increased over time from 2005 to 2020. DIABETES OBESITY METABOLISM published the most papers. The USA and China were the top 2 productive nations. The leading institution was the University of Copenhagen, and the most productive researcher was John B Buse. The most cited paper is "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes" (by Marso SP, 2016). The research hotspots include the effects of GLP1RA on cardiovascular outcomes, efficacy, complicated metabolic abnormalities, protective mechanisms, and other novel anti-diabetic drugs for cardiovascular protection. Research frontiers include cardiovascular studies on semaglutide, as well as the most prominent research approach in the field-placebo-controlled trial. Numerous countries, institutions, and authors have focused on GLP1RA in cardiovascular research and a great deal of literature has been published. Five research hotspots and two frontiers illustrate the current status and emerging trends of GLP1RA in cardiovascular research. The cardiovascular effects and clinical efficacy of GLP1RA are a current hot topic that is rapidly evolving and of high research value.

Topics: Bibliometrics; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1R agonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Humans; Pancreas; Receptors, G-Protein-Coupled; Weight Loss

Glucagon-like peptide1-receptor agonists (GLP1-RA) decrease major adverse cardiovascular events (MACE) in people with type 2 diabetes mellitus and cardiovascular disease (CVD). Caution is recommended for semaglutide and dulaglutide with risk of exacerbating diabetic retinopathy (DR). Analyses were performed to determine if worsening of DR was dependent on drug class or fall in A1c.. Meta-analyses and meta-regressions (MR) were performed on the 7 major cardiovascular outcome trial (CVOTs) (n = 56004 patients) of GLP1-RA. A second analysis of 11 studies (n = 11894 subjects) with semaglutide documenting DR followed.. Six of the CVOTs evaluated DR. For the GLP1-RA class, there was no increase in the relative rate (rr) for retinopathy (rr = 1.09,95%CI; 0.925,1.289, p = 0.30), with only an increase with parenteral semaglutide (rr = 1.73; 1.10:2.71, p = 0.02). MR showed that decreases in A1c correlated with decreases in MACE (log rr = 0.364∗(Δ A1c), p = 0.014), but increases in DR (log rr= (-0.67∗(ΔA1c), p = 0.076). The change in DR was predominantly found for subcutaneous semaglutide given for >1 year (rr = 1.559,1.068,2.276, p = 0.022) and with decreases in A1c > 1.0% (rr = 1.59; 1.092,2.316, p = 0.016). For the class of GLP1-RA, the rate difference (rd) for worsening retinopathy was = 0.001 (and number needed to harm [NNH] = 1000) compared with rd for MACE = -0.013 (number needed to treat [NNT] = 77). The computation for semaglutide was NNH = 77 and NNT = 43.. This meta-analysis may assist in decisions balancing the relative risk (of existing retinopathy) versus benefits (to existing CVD). There should be close collaboration with ophthalmology to grade the baseline degree of retinopathy when initiating and following patients.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peripheral Arterial Disease; Retrospective Studies

Evaluation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) usage in heart failure (HF) patients with or without type 2 diabetes mellitus (T2DM) could be proven to be a critical breakthrough in treatment options available for these patients. Our study focuses on understanding the safety and efficacy of GLP-1 RAs in this patient population by pooling the data from 9 randomized controlled trials (RCTs) comprising 871 subjects. As compared with the placebo, GLP-1 RAs did not improve major adverse cardiovascular events (MACE) which include cardiovascular (CV) mortality and heart failure (HF) hospitalizations, our primary outcome. CV mortality (RR = 1.03, 95% CI = 0.56-1.88, P = 0.92) and HF hospitalizations (RR = 1.18, 95%CI = 0.93-1.51, P = 0.18). Similarly, GLP-1 RAs did not improve our secondary findings of left ventricular ejection fraction (LVEF) and 6-minute walk test (6MWT). LVEF (RR = 1.96, 95%CI = -0.16-4.07, P = 0.07) or 6 MWT (RR = 8.43, 95% CI = -2.69-19.56, P = 0.14). This meta-analysis shows that GLP-1 RAs do not improve cardiovascular outcomes in HF patients with or without T2DM.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Epicardial adipose tissue (EAT) plays an important role in cardiometabolic risk. EAT is a modifiable risk factor and could be a potential therapeutic target for drugs that already show cardiovascular benefits. The aim of this study is to evaluate the effect of cardiometabolic drugs on EAT reduction.. A detailed search related to the effect on EAT reduction due to cardiometabolic drugs, such as glucagon-like peptide-1 receptor agonist (GLP-1 RA), sodium-glucose cotransporter-2 inhibitors (SGLT2-i), and statins was conducted according to PRISMA guidelines. Eighteen studies enrolling 1064 patients were included in the qualitative and quantitative analyses.. All three analyzed drug classes, in particular GLP-1 RA, show a significant effect on EAT reduction (GLP-1 RA standardize mean difference (SMD) = - 1.005; p < 0.001; SGLT2-i SMD = - 0.552; p < 0.001, and statin SMD = - 0.195; p < 0.001). The sensitivity analysis showed that cardiometabolic drugs strongly benefit EAT thickness reduction, measured by ultrasound (overall SMD of - 0.663; 95%CI - 0.79, - 0.52; p < 0.001). Meta-regression analysis revealed younger age and higher BMI as significant effect modifiers of the association between cardiometabolic drugs and EAT reduction for both composite effect and effect on EAT thickness, (age Z: 3.99; p < 0.001 and Z: 1.97; p = 0.001, respectively; BMI Z: - 4.40; p < 0.001 and Z: - 2.85; p = 0.004, respectively).. Cardiometabolic drugs show a significant beneficial effect on EAT reduction. GLP-1 RA was more effective than SGLT2-i, while statins had a rather mild effect. We believe that the most effective treatment with these drugs should target younger patients with high BMI.

Topics: Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Obesity; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs with potent glucose-lowering activity. Additionally, some GLP-1 RAs have demonstrated cardiovascular and renal benefits. Current guidelines recommend their use in patients with type 2 diabetes (T2D) at high risk of or with established cardiovascular disease (CVD), regardless of glycaemic control, with lifestyle modification and metformin. However, several studies have recently highlighted the limited number of patients with T2D benefiting from these medications worldwide. Given the huge burden of CVD among patients with T2D, efforts should be made to bring clinical practice closer to expert guidelines. This review describes the current situation of GLP-1 RA use in Spain and the reasons behind the gap between guidelines and real-world practice and suggests possible solutions. Administrative issues, lack of awareness of the cardiovascular benefits, clinical inertia, rejection of injectable medication and costs could be some of the reasons for the current situation. Possible strategies that could help to close the gap include encouraging a multidisciplinary approach to the treatment of diabetes which involves cardiologists, endocrinologists, nephrologists, primary care providers and pharmacists; improved awareness of comorbidities and earlier evaluation and treatment or risks; and better education of healthcare providers regarding the cardioprotective benefits of these drugs.. The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs that can be beneficial for patients with type 2 diabetes who are at high risk of cardiovascular complications, such as heart attacks. For this reason, the current clinical guidelines strongly recommend their use in these patients. Unfortunately, many patients with type 2 diabetes and high cardiovascular risk still do not benefit from these drugs. This review analyses the reasons for this situation in Spain, and proposes some possible solutions. The reasons for the low use of GLP-1 RAs could be related to doctors not updating a patient’s diabetes medicine as often as they should, lack of awareness about the cardiovascular benefits of these drugs, fear of medicines that involve needles, administrative issues, and costs. Some of the possible strategies to improve the use of GLP-1 RAs among patients with type 2 diabetes with high cardiovascular risk could be to foster greater cooperation among specialists, increase awareness of the need to treat cardiovascular risk in patients with diabetes, and better education of doctors regarding the benefits of these drugs.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Spain

Stroke is a leading cause of disability and death, and people with type 2 diabetes (T2D) have a greater risk of stroke and death or disability from stroke. The underlying pathophysiology associating stroke and T2D is complicated by the association of risk factors for stroke frequently seen in people with T2D. Treatments to reduce the excess risk of new-onset stroke or to improve outcomes in people with T2D following stroke would be of major clinical interest. In practice, the focus of care in people with T2D remains treating risk factors for stroke, such as lifestyle and pharmacological interventions for hypertension, dyslipidemia, obesity, and glycemic control. More recently, cardiovascular outcome trials primarily designed to assess the cardiovascular safety of GLP-1RAs (glucagon-like peptide-1 receptor analogues) have consistently observed a reduced stroke risk in people with T2D. This is supported by several meta-analyses of cardiovascular outcome trials observing clinically important risk reductions in stroke. Moreover, phase II trials have described reductions in poststroke hyperglycemia in people with acute ischemic stroke suggestive of improved outcomes following admission to hospital with acute stroke. In this review, we discuss the increased risk of stroke in people with T2D and outline the key associated mechanisms responsible. We discuss the evidence from cardiovascular outcome trials exploring GLP-1RA use and highlight areas of potential interest for future work in this rapidly developing area of clinical research.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Ischemic Stroke; Risk Factors

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and now tirzepatide, a dual GLP-1 RA/glucose-dependent insulinotropic polypeptide agonist, have numerous advantages in the treatment of type 2 diabetes and obesity, yet only 11% of patients with type 2 diabetes are prescribed a GLP-1 RA. This narrative review addresses the complexity and cost issues surrounding incretin mimetics to support clinicians.. This narrative review summarizes key trials on the differing effects of incretin mimetics on glycosylated hemoglobin and weight, provides a table with rationale for how to interchange among agents, and summarizes the key factors that guide drug selection beyond guidance from the American Diabetes Association. To support proposed dose interchanges, we preferentially selected high-quality, prospective randomized controlled trials with direct comparisons of agents and doses when available.. Tirzepatide produces the greatest reductions in glycosylated hemoglobin and weight, but its impact on cardiovascular events is still under investigation. Subcutaneous semaglutide and liraglutide are approved for weight loss specifically and are effective in the secondary prevention of cardiovascular disease. Although producing less weight loss, only dulaglutide has effectiveness in the primary and secondary prevention of cardiovascular disease. Semaglutide is the only orally available incretin mimetic; however, the oral formulation produces less weight loss versus its subcutaneous alternative and did not have cardioprotection in its outcomes trial. Although effective in controlling type 2 diabetes, exenatide extended release has the least impact on glycosylated hemoglobin and weight among commonly used agents, while not having cardioprotection. However, exenatide extended release may be preferred on some restrictive insurance formularies.. Although trials have not explicitly studied how to interchange among agents, interchanges can be guided by comparisons between agents' impact on glycosylated hemoglobin and weight. Efficient changes among agents can help clinicians optimize patient-centered care, particularly in the face of changing patient needs and preferences, insurance formularies, and drug shortages.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Prospective Studies; Weight Loss

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern that is closely related to obesity and metabolic syndrome. In particular, NAFLD has been increasingly reported in adolescents and young adults in recent years. Cardiovascular diseases (CVDs) such as cardiac remodeling, heart failure, myocardial infarction, valvular heart diseases, and arrhythmia are more common in patients with NAFLD. CVD are the major cause of mortality in NAFLD. Although NAFLD often affects patients with obesity/overweight, it can also affect subjects with normal body mass index (BMI), known as lean NAFLD, which has a strong correlation with CVD. Obesity imposes a considerably increased risk of NAFLD and CVD. Consistently, weight-lowering approaches that can pronouncedly decrease body weight and maintain it in the long term, such as bariatric surgery and treatment with semaglutide and tirzepatide, have been promising in alleviating both CVD and NAFLD. Interestingly, compared with patients with NAFLD and obesity, a minimal amount of weight loss resolves NAFLD in lean patients. Besides the widespread use of bariatric surgery, the development of new GLP-1 agonists and GLP-1 GIP agonists revolutionized the treatment of obesity in recent years. Here, we discuss the interwoven correlation between obesity, NAFLD, and CVD and the benefits of weight-lowering approaches.

Topics: Adolescent; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Weight Loss; Young Adult

Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders characterized by excess cardiovascular risk. Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists reduce body weight, glycaemia, blood pressure, postprandial lipaemia and inflammation - actions that could contribute to the reduction of cardiovascular events. Cardiovascular outcome trials (CVOTs) have demonstrated that GLP1R agonists reduce the rates of major adverse cardiovascular events in patients with T2DM. Separate phase III CVOTs of GLP1R agonists are currently being conducted in people living with heart failure with preserved ejection fraction and in those with obesity. Mechanistically, GLP1R is expressed at low levels in the heart and vasculature, raising the possibility that GLP1 might have both direct and indirect actions on the cardiovascular system. In this Review, we summarize the data from CVOTs of GLP1R agonists in patients with T2DM and describe the actions of GLP1R agonists on the heart and blood vessels. We also assess the potential mechanisms that contribute to the reduction in major adverse cardiovascular events in individuals treated with GLP1R agonists and highlight the emerging cardiovascular biology of novel GLP1-based multi-agonists currently in development. Understanding how GLP1R signalling protects the heart and blood vessels will optimize the therapeutic use and development of next-generation GLP1-based therapies with improved cardiovascular safety.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity

Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials.. GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects.. An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic

Emerging evidence suggests that treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be an interesting treatment strategy to reduce neurological complications such as stroke, cognitive impairment, and peripheral neuropathy. We performed a systematic review to examine the evidence concerning the effects of GLP-1 RAs on neurological complications of diabetes. The databases used were Pubmed, Scopus and Cochrane. We selected clinical trials which analysed the effect of GLP-1 RAs on stroke, cognitive impairment, and peripheral neuropathy. We found a total of 19 studies: 8 studies include stroke or major cardiovascular events, 7 involve cognitive impairment and 4 include peripheral neuropathy. Semaglutide subcutaneous and dulaglutide reduced stroke cases. Liraglutide, albiglutide, oral semaglutide and efpeglenatide, were not shown to reduce the number of strokes but did reduce major cardiovascular events. Exenatide, dulaglutide and liraglutide improved general cognition but no significant effect on diabetic peripheral neuropathy has been reported with GLP-1 RAs. GLP-1 RAs are promising drugs that seem to be useful in the reduction of some neurological complications of diabetes. However, more studies are needed.

Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Stroke

Adipose tissue can be divided into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, according to the differences in morphology. WAT acts as a buffer for increased energy intake and decreased energy expenditure during the development of obesity, resulting in visceral and ectopic WAT accumulation. These WAT depots are strongly associated with chronic systemic inflammation, insulin resistance, and cardiometabolic risk related to obesity. They represent a primary weight loss target in anti-obesity management. Second-generation anti-obesity medications glucagon-like peptide-1 receptor agonists (GLP-1RAs) cause weight loss and improve body composition by reducing visceral and ectopic fat depots of WAT, resulting in improved cardiometabolic health. Recently, the understanding of the physiological significance of BAT beyond its primary function in generating heat through non-shivering thermogenesis has been expanded. This has raised scientific and pharmaceutical interest in the manipulation of BAT to further enhance weight reduction and body weight maintenance. This narrative review focuses on the potential impact of GLP-1 receptor agonism on BAT, particularly in human clinical studies. It provides an overview of the role of BAT in weight management and highlights the need for further research to elucidate the mechanisms by which GLP-1RAs affect energy metabolism and weight loss. Despite encouraging preclinical data, limited clinical evidence supports the notion that GLP-1RAs contribute to BAT activation.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Cardiovascular Diseases; Energy Metabolism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Thermogenesis; Weight Loss

Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Lipids

To investigate the lowering BP effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on the risk of major cardiovascular event stratified by glucose-lowering drugs, baseline BP, glycated hemoglobin (HbA. We performed a systematic review of the MEDLINE and EMBASE databases search up to December 31, 2022, (PROSPERO, CRD42023400899) to identify all large-scale cardiovascular outcomes (CVO) trials of SGLT2i and GLP-1 RAs in which more than 1,000 patient-years of follow-up in each randomized group. Outcomes included all-cause mortality, major adverse cardiovascular event (MACE) and its component (cardiovascular death, myocardial infarction [MI], and stroke), heart failure, and renal failure. A random-effects meta-analyses were used to pool the estimates.. Eighteen CVOTs (ten for SGLT2i and eight for GLP-1 RAs) with 127,606 patients with type 2 diabetes were included. Over 2.5 years median follow-up, the average reduction of systolic BP was 2.2 mmHg (mean difference [MD] - 2.2; 95% CI - 2.7 to - 1.7) with more important reduction (P. In patients with type 2 diabetes, the hypotensive effects of SGLT2i and GLP-1 RAs were significantly associated with a reduction in mortality and cardiorenal events. These findings suggest that the lowering BP effect could be seen as an additive indicator of cardiovascular protection by SGLT2i and GLP-1 RAs drugs.

Topics: Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Myocardial Infarction; Renal Insufficiency; Sodium-Glucose Transporter 2 Inhibitors; Stroke

Whether to recommend specifically the glucose-lowering therapies with cardiovascular benefit only in secondary prevention, or also in patients with multiple risk factors (MRF) but without established atherosclerotic cardiovascular disease (ASCVD), is controversial across the guidelines for diabetes.. We performed a meta-analysis of clinical trials with major adverse cardiovascular events (MACE) as an outcome.. The definitions of ASCVD and MRF were heterogeneous across trials; nevertheless, the incidence of MACE was 2.8-fold higher in people with ASCVD in trials with sodium-glucose cotransporter 2 inhibitors (SGLT2is), and 3.9-fold in trials with glucagon-like peptide-1 receptor agonists (GLP-1 RA). Both SGLT2i and GLP-1 RA were associated with a significant reduction in the incidence of MACE in people with previous ASCVD [inverse variance-odds ratio 0.91, 95% confidence interval (0.86: 0.97) for SGLT2i, Mantel-Haenszel odds ratio 0.85, 95% confidence interval (0.81: 0.90) for GLP-1 RA], whereas no significant reduction was detected in those without; on the other hand, no significant difference in effect was found between the two groups as well. The sample of patients without ASCVD enrolled in clinical trials is insufficient to draw reliable conclusions in this population; however, even assuming the same benefit detected in people with ASCVD also in those with MRF, the number needed to treat would differ (35 for secondary, 99 for primary prevention of a MACE with a SGLT2i; 21 for secondary, 82 for primary prevention with a GLP-1 RA, respectively), given the difference in absolute cardiovascular risk at baseline.. The distinction between patients with ASCVD and those without ASCVD and MRF appears therefore justified by available evidence.

Topics: Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Secondary Prevention; Sodium-Glucose Transporter 2 Inhibitors

Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins

Obesity is a prevalent chronic disorder and a well-known risk factor for cardiovascular disease. However, the evidence of treating obesity for primary prevention of major cardiovascular events is still scarce and controversial. In this review, we provided a comprehensive description of the current evidence in treating obesity regarding cardiovascular protection. Bariatric surgery appears to be the most robust method to reduce events in people without established cardiovascular disease. High compliance to lifestyle interventions can further reduce cardiovascular risk. Concerning pharmacological therapies, a post hoc analysis from SUSTAIN-6 and a meta-analysis from STEP trials suggest that semaglutide, a GLP-1 receptor agonist, could reduce cardiovascular events in people without established cardiovascular disease. The first study addressed specifically a high-risk population with diabetes and, the second, low- or intermediary-risk individuals without diabetes. Tirzepatide, a novel dual GIP/GLP-1 agonist, although not yet tested in specific cardiovascular outcomes trials, could be an alternative since it induces loss in weight similar to the achieved by bariatric surgery. Therefore, extrapolated data in distinct baseline cardiovascular risk populations suggest that these two drugs could be used in primary prevention with the aim of preventing cardiovascular events, but the grade of this evidence is still low. Specifically designed studies are needed to address this specific topic.

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Obesity; Primary Prevention

Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death.. A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide. Obesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.

Topics: Adult; Anti-Obesity Agents; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Gastric Balloon; Glucagon-Like Peptide 1; Glucose; Humans; Hypertension; Male; Obesity; Obesity Management; Overweight; Peptides; United States; Weight Loss

Alterations of endothelial function, inflammatory activation, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway are involved in the pathophysiology of heart failure. Metabolic alterations have been studied in the myocardium of heart failure (HF) patients; alterations in ketone body and amino acid/protein metabolism have been described in patients affected by HF, as well as mitochondrial dysfunction and other modified metabolic signaling. However, their possible contributions toward cardiac function impairment in HF patients are not completely known. Recently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have emerged as a new class of drugs designed to treat patients with type 2 diabetes (T2D), but have also been shown to be protective against HF-related events and CV mortality. To date, the protective cardiovascular effects of these drugs in patients with and without T2D are not completely understood and several mechanisms have been proposed. In this review, we discuss on vascular and metabolic effects of SGLT2i and GLP-1 in HF patients.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Failure; Humans; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by the ileal endocrine system and is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects by regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cellular physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation, and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD) and discuss how GLP-1 exerts cardiovascular protective effects through the MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular levels. A better understanding of the MAPK signaling pathway that is dysregulated in CVD may aid in the design and development of promising GLP-1RA.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Mitogen-Activated Protein Kinases; Signal Transduction

Glucagon-like peptide 1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are two novel classes of hypoglycemic agents. The relative cardiovascular effectiveness between these two drug classes in patients with type 2 diabetes (T2D) is unestablished due to the absence of large cardiovascular outcome trials directly comparing DPP-4i with GLP-1RA. We aimed to incorporate large propensity score-matched cohort studies to conduct a meta-analysis, to determine the relative effectiveness of GLP-1RA versus DPP-4i on cardiovascular endpoints in T2D patients. Compared to DPP-4i, GLP-1RA was associated with the significantly lower risks of major adverse cardiovascular events [MACE] (HR 0.76, 95% CI 0.63-0.92), cardiovascular mortality (HR 0.59, 95% CI 0.37-0.95), myocardial infarction (HR 0.89, 95% CI 0.80-0.98), stroke (HR 0.86, 95% CI 0.76-0.96), and all-cause mortality (HR 0.63, 95% CI 0.42-0.96) in T2D patients; whereas these two drug classes had the similar risk of hospitalization for heart failure [HHF] (HR 0.95, 95% CI 0.77-1.16). Meta-regression analyses showed that six factors (i.e., mean age, female proportion, cardiovascular disease proportion, heart failure proportion, and the proportions of receiving metformin and insulin at baseline) did not significantly affect the effects of GLP-1RA on MACE and HHF (P ≥ 0.076). This meta-analysis provides the direct evidence regarding the relative cardiovascular effectiveness of GLP-1RA versus DPP-4i from real-world studies, and its findings suggest that among T2D patients GLP-1RA should be considered in preference to DPP-4i as for preventing atherosclerotic cardiovascular events and death in clinical practice.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Propensity Score

Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular morbidity and mortality, and cardiovascular diseases are the leading causes of death and disability in people with T2DM. Unfortunately, therapies strictly aimed at glycemic control have poorly contributed to a significant reduction in the risk of cardiovascular events. On the other hand, randomized controlled trials have shown that five glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and one exendin-based GLP-1 RA reduced atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk. Furthermore, a meta-analysis including these six agents showed a reduction in major adverse cardiovascular events as well as all-cause mortality compared with placebo, regardless of structural homology. Evidence has also shown that some drugs in this class have beneficial effects on renal outcomes, such as preventing the onset of macroalbuminuria. In addition to lowering blood pressure, these drugs also favorably impacted on body weight in large randomized controlled trials as in real-world studies, a result considered a priority in T2DM management; these and other factors may justify the benefits of GLP-1 RAs upon the cardiovascular system, regardless of glycemic control. Finally, studies showed safety with a low risk of hypoglycemia and no increase in pancreatitis events. Given these benefits, GLP-1 RAs were preferentially endorsed in the guidelines of the European and American societies for patients with these conditions. This narrative review provides a current and comprehensive overview of GLP-1 RAs as cardiovascular and renal protective agents, far beyond their use as glucose-lowering drugs, supporting their effectiveness in treating patients with T2DM at high cardiovascular risk.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

To evaluate the cardiovascular and renal outcomes of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the associations between these outcomes and HbA1c or weight reduction.. We searched PubMed/MEDLINE, EMBASE, and CENTRAL databases for randomized, placebo-controlled trials of GLP-1 RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes.. The reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for the cardiovascular and renal benefits of treatment with GLP-1 RAs.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Regression Analysis; Weight Loss

The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM).. Recently, societal guideline recommendations have expanded the management of T2DM to incorporate therapies with CV risk factor modification. This is due to CV outcome trials (CVOT) uncovering advantageous cardioprotective effects of several novel therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Providers who manage high-risk patients with T2DM, such as those with concomitant PAD, are expected to incorporate these novel medical therapies into routine patient care. The body of evidence surrounding GLP-1 RA demonstrates a strong benefit in mitigating the innate heightened CV risk among patients with T2DM. Furthermore, SGLT2i not only have a favorable CV profile but also reduce the risk of HF hospitalizations and progression of renal disease. Patients with T2DM and PAD are known to be at a heightened risk for major adverse cardiac and lower extremity events, heart failure, and chronic kidney disease. As such, the use of novel therapies such as GLP-RA and SGLT2i should be strongly considered to minimize morbidity and mortality in this vulnerable population.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peripheral Arterial Disease; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors.. We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome.. Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes.. SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Myocardial Infarction; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Stroke

Our aim was to study the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on the risk of any cardiovascular event in adults with overweight or obesity and without diabetes. We conducted a random-effects meta-analysis of placebo-controlled randomized controlled trials. Nine trials were eligible and, in total, 11 430 patients were included, of which 7702 (67%) were submitted to treatment with GLP-1 RA. During follow-up, 673 participants receiving GLP-1 RA treatment (8.7%) and 416 participants receiving placebo (11.2%) had a cardiovascular event. Treatment with GLP-1 RA versus placebo resulted in a reduction in the risk of any cardiovascular event (RR = 0.81, CI 0.70-0.92; p = .001). In overweight or obese adults without diabetes, treatment with GLP-1 RA reduced the risk of cardiovascular events. Our findings support the use of GLP-1 RA for reducing the cardiovascular risk of these patients.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Overweight; Randomized Controlled Trials as Topic

The introduction of sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in type 2 diabetes mellitus treatment has shown an unexpectedly significant improvement in heart disease outcome trials. Although they have very different modes of action, a portion of the salutary cardiovascular disease improvement may be related to their impact on diabetic dyslipidemia. As discussed in this focused review, the sodium glucose transporter-2 inhibitors as a class show a mild increase in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, while triglycerides (TG) decrease inconsistently. In particular, the rise in LDL appears to be related to the less atherogenic, large buoyant LDL particles. The glucagon-like peptide-1 receptor agonists show more of an impact on weight loss and improvement in the underlying low HDL and high TG dyslipidemia. The effect of sodium glucose transporter-2 inhibitors and glucagon-like peptide 1 receptor agonists when used in combination remains largely unknown. Also unexplored is difference in effect of these medications among various ethnicities and metabolic syndrome.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metabolic Syndrome; Sodium-Glucose Transporter 2 Inhibitors; Triglycerides

The cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.. PubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.. We included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83-0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77-0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 - 1.01; P = 0.06).. We concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Myocardial Infarction; Randomized Controlled Trials as Topic; Stroke

Recent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF). Moreover, studies have revealed that HF is associated with generalized insulin resistance. Recent clinical outcomes parallel to the experimental data undertaken with antihyperglycemic drugs have shown their beneficial effects on the cardiovascular system through a direct effect on the myocardium, beyond their ability to lower blood glucose levels and their receptor-associated actions. In this regard, several new-class drugs, such as glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium-glucose cotransport 2 inhibitors (SGLT2i), can improve cardiac health beyond their ability to control glycemia. In recent years, great improvements have been made toward the possibility of direct heart-targeting effects including modulation of the expression of specific cardiac genes in vivo for therapeutic purposes. However, many questions remain unanswered, regarding their therapeutic effects on cardiomyocytes in heart failure, although there are various cellular levels studies with these drugs. There are also some important comparative studies on the role of SGLT2i versus GLP-1Ra in patients with and without CVD as well as with or without hyperglycemia. Here, we sought to summarize and interpret the available evidence from clinical studies focusing on the effects of either GLP-1Ra or SGLT-2i or their combinations on cardiac structure and function. Furthermore, we documented data from experimental studies, at systemic, organ, and cellular levels. Overall, one can summarize that both clinical and experimental data support that either SGLT2i or GLP-1R agonists have similar benefits as cardioprotective agents in patients with or without impaired glucose tolerance.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose Intolerance; Heart Failure; Humans; Hypoglycemic Agents; Insulin Resistance; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers important additional benefits to these patients due to reducing the risk of developing major adverse cardiac events (MACE). This risk reduction is, in part, due to effective glycemic control in patients; however, the various outcomes trials, further validated by subsequent meta-analysis of the outcomes trials, suggest that the risk reduction in MACE is also dependent on glycemic-independent mechanisms operant in cardiovascular tissues. These glycemic-independent mechanisms are likely mediated by GLP-1 receptors found throughout the cardiovascular system and by the complex signaling cascades triggered by the binding of agonists to the G-protein coupled receptors. This heterogeneity of signaling pathways underlying different downstream effects of GLP-1 agonists, and the discovery of biased agonists favoring specific signaling pathways, may have import in the future treatment of MACE in these patients. We review the evidence supporting the glycemic-independent evidence for risk reduction of MACE by the GLP-1 receptor agonists and highlight the putative mechanisms underlying these benefits. We also comment on the different signaling pathways which appear important for mediating these effects.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Patients with diabetes have a high cardiovascular risk, which can be efficiently addressed by the administration of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1-RA). Nevertheless, the use of GLP-1-RA has so far been limited in cardiology. This review describes the existing evidence for cardiovascular benefits of GLP-1-RA and presents the available substances with recommendations on administration and titration and taking the side effects into consideration.. Patienten mit Diabetes haben ein hohes kardiovaskuläres Risiko, das durch die Gabe von GLP(„glucagon-like peptide“)-1-Rezeptor-Agonisten (GLP-1-RA) effektiv gesenkt werden kann. Trotzdem finden GLP-1-RA bisher nur eine geringe Anwendung in der Kardiologie. Die vorliegende Übersicht beschreibt die bestehende Evidenz für den kardiovaskulären Nutzen der GLP-1-RA und stellt die zur Verfügung stehenden Substanzen mit Empfehlungen zu Applikation und Auftitration und unter Berücksichtigung von Nebenwirkungen dar.

Topics: Cardiology; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

The prevalence of type 2 diabetes mellitus (DM2) is increasing, generating a great impact both at individual and public health level. Nearly half of the patients with DM2 develop impaired renal function, so nephron-protection is highly important. The robust body of evidence that shifted the therapeutic focus from glycemic to cardio-renal metabolic therapy in DM2 led to the inclusion of new therapies with cardiovascular and renal benefits in international guidelines. Type 1 glucagon (GLP-1) receptor agonists have showed favorable effects on renal function and their potential protective actions are multifactorial, beyond glycemic control. These benefits have been demonstrated in efficacy and safety clinical studies, as well as in cardiovascular outcomes and real-life studies. This comprehensive review describes the direct and indirect effects of these molecules, as well as evidence obtained from pivotal clinical (LEADER, SUSTAIN 6 and REWIND) and real-life studies demonstrating their beneficial effects on renal function, and also introduces expectations of future results from ongoing studies with renal endpoints.. La prevalencia de diabetes mellitus tipo 2 (DM2) está en aumento, generando un gran impacto tanto a nivel individual como en salud pública. Cerca de la mitad de los pacientes con DM2 sufren un deterioro de la función renal, por esto la nefroprotección resulta de fundamental importancia. El conjunto de evidencia que cambió del enfoque terapéutico glucocéntrico al cardiorrenometabólico en la DM2 motivó la inclusión en las recomendaciones internacionales de nuevas terapias con beneficios cardiovasculares y renales. Los agonistas del receptor del péptido similar al glucagón tipo 1 (GLP-1) tienen efectos favorables sobre la función renal y sus posibles acciones protectoras son multifactoriales, más allá del control glucémico. Estos beneficios han sido demostrados en los estudios clínicos de eficacia y seguridad, así como también en los estudios de resultados cardiovasculares y de vida real. En esta revisión narrativa se describen los efectos directos e indirectos de estas moléculas, así como su evidencia en los principales estudios clínicos (LEADER, SUSTAIN 6 y REWIND) y de vida real que demuestran sus efectos beneficiosos sobre la función renal e introduce la expectativa de los resultados futuros de los estudios en curso con objetivos renales.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Kidney

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data-crystallising the key findings, from safety to efficacy-and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Dipeptidyl peptidase 4 (DPP4) inhibitors are a class of antidiabetic medications that cause glucose-dependent increase in incretins in diabetic patients. One of the two incretins, glucagon-like peptide-1 (GLP-1), beside its insulinotropic activity, has been studied for extra pancreatic effects. Most of DPP4 inhibitors (DPP4i) have been investigated in in vivo and in vitro models of diabetic and nondiabetic cardiovascular diseases including heart failure, hypertension, myocardial ischemia or infarction, atherosclerosis, and stroke. Results of preclinical studies proved prominent therapeutic potential of DPP4i in cardiovascular diseases, regardless the presence of diabetes. This review aims to present an updated summary of the cardiovascular protective and therapeutic effects of DPP4 inhibitors through the past 5 years focusing on the molecular mechanisms beneath these effects. Additionally, based on the results summary presented here, future studies may be conducted to elucidate or illustrate some of these findings which can add clinical benefits towards management of diabetic cardiovascular complications.

Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Incretins

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the "Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes" trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.

Topics: Bayes Theorem; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drugs, Investigational; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

To discuss evidence supporting the use of glucagon-like peptide 1 receptor agonists (GLP-1RA) to treat obesity and their role as a cardioprotective drug. Obesity is not just a hypertrophy of the adipose tissue because it may become dysfunctional and inflamed resulting in increased insulin resistance. Being overweight is associated with increased incidence of cardiovascular events and weight loss achieved through lifestyle changes lowers risk factors, but has no clear effect on cardiovascular outcomes. In contrast, treating obesity with GLP-1RA decreases cardiovascular risk and the possible mechanisms of cardioprotection achieved by this class of drugs are discussed. GLP-1RA were initially developed to treat type 2 diabetes patients, in whom the effects upon glycemia and, moreover, weight loss, especially with long-acting GLP-1RA, were evident. However, cardiovascular safety trials in type 2 diabetes patients, the majority presenting cardiovascular disease and excess weight, showed that GLP-1 receptor agonists were indeed capable of decreasing cardiovascular risk.. Type 2 diabetes treatment with GLP-1RA liraglutide and semaglutide paved way to a ground-breaking therapy specific for obesity, as shown with the SCALE 3 mg/day liraglutide program and the STEP 2.4 mg/week semaglutide program. A novel molecule with superior performance is tirzepatide, a GLP-1 and GIP (Gastric Inhibitory Peptide) receptor agonist and recent results from the SURPASS and SURMOUNT programs are briefly described. Liraglutide was approved without a CVOT (Cardiovascular Outcome Trial) because authorities accepted the results from the LEADER study, designed for superiority. The SELECT study with semaglutide will report results only in 2023 and tirzepatide is being tested in patients with diabetes in the SURPASS-CVOT. Clinical studies highlight that GLP-1RA to treat obesity, alongside their concomitant cardioprotective effects, have become a hallmark in clinical science.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Loss

Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1-5) have shown that tirzepatide at 5-15 mg per week reduces both HbA

Topics: Body Weight; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycemic Control; Humans; Hypoglycemic Agents; Insulin; Meta-Analysis as Topic; Weight Loss

The increasing prevalence of obesity and type 2 diabetes (T2DM) is provoking an important socioeconomic burden mainly in the form of cardiovascular disease (CVD). One successful strategy is the so-called metabolic surgery whose beneficial effects are beyond dietary restrictions and weight loss. One key underlying mechanism behind this surgery is the cooperative improved action of the preproglucagon-derived hormones, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) which exert their functions through G protein-coupled receptors (GPCR). Great success has been reached with therapies based on the GLP-1 receptor monoagonism; therefore, a logical and rational approach is the use of the dual and triagonism of GCPC to achieve complete metabolic homeostasis. The present review describes novel findings regarding the complex biology of the preproglucagon-derived hormones, their signaling, and the drug development of their analogues, especially those acting as dual and triagonists. Moreover, the main investigations into animal models and ongoing clinical trials using these unimolecular dual and triagonists are included which have demonstrated their safety, efficacy, and beneficial effects on the CV system. These therapeutic strategies could greatly impact the treatment of CVD with unprecedented benefits which will be revealed in the next years.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Incretins; Peptides; Proglucagon

To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis.. Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI).. 18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80-0.97], 0.86 [0.79-0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78-0.90]), renal outcome (RR [95% CI]; 0.67 [0.60-0.74], HHF (RR [95% CI]; 0.60 [0.53-0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81-0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77-0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78-0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13-1.47], 1.31 [1.07-1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16-1.59], 1.49 [1.18-1.89], respectively) in renal outcome and HHF.. In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Network Meta-Analysis; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

The interplay between cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D) is well established. We aim at providing an evidence-based expert opinion regarding the prevention and treatment of both heart failure (HF) and renal complications in people with T2D.. ology: The consensus recommendations were developed by subject experts in endocrinology, cardiology, and nephrology. The criteria for consensus were set to statements with ≥80% of agreement among clinicians specialized in endocrinology, cardiology, and nephrology. Key expert opinions were formulated based on scientific evidence and clinical judgment.. Assessing the risk factors of CVD or CKD in people with diabetes and taking measures to prevent HF or kidney disease are essential. Known CVD or CKD among people with diabetes confers a very high risk for recurrent CVD. Metformin plus lifestyle modification should be the first-line therapy (unless contraindicated) for the management of T2D. Glucagon-like peptide 1 (GLP-1) agonists can be preferred in people with atherosclerotic cardiovascular disease (ASCVD) or with high-risk indicators, along with sodium-glucose cotransporter-2 inhibitors (SGLT2i), whereas SGLT2i are the first choice in HF and CKD. The GLP-1 agonists can be used in people with CKD if SGLT2i are not tolerated.. Current evidence suggests SGLT2i as preferred agents among people with T2D and HF, and for those with T2D and ASCVD. SGLT2i and GLP-1RA also lower CV outcomes in those with diabetes and ASCVD, and the treatment choice should depend on the patient profile.

Topics: Atherosclerosis; Cardiovascular Diseases; Consensus; Diabetes Mellitus, Type 2; Disease Management; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypertension, Renal; Hypoglycemic Agents; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

This forward-looking review summarizes existing evidence from cardiovascular outcome trials on cardiometabolic risk-reduction in type 2 diabetes (T2DM) management, with attention to updating and personalizing recommendations from recent diabetes practice guidelines issued by cardiology societies.. T2DM management has shifted towards cardiometabolic outcome improvement rather than purely glycemic control. According to large clinical trials, sodium-glucose cotransporter-2 inhibitors showed robust results in reducing heart failure (HF) hospitalization and chronic kidney disease (CKD) progression, while glucagon-like peptide-1 receptor agonists demonstrated the largest effects on HbA1c reduction, weight loss, and atherosclerotic cardiovascular disease outcomes prevention, including stroke. Considering the distinct features of these new cardiometabolic agents, initial selection of therapy should be targeted to each individual patient, with consideration of combination therapy for the highest risk patients. Moreover, future studies should investigate the addition of obesity-predominant risk, in conjunction with coronary artery disease, stroke, CKD, and HF, as a new influential indicator for choosing the optimal cardiometabolic agent.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Stroke

According to available research, there have been no head-to-head studies comparing the effect of glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors on cardiovascular outcomes among patients with type 2 diabetes not reaching glycemic goal with metformin.. Relevant studies were identified through electronic searches of PubMed and EMBASE published up to January 15, 2020. Efficacy outcomes of interest included the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke, its individual components, all-cause death, and hospitalization for heart failure (HF). Safety outcomes included all suggested side effects of both agents previously reported.. Eleven studies, including 94,727 patients were used for the analysis. The risk of composite end point was significantly lower in both groups compared to the control group (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.85-0.92, p < 0.001). The risk of hospitalization for HF was significantly lower in both groups but the magnitude of the effect was more pronounced in the SGLT-2 inhibitors group (HR 0.68, 95% CI 0.60-0.76, p < 0.001) than the GLP-1 agonists group (HR 0.92, 95% CI 0.84-0.99, p = 0.03). Patients treated with GLP-1 agonists discontinued trial medications more frequently compared to conventionally treated patients because of serious side effects.. Both GLP-1 agonists and SGLT-2 inhibitors showed comparable cardiovascular outcomes in patients with type 2 diabetes. However, the SGLT-2 inhibitors were associated with more pronounced reduction of hospitalization for HF and lower risk of treatment discontinuation than GLP-1 agonists.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Obesity and associated comorbidities reach epidemic proportions nowadays. Several treatment strategies exist, but bariatric surgery has the only longstanding effects. Since a few years, there is increasing interest in the effects of gastro-intestinal hormones, in particular Glucagon-Like Peptide-1 (GLP-1) on the remission of Type 2 Diabetes (T2DM) and its effects on cardiac cardiovascular morbidity, cardiac remodeling, and mortality. In the past years several high quality multicenter randomized controlled trials were developed to assess the effects of GLP-1 receptor agonist therapy on cardiovascular morbidity and mortality. Most of the trials were designed and powered as non-inferiority trials to demonstrate cardiovascular safety. Most of these trials show a reduction in cardiovascular morbidity in patients with T2DM. Some follow-up studies indicate potential beneficial effects of GLP-1 receptor agonists on cardiovascular function in patients with heart failure, however the results are contradictory, and we need long-term studies to make firm conclusions about the pleiotropic properties of incretin-based therapies. However, it seems that GLP-1 receptor agonists have different effects than the increased GLP-1 production after bariatric surgery on cardiovascular remodeling. One of the hypotheses is that the blood concentrations of GLP-1 receptor agonists are three times higher compared to GLP-1 increase after bariatric and metabolic surgery. The purpose of this narrative review is to summarize the effects of GLP-1 on cardiovascular morbidity, mortality and remodeling due to medication but also due to bariatric and metabolic surgery. The second objective is to explain the possible differences in effects of GLP-1 agonists and bariatric and metabolic surgery.

Topics: Bariatric Surgery; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Multicenter Studies as Topic; Obesity; Ventricular Remodeling

Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long-acting glucagon-like peptide-1 (GLP-1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP-1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP-1 and receptor agonists, and the GLP-1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP-1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP-1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP-1 receptor-dependent versus independent effects secondary of GLP-1 metabolites. We conclude that the favourable cardiovascular profile of GLP-1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non-diabetic populations. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

The continuous progress in cardiovascular risk prevention strategies has led to an impressive reduction in mortality and recurrent ischemic events in patients with coronary artery disease (CAD). However, the control of several cardiovascular risk factors remains suboptimal in many CAD patients, with a high rate of recurrent events, underlying the need for more new prevention strategies. The GAPS-I (glucagon-like peptide 1 analogues, antithrombotic agents, proprotein convertase subtilisin/kexin type 9 inhibitors, sodium glucose cotransporter type 2 inhibitors and immunomodulators) strategy offers a promising potential in patients with a high-residual cardiovascular risk, who are frequently encountered in daily practice, by offering an individualized and structured approach to addressing their individual risk factors. The current review summarizes the evidence to date on each of its components, with respect to clinical outcomes and economic feasibility. The current evidence points to an efficacy of GAPS-I in reducing major adverse cardiovascular events and mortality, without a compromise on safety, albeit with the need for longer follow-up data.

Topics: Cardiovascular Diseases; Cholesterol, LDL; Coronary Artery Disease; Fibrinolytic Agents; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Immunologic Factors; PCSK9 Inhibitors; Proprotein Convertase 9; Secondary Prevention; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular disease is a leading cause of morbidity, mortality and financial burden to the United States health system. A change in focus towards preventive medicine along with advances in pharmacologic and invasive therapies, has led to improved cardiac death rates. These benefits however, come with increased prevalence of heart failure and soaring readmission rates. Reducing burden of hospitalizations has therefore, been a focus of clinicians and researchers over the years. An improvement in clinical outcomes has been demonstrated in multiple trials investigating HF therapies, however, execution of guideline recommendations has been trailing. Over the past decade, 2 classes of hypoglycemic agents, the glucagon-like peptide-1 (GLP-1) receptor agonists and the sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been recognized for their cardiovascular morbidity and mortality benefits. Studies have shown that there has been a steady increase in prescription rates of these medications, however, overall usage remains quite low. Various patient, physician and system-based factors have been identified that cause barriers to translation of trial data to real-world clinical outcomes. A strategy focused on physician and patient education, quality improvement, multi-disciplinary team approach, and patient centered care is essential to meet treatment goals.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Patients with type 2 diabetes mellitus (T2DM) are at increased risk for severe coronavirus disease 2019 (COVID-19) and related mortality. Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) have significant cardiovascular and renal benefits for patients with T2DM and related comorbidities. Their anti-inflammatory properties could be beneficial in these patients. This work provides less-biased estimates regarding the risk for respiratory tract infections and acute respiratory distress syndrome by performing the first significant meta-analysis of cardiovascular outcome trials in the literature. Notably, GLP-1-RAs do not seem to increase the risk for respiratory tract infection, pneumonia, or acute respiratory distress syndrome in patients with T2DM and cardiovascular comorbidities.

Topics: Cardiovascular Diseases; COVID-19; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Pandemics; Respiratory Distress Syndrome

Cardiovascular disease (CVD) is a leading cause of death globally. Recently, dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) were approved for treating people with type 2 diabetes mellitus. Although metformin remains the first-line pharmacotherapy for people with type 2 diabetes mellitus, a body of evidence has recently emerged indicating that DPP4i, GLP-1RA and SGLT2i may exert positive effects on patients with known CVD.. To systematically review the available evidence on the benefits and harms of DPP4i, GLP-1RA, and SGLT2i in people with established CVD, using network meta-analysis.. We searched CENTRAL, MEDLINE, Embase, and the Conference Proceedings Citation Index on 16 July 2020. We also searched clinical trials registers on 22 August 2020. We did not restrict by language or publication status.. We searched for randomised controlled trials (RCTs) investigating DPP4i, GLP-1RA, or SGLT2i that included participants with established CVD. Outcome measures of interest were CVD mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, all-cause mortality, hospitalisation for heart failure (HF), and safety outcomes.. Three review authors independently screened the results of searches to identify eligible studies and extracted study data. We used the GRADE approach to assess the certainty of the evidence. We conducted standard pairwise meta-analyses and network meta-analyses by pooling studies that we assessed to be of substantial homogeneity; subgroup and sensitivity analyses were also pursued to explore how study characteristics and potential effect modifiers could affect the robustness of our review findings. We analysed study data using the odds ratios (ORs) and log odds ratios (LORs) with their respective 95% confidence intervals (CIs) and credible intervals (Crls), where appropriate. We also performed narrative synthesis for included studies that were of substantial heterogeneity and that did not report quantitative data in a usable format, in order to discuss their individual findings and relevance to our review scope.. We included 31 studies (287 records), of which we pooled data from 20 studies (129,465 participants) for our meta-analysis. The majority of the included studies were at low risk of bias, using Cochrane's tool for assessing risk of bias. Among the 20 pooled studies, six investigated DPP4i, seven studied GLP-1RA, and the remaining seven trials evaluated SGLT2i. All outcome data described below were reported at the longest follow-up duration. 1. DPP4i versus placebo Our review suggests that DPP4i do not reduce any risk of efficacy outcomes: CVD mortality (OR 1.00, 95% CI 0.91 to 1.09; high-certainty evidence), myocardial infarction (OR 0.97, 95% CI 0.88 to 1.08; high-certainty evidence), stroke (OR 1.00, 95% CI 0.87 to 1.14; high-certainty evidence), and all-cause mortality (OR 1.03, 95% CI 0.96 to 1.11; high-certainty evidence). DPP4i probably do not reduce hospitalisation for HF (OR 0.99, 95% CI 0.80 to 1.23; moderate-certainty evidence). DPP4i may not increase the likelihood of worsening renal function (OR 1.08, 95% CI 0.88 to 1.33; low-certainty evidence) and probably do not increase the risk of bone fracture (OR 1.00, 95% CI 0.83 to 1.19; moderate-certainty evidence) or hypoglycaemia (OR 1.11, 95% CI 0.95 to 1.29; moderate-certainty evidence). They are likely to increase the risk of pancreatitis (OR 1.63, 95% CI 1.12 to 2.37; moderate-certainty evidence). 2. GLP-1RA versus placebo Our findings indicate that GLP-1RA reduce the risk of CV mortality (OR 0.87, 95% CI 0.79 to 0.95; high-certainty evidence), all-cause mortality (OR 0.88, 95% CI 0.82 to 0.95; high-certainty evidence), and stroke (OR 0.87, 95% CI 0.77 to 0.98; high-certainty evidence). GLP-1RA probably do not reduce the risk of myocardial infarction (OR 0.89, 95% CI 0.78 to 1.01; moderate-certainty evidence), and hospitalisation for HF (OR 0.95, 95% CI 0.85 to 1.06; high-certainty evidence). GLP-1RA may reduce the risk of worsening renal function (OR 0.61, 95% CI 0.44 to 0.84; low-certainty evidence), but may have no impact on pancreatitis (OR 0.96, 95% CI 0.68 to 1.35; low-certainty evidence). We are uncertain about the effect of GLP-1RA on hypoglycaemia and bone fractures. 3. SGLT2i versus placebo This review shows that SGLT2i probably reduce the risk of CV mortality (OR 0.82, 95% CI 0.70 to 0.95; moderate-certainty evidence), all-cause mortality (OR 0.84, 95% CI 0.74 to 0.96; moderate-certainty evidence), and reduce the risk of HF hospitalisation (OR 0.65, 95% CI 0.59 to 0.71; high-certainty. Findings from both standard and network meta-analyses of moderate- to high-certainty evidence suggest that GLP-1RA and SGLT2i are likely to reduce the risk of CVD mortality and all-cause mortality in people with established CVD; high-certainty evidence demonstrates that treatment with SGLT2i reduce the risk of hospitalisation for HF, while moderate-certainty evidence likely supports the use of GLP-1RA to reduce fatal and non-fatal stroke. Future studies conducted in the non-diabetic CVD population will reveal the mechanisms behind how these agents improve clinical outcomes irrespective of their glucose-lowering effects.

Topics: Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Glucose; Humans; Network Meta-Analysis; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Symporters

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for people with type 2 diabetes mellitus (T2DM). Previous pharmacological management recommendations focused primarily on glucose lowering. However, new data demonstrate that select glucagon-like peptide 1 receptor agonists (GLP1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) not only provide glucose lowering but also can reduce the risk of cardiovascular (CV) disease.. The purpose of this study was to evaluate the current data regarding CV benefits of GLP1 RA and SGLT2i in select patients with T2DM and the impact on clinical guidelines so that nurse practitioners may optimize pharmacologic management of patients with T2DM.. A literature review was conducted using the PubMed and CINAHL complete databases to identify studies with CV benefits of GLP1 RA and SGLT2i. Pivotal clinical trials were selected for review.. Select GLP1 RA and SGLT2i can reduce the risk of major adverse CV events, death from CV cases, or hospitalization due to heart failure (HF) in patients with a history of, or at high risk for, CV disease.. Based on data from major CV outcomes trials, clinical guidelines recommend GLP1a or SGLT2i in select patients for glucose lowering and CV risk reduction. In addition, even in patients who have achieved glycemic goals, these agents can provide additional benefit by reducing the incidence of major CV adverse events or hospitalization for HF. Understanding the data will help nurse practitioners select the most appropriate agent for a given individual based on comorbidities.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Sodium; Sodium-Glucose Transporter 2 Inhibitors

Latent autoimmune diabetes in adults (LADA) is characterised by pathophysiological and clinical heterogeneity. Hence, the optimal treatment strategy for this type of diabetes remains a clinical challenge.. To discuss the potential of a modern therapeutic approach for LADA in the context of the novel findings of cardiovascular outcomes trials and stress the controversies surrounding LADA and the barriers in the effective management of people with this type of diabetes.. We performed a literature search in major biomedical databases in order to retrieve relevant literature. The results of key studies, along with the authors' clinical experience and perspective, are summarised and discussed in this narrative, mini review article.. Insulin remains the primary treatment choice in individuals with low C-peptide levels. Although cardiovascular outcomes trials have mainly recruited participants with type 2 diabetes, recent data suggest that the cardiorenal protective properties of the new therapies are even present in people without diabetes and thus, the extrapolation of their results on LADA individuals sounds reasonable. Therefore, sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists should be considered for the management of people with preserved insulin production being at high cardiovascular risk. The risk of diabetic ketoacidosis with SGLT2is requires increased vigilance by treating physicians.. Individualisation, preservation of beta-cell mass and function and cardiorenal protection are the new challenges in LADA therapy.

Topics: Adult; Cardiovascular Diseases; Clinical Trials as Topic; Diabetic Angiopathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Latent Autoimmune Diabetes in Adults; Research Design; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Type 2 diabetes (T2D) and obesity represent entangled pandemics that accelerate the development of cardiovascular disease (CVD). Given the immense burden of CVD in society, non-invasive prevention and treatment strategies to promote cardiovascular health are desperately needed. During T2D and obesity, chronic dysglycemia and abnormal adiposity result in systemic oxidative stress and inflammation that deplete the vascular regenerative cell reservoir in the bone marrow that impairs blood vessel repair and exacerbates the penetrance of CVD co-morbidities. This novel translational paradigm, termed 'regenerative cell exhaustion' (RCE), can be detected as the depletion and dysfunction of hematopoietic and endothelial progenitor cell lineages in the peripheral blood of individuals with established T2D and/or obesity. The reversal of vascular RCE has been observed after administration of the sodium-glucose cotransporter-2 inhibitor (SGLT2i), empagliflozin, or after bariatric surgery for severe obesity. In this review, we explore emerging evidence that links improved dysglycemia to a reduction in systemic oxidative stress and recovery of circulating pro-vascular progenitor cell content required for blood vessel repair. Given that bariatric surgery consistently increases systemic glucagon-like-peptide 1 (GLP-1) release, we also focus on evidence that the use of GLP-1 receptor agonists (GLP-1RA) during obesity may act to inhibit the progression of systemic dysglycemia and adiposity, and indirectly reduce inflammation and oxidative stress, thereby limiting the impact of RCE. Therefore, therapeutic intervention with currently-available GLP-1RA may provide a less-invasive modality to reverse RCE, bolster vascular repair mechanisms, and improve cardiometabolic risk in individuals living with T2D and obesity.

Topics: Bariatric Surgery; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Receptors, Gastrointestinal Hormone

Cardiovascular complications account for the majority of deaths caused by diabetes mellitus. Platelet hyperactivity has been shown to increase the risk of thrombotic events and is a therapeutic target for their prevention in diabetes. Modulation of platelet function by diabetes agents in addition to their hypoglycemic effects would contribute to cardiovascular protection. Newly introduced antidiabetic drugs of sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors may have anti-platelet effects, and in the case of SGLT2i and GLP-1RA may contribute to their proven cardiovascular benefit that has been shown clinically.. Here, we reviewed the potential effects of these agents on platelet function in diabetes.. GLP-1RA and DPP-4i drugs have antiplatelet properties beyond their primary hypoglycemic effects. Whilst we have little direct evidence for the antiplatelet effects of SGLT2 inhibitors, some studies have shown that these agents may inhibit platelet aggregation and reduce the risk of thrombotic events in diabetes.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Platelet Aggregation Inhibitors; Platelet Function Tests; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

This article provides comprehensive and collective facts about teneligliptin. Teneligliptin is a dipeptide peptidase-4 (DPP-4) inhibitor that belongs to the third generation, used in the management of type 2 diabetes. It inhibits human DPP-4 enzyme activity. This drug falls under class 3; it interacts with S1, S2, and S2E extensive sub-sites. Teneligliptin and its metabolites are mainly determined in the human plasma matrix by hyphenated chromatographic methods. These developed methods could be foreseen for their clinical applications. Moreover, the stress degradation studies of Teneligliptin under different stress conditions provide an insight into degradation pathways and help in the elucidation of the structure of the degradation products by liquid mass spectroscopy. These methods are also used for routine quality control analysis of teneligliptin in pharmaceutical dosage forms.

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glucagon-Like Peptide 1; Half-Life; Humans; Pyrazoles; Thiazolidines

Despite plenty of currently available information on metabolic syndrome (MetS) in children and adolescents, there are still uncertainties regarding definition, prevention, management and treatment of MetS in children. The first approach to MetS in children consists of lifestyle interventions (nutritional education, physical activity). These recommendations are often difficult to achieve, especially for adolescents, therefore, there is usually a lack of successful outcomes. A pharmacological intervention in obese children may be needed in some cases, with the aim to improve the effects of these primary prevention interventions. Metformin seems to be safe and presents evident positive effects on insulin sensitivity, but long-term and consistent data are still missing to establish its role in the pediatric population and the possible effectiveness of other emergent treatments such as glucagon-like peptide-1 analogues, dipeptidylpeptidase-4 inhibitors, dual inhibitors of SGLT1 and SGLT2 and weight loss drugs. Bariatric surgery might be helpful in selected cases. The aim of this review is to present the most recent available treatments for the main components of metabolic syndrome, with a focus on insulin resistance. A short mention of management of congenital forms of insulin resistance will be included too.

Topics: Adolescent; Anti-Obesity Agents; Bariatric Surgery; Cardiovascular Diseases; Child; Dipeptidyl-Peptidase IV Inhibitors; Exercise; Forecasting; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metformin; Non-alcoholic Fatty Liver Disease; Nutrition Assessment; Pediatric Obesity; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2 Inhibitors

Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.. To assess the effects of metformin monotherapy in adults with T2DM.. We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).. We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.. Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.. We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trial. There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.

Topics: Adult; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Myocardial Infarction; Piperidines; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Sulfonylurea Compounds

Type 2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular (CV) disease (CVD). Optimal anti-hyperglycemic agents should include control of multiple CV risk factors (RF) to improve macrovascular and microvascular complications, as well as glycemia.. In this narrative review, the authors focus on the effects of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on blood pressure (BP) and the lipid profile, two well-established CV RF.. Results from recent CV outcome trials (CVOTs), showed the impact of GLP-1 RA and SGLT2i on BP and lipid levels. These classes of medication can alter cardiac function by affecting the process of atherosclerosis and/or hemodynamic status. The results of published GLP1-RA and SGLT2i CVOTs have shown multifactorial benefits; in addition to the main effects on glycemia and body weight (BW), there are also positive but moderate effects on BP and lipid levels. Full advantage of the pleiotropic benefit of these agents should be taken to prevent CV events.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Lipids; Sodium-Glucose Transport Proteins; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.

Topics: Administration, Oral; Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Injections; Liraglutide; Practice Guidelines as Topic; Recombinant Fusion Proteins; Treatment Outcome; United States; United States Food and Drug Administration

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.

Topics: Cardiovascular Diseases; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Liraglutide; Recombinant Fusion Proteins; United States

The latest recommendations from the American Diabetes Association and the European Association for the Study of Diabetes prioritize the use of drugs with proven cardiovascular (CV) benefit in patients with established CV disease. Especially among the glucagon-like peptide (GLP)-1 receptor agonists (GLP-1RA) class, results of cardiovascular outcomes trials (CVOT) have been heterogeneous. Baseline characteristics of the population, study design, drugs in the control arm, modifications of CV risk factors, including glycemic control, reduction of hypoglycemia, and the GLP-1RA direct effects on CV cells and tissues, were considered. Ultimately, the time of exposure to the GLP-1RA appears to be the factor most prominently explaining trial heterogeneity. Thus, the CV benefit should be regarded as a class effect of GLP-1RA, as largely similar results are seen for drugs sharing a common mechanism of action.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia

Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Europe; Glucagon-Like Peptide 1; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin Resistance; Practice Guidelines as Topic; Prognosis; Risk Factors; Risk Reduction Behavior; Sodium-Glucose Transporter 2 Inhibitors

Cardiovascular disease is responsible for 205 deaths per 100,000 persons annually and is the leading cause of death worldwide. The public health burden of cardiovascular disease is expected to continue to grow as the prevalence of many cardiovascular risk factors increases. Several novel classes of glucose-lowering, lipid-lowering, and weight-loss therapeutics have shown mortality benefits in outcomes trials. However, a large proportion of subjects in those trials had established cardiovascular disease, so, as a result, the role of these novel therapeutics in primary cardiovascular prevention is controversial. In this review, we highlight recent advances in the pharmacotherapeutic management of the cardiovascular risk factors of hyperglycemia, dyslipidemia, and obesity. We examine key subgroups within recent cardiovascular outcome trials, weigh the risks and benefits of several novel therapeutics, and provide practical insight into the use of these agents. Our article concludes with a look toward the future and provides the practitioner and scientist with an early view of emerging therapeutics that may play an important role in primary cardiovascular prevention.

Topics: Anticholesteremic Agents; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; PCSK9 Inhibitors; Primary Prevention; Sodium-Glucose Transporter 2 Inhibitors

Periodontitis is an infectious and inflammatory disease of the tooth-supporting tissues caused by the accumulation of subgingival plaque and the action of specific periodontopathogenic bacteria. Periodontitis has been associated with cardiovascular diseases and considered a cardiovascular risk factor. Several mechanisms have been proposed to explain this association, such as the infection of atherosclerotic plaques by periodontal pathogens, the pro-atherogenic effect on the lipid profile, the systemic dissemination of pro-inflammatory mediators or the contribution to type 2 diabetes mellitus. Periodontal treatment has also been related to improvement in cardiometabolic risk variables, and oral hygiene techniques may be useful in reducing cardiometabolic risk. The aim of this review is to provide new and recent insights on the relationship between periodontitis and cardiometabolic risk, focusing on recent evidence. Comments on shared potential therapeutic targets, such as the role of glucagon-like peptide 1, are also highlighted.

Topics: Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Lipids; Microbiota; Periodontitis; Risk Factors

Patients with type 2 diabetes have a significantly increased risk of cardiovascular disease (CVD) compared to the general population-with CVD accounting for two out of every three deaths in patients with diabetes. In 2008, the FDA suggested that CVD risk should be evaluated for any new antidiabetic therapy, leading to a multitude of large CVD outcome trials to assess CVD risk from these medications. Interestingly, several of these outcome trials with new novel antidiabetic therapies have demonstrated a clear and definite CVD advantage at mid-term follow up in high-risk patients with T2DM. In this review, we discuss two relatively new classes of diabetic drugs, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonists, and their efficacy in improving cardiovascular outcomes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Global Health; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Prognosis; Secondary Prevention; Sodium-Glucose Transporter 2 Inhibitors; Survival Rate

To assess the effects DPP-4i; SGLT2-i & GLP1-RA on CV death, MI, stroke and hHF. This is probably the first meta-analysis to assess the effects of these drugs on MI and stroke in totality, including non-fatal & fatal MI and stroke.. Scientific databases were searched for RCTs with pre-specified inclusion criteria and each end-point from the selected 13 studies was reported as an effect size (M H odds ratio) with a 95% confidence interval P value.. The pooled analysis of all the 5 available CVOT with DPP-4i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke, CV death and hHF. The pooled analysis of all the 5 available CVOTs with GLP1-RA resulted in a neutral effect on MI. However, there was a statistically significant 12% reduction in CV death (P = 0.01), 13% reduction in stroke (P = 0.02) and 11% reduction the combined end points of MI & Stroke (P = 0.001). The impact of GLP1-RA inhibitors on hHF was neutral. The pooled analysis of all the 3 available CVOTs with SGLT2-i resulted in a neutral effect on MI, stroke, the combined end points of MI & Stroke and CV death. There was however a statistically significant 28% reduction in hHF (P < 0.001).. DPP-4i & SGLT-2i are neutral as far as all aspects of CV outcomes are concerned except for hHF which is significantly reduced by the latter. GLP1-RA as a class reduce risk of ASCVD showing a significant reduction in MI and stroke.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Incidence; Myocardial Infarction; Sodium-Glucose Transporter 2 Inhibitors; Stroke

Obesity has many deleterious effects on the cardiovascular system, mediated by changes in insulin sensitivity, dyslipidaemia, oxidative stress and inflammation. Current therapies mainly focus on caloric intake suppression and bariatric surgery, however the efficacy of these approaches remains elusive as most patients regain their body weight within the next 5 years. A better understanding of the pathophysiology of obesity is of paramount importance for the development of new therapeutic strategies to prevent vascular complications. Autophagy has emerged as key self-degrading process responsible for the maintenance of cellular homeostasis. Defects in autophagy homeostasis are implicated in metabolic disorders, including obesity, insulin resistance, diabetes mellitus and atherosclerosis. Most importantly, autophagy regulates animal lifespan. Albeit ample preclinical evidence supports the therapeutic promise of autophagy modulators for the treatment of obesity and metabolic diseases, the clinical efficacy of pharmacological modulation of autophagy remains to be proven. Recent work has shown that GLP-1-based therapeutic approaches may positively affect autophagy in perivascular adipose tissue, thus improving obesity-related endothelial dysfunction. In the present review we discuss current evidence on the role of autophagy in obesity, with a specific focus on DPP-4 inhibitors (DPP-4i) and GLP-1 receptor agonists (GLP-1 RA) as modulators of this process. Experimental evidence on GLP-1-based approaches is critically discussed in light of recent clinical trials with DPP-4i and GLP-1 RA.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Autophagy; Cardiovascular Diseases; Clinical Trials as Topic; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Risk Factors; Signal Transduction; Treatment Outcome

The purpose of this review is to emphasize the pivotal role of glucagon-like peptide 1 (GLP-1) in tackling the parallel epidemics of obesity and type 2 diabetes (T2DM).. GLP-1-based therapies and in particular GLP-1 receptor agonists (GLP-1 RA) have proven to be effective in lowering blood glucose and decreasing weight. GLP-1 RA not only mitigate these significant medical burdens but also result in weight loss and weight loss independent factors that decrease cardiovascular disease (CVD) and microvascular complications of T2DM, such as diabetic nephropathy. GLP-1-based therapies are critical for a patient-centered approach in choosing appropriate pharmacotherapy for T2DM and obesity while also taking into consideration comorbidities, such as cardiovascular and chronic kidney diseases.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Renal Insufficiency, Chronic; Weight Loss

Substantial evidence from nutritional epidemiology links polyphenol-rich diets with reduced incidence of chronic disorders; however, biological mechanisms underlying polyphenol-disease relations remain enigmatic. Emerging evidence is beginning to unmask the contribution of the gastrointestinal tract on whole-body energy homeostasis, suggesting that the intestine may be a prime target for intervention and a fundamental site for the metabolic actions of polyphenols. During their transit through the gastrointestinal tract, polyphenols may activate enteric nutrient sensors ensuing appropriate responses from other peripheral organs to regulate metabolic homeostasis. Furthermore, polyphenols can modulate the absorption of glucose, attenuating exaggerated hormonal responses and metabolic imbalances. Polyphenols that escape absorption are metabolized by the gut microbiota and the resulting catabolites may act locally, activating nuclear receptors that control enteric functions such as intestinal permeability. Finally, polyphenols modulate gut microbial ecology, which can have profound effects on cardiometabolic health.

Topics: AMP-Activated Protein Kinases; Cardiovascular Diseases; Diet; Energy Metabolism; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucagon-Like Peptide 1; Glucose; Humans; Intestinal Absorption; Metabolic Diseases; Polyphenols

Diabetes mellitus is a leading cause of cardiovascular morbidity and mortality worldwide. Traditional antidiabetic therapies targeting hyperglycemia reduce diabetic microvascular complications but have minor effects on macrovascular complications, including cardiovascular disease. Instead, cardiovascular complications are improved by antidiabetic medications (metformin) and other therapies (statins, antihypertensive medications) ameliorating insulin resistance and other associated metabolic abnormalities. Novel classes of antidiabetic drugs have proven efficacious in improving glycemia, while at the same time exert beneficial effects on pathophysiologic mechanisms of diabetes-related cardiovascular disease. In the present review, we will present current evidence of the cardiovascular effects of two new classes of antidiabetic medications, glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors, focusing from mechanistic preclinical and clinical investigation to late-phase clinical testing.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Global Health; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Morbidity

Patients with Type 2 diabetes have an excess risk for cardiovascular disease. One of the several approaches, included in the guidelines for the management of Type 2 diabetes, is based on dipeptidyl peptidase 4 (DPP-4; also termed CD26) inhibitors, also called gliptins. Gliptins inhibit the degradation of glucagon-like peptide-1 (GLP-1): this effect is associated with increased circulating insulin-to-glucagon ratio, and a consequent reduction of HbA1c. In addition to incretin hormones, there are several proteins that may be affected by DPP-4 and its inhibition: among these some are relevant for the cardiovascular system homeostasis such as SDF-1α and its receptor CXCR4, brain natriuretic peptides, neuropeptide Y and peptide YY. In this review, we will discuss the pathophysiological relevance of gliptin pleiotropism and its translational potential.

Topics: Cardiovascular Diseases; Cardiovascular System; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Natriuretic Peptide, Brain; Neuropeptide Y; Practice Guidelines as Topic; Proteolysis; Receptors, CXCR4

The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.. To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.. MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.. Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.. Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.. The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.. This network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors (absolute risk difference [RD], -1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, -0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, -0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]) than were the control groups. SGLT-2 inhibitors (absolute RD, -0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) were significantly associated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups. GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]).. In this network meta-analysis, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment. Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

We review the cardiovascular and renal outcomes and safety of newer anti-diabetic medications in high-risk patients. We examine the outcomes of the IRIS, EMPA-REG OUTCOME, CANVAS, LEADER, SAVOR-TIMI 53, and EXAMINE trials demonstrating the cardiovascular and renal benefits of thiazolidinediones, SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors.. Diabetes mellitus is a leading risk factor for cardiovascular disease with rising prevalence and disease burden. The microvascular and macrovascular complications of diabetes are well-recognized and include increased risk of cardiovascular disease, myocardial infarction, and stroke. Newer diabetes medications have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality benefits in high risk patients with diabetes. In addition to their glucose-lowering effects, the thiazolidinedione pioglitazone, SGLT2 inhibitors, GLP-1 agonist, and DPP-4 inhibitors have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality effects. The outcomes and safety data of newer diabetes medications from recent trials demonstrate cardiovascular and mortality effects with significant implications for clinical practice.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney; Pioglitazone; Randomized Controlled Trials as Topic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors

Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality.. Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p < 0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p = 0.01 and p = 0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p = 0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p = 0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class. Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence "class effect" claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Risk Factors; Risk Reduction Behavior

Type 2 diabetes mellitus is a common and severe chronic metabolic disease, which confers increased risk of cardiovascular disease and mortality. During the last decade a large number of new drugs within the classes dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4Is), glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and sodium/glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2Is) have been developed and tested in nine large-scale cardiovascular outcome trials (CVOTs). Here we review the evidence behind antihyperglycemic treatment of patients with type 2 diabetes with a particular focus on compiling and summarizing the evidence of hard clinical endpoints stemming from these large CVOTs.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The cardiovascular safety outcomes of newer antidiabetic agents were reviewed.. Seven randomized, placebo-controlled trials involving patients with type 2 diabetes mellitus with or at risk for cardiovascular disease were reviewed. The trials examined the cardiovascular safety outcomes of the following agents: alogliptin, saxagliptin, and sitagliptin (dipeptidyl peptidase-4 [DPP-4] inhibitors); liraglutide, lixisenatide, and semaglutide (glucagon-like peptide-1 agonists); and empagliflozin (a sodium glucose cotransport-2 inhibitor). The DPP-4 inhibitor and lixisenatide trials showed a neutral effect on cardiovascular events (composite of cardiovascular death, myocardial infarction, or stroke, with or without unstable angina). Empagliflozin showed a significant reduction in cardiovascular events, cardiovascular death, all-cause death, and hospitalization due to heart failure (HF); liraglutide reduced cardiovascular events, cardiovascular death, and all-cause death, and semaglutide reduced cardiovascular events and nonfatal stroke. Most studies showed a neutral effect of the drug on hospitalization for HF; however, saxagliptin and alogliptin (in the subgroups of patients without a history of HF) showed a significant increase while empagliflozin showed a significant reduction in hospitalizations for HF. The data for empagliflozin, liraglutide, and semaglutide are compelling; however, further studies are necessary to confirm observed benefits and better characterize long-term safety and their use as a strategy to reduce cardiovascular events.. A review of cardiovascular safety outcomes for new antidiabetic agents found that saxagliptin and alogliptin were associated with an increase in hospitalization for HF. The data for empagliflozin, liraglutide, and semaglutide showed a reduction in cardiovascular events and death or a neutral effect on cardiovascular endpoints.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The purpose of the study is to review the use of statins and the role of both non-statin lipid-lowering agents and diabetes-specific medications in the treatment of diabetic dyslipidemia.. Statins have a primary role in the treatment of dyslipidemia in people with type 2 diabetes, defined as triglyceride levels >200 mg/dl and HDL cholesterol levels <40 mg/dL. A number of clinical trials suggest that treatment with a fibrate may reduce cardiovascular events. However, the results of these trials are inconsistent, probably because many of their participants did not have dyslipidemia. The choice of medications used to treat diabetes can have major implications regarding management of dyslipidemia; metformin, GLP-1 agonists, and pioglitazone all have favorable lipid effects. These agents, as well as the new SGLT2 inhibitors, may reduce cardiovascular events. Management of dyslipidemia in people with type 2 diabetes should start with statin therapy and optimal glycemic control with agents that have favorable lipid and cardiovascular effects. We believe that there is a role for adding fenofibrate to moderate-intensity statins in selected patients with true dyslipidemia. We propose an algorithm for selecting add-on medications for diabetes (after metformin) based on lipid status.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dyslipidemias; Fenofibrate; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Metformin; Pioglitazone; Thiazolidinediones

Cardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in diabetic patients. Improvement in cardiovascular complications with glycaemic control and managing cardiovascular risk factors is well established. However, the impact of hypoglycaemic medications on CVD is of increasing importance. In 2008, the U.S. Food and Drug Administration issued study regulations for hypoglycaemic agents after rosiglitazone was shown to increase the incidence of myocardial infarction, and the European Medicines Agency provided their own guidance in 2012. As a result, multiple studies have been published evaluating the cardiovascular safety of newer hypoglycaemic medications. Empagliflozin and liraglutide are among the newer agents that have shown cardiovascular benefit and are now recommended for patients with CVD or are at an increased risk of CVD per the 2017 American Diabetes Association Guidelines. Given the influx of new literature and other ongoing studies, it is important to understand the cardiovascular safety of newer hypoglycaemic medications. The purpose of this article is to provide a comprehensive review of clinical trials conducted evaluating cardiovascular outcomes of newer hypoglycaemic medications and their role within diabetic management. Key Messages With the prevalence of cardiovascular disease in diabetic patients, clinicians should develop a medication regimen that provides both sufficient efficacy for diabetes while also maintaining cardiovascular safety. Of the new diabetic classes, empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and liraglutide, a glucagon-like peptide-1 receptor agonist, have shown cardiovascular benefit in diabetic patients with established cardiovascular disease and are now recommended in current guidelines for this population. Ongoing trials will give more insight to whether cardiovascular benefit is a class effect with sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists and the cardiovascular safety of dipeptidyl peptidase-4 inhibitors.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Practice Guidelines as Topic; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Diabetes mellitus type 2 (T2DM) has been associated with an increased cardiovascular risk. Improving glycaemia or other traditional cardiovascular risk factors may reduce cardiovascular risk in patients with T2DM. However, single risk intervention in T2DM has not provided convincing evidence in the reduction of cardiovascular risk. The aim of this paper is to provide an overview of clinical trials involving reduction of cardiovascular outcomes in patients with T2DM. Trials with glucose lowering therapies have shown conflicting results. Intensive therapy to reduce glycaemia has shown some benefit on composite cardiovascular endpoints but these benefits take a longer period to emerge. Recent studies with empagliflozin and glucagon-like peptide-1 (GLP-1) agonists show promising results, but the mechanisms are most likely not mediated by improved glycaemia, given the relatively rapid effects. Both LDL-cholesterol and blood pressure reduction have been proven by large meta-analysis to reduce both cardiovascular events and mortality in all patients with T2DM. Treatment of microalbuminuria and anti-platelet therapy have only been proven in diabetic patients with increased cardiovascular risk. Classical lifestyle interventions have been disappointing with respect to cardiovascular outcome, possibly due to limited weight reduction. So far, the strongest evidence lies on bariatric surgery and a multifactorial intervention to reduce mortality and cardiovascular events in the long term.

Topics: Benzhydryl Compounds; Blood Pressure; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucosides; Humans; Hypoglycemic Agents; Life Style; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors

The field of type 2 diabetes is undergoing a major transformation. Recent cardiovascular outcomes trials of glucose-lowering agents - including EMPA-REG, IRIS and LEADER, have all demonstrated convincing cardiovascular benefits within a relatively short period of time - all likely driven via non-glycemic effects of compounds under study. The implications of these studies (with primary focus on the LEADER trial) - and how their result may be paradigm shifting for type 2 diabetes management, are discussed in this article.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Precision Medicine; Risk Factors

To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM).. A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used.. The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin.. The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.

Topics: Bayes Theorem; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Mortality; Myocardial Infarction; Proportional Hazards Models; Sodium-Glucose Transporter 2 Inhibitors; Stroke; Sulfonylurea Compounds; Survival Rate; Thiazolidinediones

Incretin-based agents, including dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 agonists (GLP-1As), work via GLP-1 receptor for hyperglycemic control directly or indirectly, but have different effect on cardiovascular (CV) outcomes. The present study is to evaluate and compare effects of incretin-based agents on CV and pancreatic outcomes in patients with type 2 diabetes mellitus (T2DM) and high CV risk.. Six prospective randomized controlled trials (EXMAINE, SAVOR-TIMI53, TECOS, ELIXA, LEADER and SUSTAIN-6), which included three trials for DPP-4Is and three trials for GLP-1As, with 55,248 participants were selected to assess the effect of different categories of incretin-based agents on death, CV outcomes (CV mortality, major adverse CV events, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization), pancreatic events (acute pancreatitis and pancreatic cancer) as well as on hypoglycemia.. When we evaluated the combined effect of six trials, the results suggested that incretin-based treatment had no significant effect on overall risks of CV and pancreatic outcomes compared with placebo. However, GLP-1As reduced all-cause death (RR = 0.90, 95% CI 0.82-0.98) and CV mortality (RR = 0.84, 95% CI 0.73-0.97), whereas DPP-4Is had no significant effect on CV outcomes but elevated the risk for acute pancreatitis (OR = 1.76, 95% CI 1.14-2.72) and hypoglycemia (both any and severe hypoglycemia), while GLP-1As lowered the risk of severe hypoglycemia.. GLP-1As decreased risks of all-cause and CV mortality and severe hypoglycemia, whereas DPP-4Is had no effect on CV outcomes but increased risks in acute pancreatitis and hypoglycemia.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Pancreatitis; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.

Topics: Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina.

Topics: Adamantane; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Piperidines; Sitagliptin Phosphate; Uracil

Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

Topics: Cardiovascular Diseases; Endothelium; Glucagon-Like Peptide 1; Humans; Risk Factors; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease. The presence of concomitant hypertension in diabetics is a major driver of excess cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1a) act on numerous pathways that intersect glycemic, weight, and blood pressure (BP) control. BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1a. Acute administration of GLP-1a in humans has been shown to no effects and sometimes increased BP in humans. Chronic administration of GLP-1a, however, reduces clinic systolic BP (≈2 mmHg) at least when evaluated as a secondary end point in glycemia-lowering studies while simultaneously increasing heart rate. BP lowering has not been consistently observed in two recent double-blind controlled clinical trials evaluating ambulatory BP as the primary end point. While a number of mechanisms including vascular, myocardial, renal, and central nervous system pathways have been suggested in animal studies, these mechanistic pathways have not been sufficiently detailed in humans and it is unclear if the same pathways are operational. Further studies need to be conducted to unravel the full spectrum of effects of this drug class. An understanding of their effects on BP may help provide an explanation for the ability of GLP-1a to influence cardiovascular (CV) events in ongoing event-driven CV trials.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Glucagon-Like Peptide 1; Heart Rate; Humans; Hypertension; Risk Factors

Diabetic patients suffer from a high rate of cardiovascular events and such risk increases with HbA1c. However, lowering HbA1c does not appear to yield the same benefit on macrovascular endpoints, as observed for microvascular endpoints. As the number of glucose-lowering medications increases, clinicians have to consider several open questions in the management of type 2 diabetes, one of which is the cardiovascular risk profile of each regimen. Recent placebo-controlled cardiovascular outcome trials (CVOTs) have responded to some of these questions, but careful interpretation is needed. After general disappointment around CVOTs assessing safety of DPP-4 inhibitors (SAVOR, TECOS, EXAMINE) and the GLP-1 receptor agonist lixisenatide (ELIXA), the EMPA-REG Outcome trial and the LEADER trial have shown superiority of the SGLT2-I empagliflozin and the GLP-1RA liraglutide, respectively, on the 3-point MACE outcome (cardiovascular death, non-fatal myocardial infarction or stroke) and cardiovascular, as well as all-cause mortality. While available mechanistic studies largely support a cardioprotective effect of GLP-1, the ability of SGLT2 inhibitor(s) to prevent cardiovascular death was unexpected and deserves future investigation. We herein review the results of completed CVOTs of glucose-lowering medications and suggest a possible treatment algorithm based on cardiac and renal co-morbidities to translate CVOT findings into clinical practice.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Clinical Studies as Topic; Glucagon-Like Peptide 1; Humans; Morbidity; Risk

The effect of glucagon-like peptide-1 (GLP-1) treatment in patients with type 2 diabetes mellitus (T2DM) remains controversial. The purpose of this study was to compare the effect of GLP-1 and placebo/conventional antidiabetic agents on cardiovascular risk in T2DM patients. PubMed, EmBase and the Cochrane Library were searched to identify its eligible studies as well as manual searches for the reliability of this study. All eligible trials were performed in T2DM patients who received GLP-1 therapy or placebo/conventional antidiabetic agents. The reported outcomes included major cardiovascular events (MACE), and total mortality. Of 490 identified studies, we included 13 trials reporting data on 11,943 T2DM patients. Overall, the pooled results suggested that GLP-1 therapy has no or little effect on MACE (RR: 0.99; 95% CI: 0.88-1.12; P=0.872) and total mortality (RR: 0.90; 95% CI: 0.70-1.15; P=0.399). Furthermore, sensitivity analysis indicated that GLP-1 was associated with lower incidence of total mortality (RR: 0.28; 95% CI: 0.08-0.93; P=0.037). We concluded that GLP-1 therapy was not associated with MACE and total mortality compared with placebo or antidiabetic agents.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Global Health; Glucagon-Like Peptide 1; Humans; Incretins; Randomized Controlled Trials as Topic; Reproducibility of Results; Survival Rate

To evaluate the literature about the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of cardiac disorders, specifically myocardial infarction (MI) and heart failure (HF).. Searches were conducted in MEDLINE (1946-May 2016) and Excerpta Medica (1980-May 2016) using EMBASE with the search terms glucagon-like peptide 1, exenatide, albiglutide, liraglutide, dulaglutide, myocardial infarction, heart failure, and cardiovascular The references of relevant articles were reviewed to identify additional citations.. Clinical trials were limited to the English language and human trials. In all, 18 trials explored the use of GLP-1 RAs in the treatment of cardiac disorders in patients with and without diabetes mellitus.. Of the 18 trials reviewed, 11 trials studied the impact of GLP-1 RAs in MI. All showed a significant beneficial effect on various cardiac parameters. Favorable outcome improvements included myocardial blood flow, left ventricular (LV) function, and MI size. Seven trials reviewed the use of GLP-1 RAs in the treatment of HF. Three trials showed significant improvements in LV ejection fraction, cardiac index, and peak oxygen consumption.. Limited data suggest that GLP-1 RAs may be effective for the treatment of cardiac disorders in patients with and without diabetes mellitus. These studies suggest that GLP-1 RAs may have potential pleiotropic beneficial effects in patients with cardiovascular disease beyond their role in managing diabetes. These medications may be cardioprotective after a MI but are less promising in HF.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Recombinant Fusion Proteins; Venoms

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Risk Factors; Signal Transduction

Albiglutide is a glucagon-like peptide-1 receptor agonist, a new class of drugs used to treat type 2 diabetes. We did a prospective meta-analysis of the cardiovascular safety of albiglutide as stipulated by the US Food and Drug Administration recommendations for the assessment of new treatments for diabetes.. We did a meta-analysis of eight phase 3 trials and one phase 2b trial in which patients were randomly assigned to albiglutide, placebo, or active comparators (glimepiride, insulin glargine, insulin lispro, liraglutide, pioglitazone, or sitagliptin). The safety population included 5107 patients, of whom 2524 took albiglutide (4870 person-years) and 2583 took comparators (5213 person-years). Possible major cardiovascular events were recorded prospectively and adjudicated by an independent endpoint committee masked to treatment allocation. The primary endpoint was a composite of first occurrence of major adverse cardiovascular events (ie, cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) or hospital admission for unstable angina. Secondary endpoints were major adverse cardiovascular events alone, all-cause mortality, silent myocardial infarction, hospital admission for heart failure, chest pain, other angina, and subdural or extradural haemorrhage. The occurrence of all other adverse events classified by the investigators as cardiovascular events were documented, but these were not adjudicated.. The primary endpoint was not significantly different between albiglutide and all comparators (58 events vs 58 events; hazard ratio [HR] 1·00, 95% CI 0·68-1·49, p=0·0019 for non-inferiority). Major adverse cardiovascular event alone was also not significantly different (52 events vs 53; HR, 0·99; 95% CI, 0·65-1·49). When albiglutide was compared separately with placebo or active comparators, we noted no significant differences. We detected no significant differences in the other secondary endpoints. More patients had atrial fibrillation or atrial flutter in the albiglutide group (35 [1·4%] of 2524 patients; 8·6 events per 1000 patient-years) than in the all-comparators group (16 [0·6%] of 2583 patients; 3·4 events per 1000 patient-years).. Cardiovascular events were not significantly more likely to occur with albiglutide than with all comparators. Because the upper bound of the 95% CI for major adverse cardiovascular event plus hospital admission for unstable angina was greater than 1·3, a dedicated study with a cardiovascular endpoint is underway to confirm the safety of albiglutide.. GlaxoSmithKline.

Topics: Aged; Cardiovascular Diseases; Cardiovascular System; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Randomized Controlled Trials as Topic

Type 2 diabetes (T2D) imparts an increased risk of adverse health outcomes in patients unable to achieve glycemic control. Patient education and individualization of treatment are important for effective management of T2D. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a class of injectable glucose-lowering agents that lower A1C with added benefits of weight loss and improved cardiovascular risk markers. This review discusses the role of GLP-1RAs currently approved in the United States (exenatide, liraglutide, albiglutide, dulaglutide) for T2D management and characterizes the efficacy and safety profiles of individual GLP-1RAs.. GLP-1RAs are recommended as a preferred add-on agent to existing metformin monotherapy, as first-line therapy if metformin is contraindicated or poorly tolerated, and for use in combination with other oral glucose-lowering agents or basal insulin. Shorter-acting GLP-1RAs (exenatide and liraglutide) offer improved coverage of postprandial hyperglycemia, while longer-acting GLP-1RA formulations (exenatide extended-release, dulaglutide, and albiglutide) further improve fasting plasma glucose, which can result in additional A1C lowering. Reductions in body weight and blood pressure appear similar among individual agents, and small increases in heart rate are of unknown clinical relevance. Gastrointestinal adverse events abate over time with continued treatment and are less frequent with longer-acting GLP-1RAs. Hypoglycemia incidence is low but increased when GLP-1RAs are used with insulin secretagogues or insulin. GLP-1RAs target multiple pathophysiologic mechanisms in patients with T2D and improve glycemic control, although there are some differences within this drug class that may be relevant in clinical practice. Therefore, selection of the most appropriate treatment for individual patients is important.

Topics: Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Metformin; Peptides; Recombinant Fusion Proteins; Risk Factors; Venoms

Type 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic β-cells and reduces glucagon secretion from pancreatic α-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM.. A PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included "saxagliptin" and "DPP-4 inhibitors".. In clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure.. Saxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure.. AstraZeneca LP.

Topics: Adamantane; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents

New drugs for type 2 diabetes need to demonstrate their cardiovascular safety, due regulatory requirements from the Food and Drug Administration. For this reason, glucagon-like peptide-1 receptor agonists (GLP-1 RA) are currently undergoing large-scale, long-term randomized trials specifically designed for cardiovascular outcomes. Aim of the present meta-analysis of randomized clinical trials is the assessment of the effects of GLP-1 RA on major cardiovascular events (MACE), mortality and cardiovascular risk factors.. A meta-analysis was performed including all trials with a duration of at least 6 months, comparing a GLP-1 RA with a non-GLP-1 RA agent in type 2 diabetes. MACE and mortality were retrieved and combined to calculate Mantel-Haenzel odds ratio (MH-OR). Furthermore, data on endpoint systolic and diastolic blood pressure, total and high-density lipoprotein (HDL) cholesterol and triglyceride were collected.. Of 37 selected trials, 33 reported information on MACE, and 25 reported at least one event. The difference in the incidence of MACE between GLP-1 RA and comparators did not reach statistical significance [MH-OR 0.78 (0.54-1.13), p = 0.18]. GLP-1 RA were associated with a significant reduction in the incidence of MACE in comparisons with placebo and pioglitazone, with a non-significant trend towards reduction in DPP4i-controlled studies. No significant effect of GLP-1 RA was observed on mortality, although a non-significant favourable trend was observed in comparisons with placebo.. The present meta-analysis confirms the cardiovascular safety of GLP-1 RA, at least in the short term and in low-risk individuals. GLP-1 RA could have a beneficial effect on the incidence of MACE, at least in comparison with placebo.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Factors; Venoms

In the current context of limited economic and health resources, efficiency of drug treatments is of paramount importance, and their clinical effects and related direct costs should therefore be analyzed. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM) which, in addition to its normoglycemic effects, induces a significant improvement in body weight and several cardiovascular risk factors. The aim of this narrative review is to summarize the available evidence about the effects of liraglutide upon cardiovascular risk factors and how these improve its cost-effectiveness profile. Despite the relatively higher cost of liraglutide as compared to other alternative therapies, liraglutide has been shown to be cost-effective when clinical indicators and total costs associated to T2DM management are analyzed.

Topics: Cardiovascular Diseases; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Risk Factors; Treatment Outcome

CD26 is a widely expressed transmembrane glycoprotein with peptidase activity in its extracellular domain and which regulates multiple biological processes. It acts mainly as catabolic enzyme for a number of circulating proteins involved in common pathological conditions such as diabetes and cardiovascular disease and may represent a target to modulate bioavailability of crucial substrates. The aim of the present review is to summarize data regarding CD26-based pharmacological interventions. Four main subtopics were identified:1) CD26 as the target of pharmacological inhibitors to increase bioavailability of glucagon-like petide-1 (GLP-1) and hence to enhance GLP-1 glucose-lowering activity in diabetic patients; 2) role of CD26 in the physiology and pathology of the cardiovascular system; 3) the adverse prognostic value of CD26 expression on cancer cells; 4) CD26 down-regulation on lymphocytes as a mechanism of TGF-beta immunomodulation.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Molecular Targeted Therapy; Neoplasms

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease.New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system.This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Risk Factors

TGR5 (Takeda G-protein-coupled receptor 5) [also known as GPBAR1 (G-protein-coupled bile acid receptor 1), M-BAR (membrane-type receptor for bile acids) or GPR131 (G-protein-coupled receptor 131)] is a G-protein-coupled receptor that was discovered as a bile acid receptor. TGR5 has specific roles in several tissues, among which are the regulation of energy expenditure, GLP-1 (glucagon-like peptide 1) secretion and gall bladder filling. An accumulating body of evidence now demonstrates that TGR5 also acts in a number of processes important in inflammation. Most striking in this context are several observations that TGR5 signalling curbs the inflammatory response of macrophages via interfering with NF-κB (nuclear factor κB) activity. In line with this, recent animal studies also suggest that TGR5 could be exploited as a potential target for intervention in a number of inflammation-driven diseases, including atherosclerosis. In the present paper, I review our current understanding of TGR5 with a strong focus on its potential as target for intervention in inflammation-driven diseases.

Topics: Atherosclerosis; Bile Acids and Salts; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Inflammation; Receptors, G-Protein-Coupled

Incretin-based therapy became recently available as antihyperglycemic treatment for patients with type 2 diabetes (T2DM). Incretin therapy comprises glucagon-like peptide receptor agonists (GLP-1RA) and dipeptidyl-peptidase 4 inhibitors (DPP4-I): these classes of drugs not only have the ability to reduce blood glucose, but also can exert several cardioprotective effects. They have been shown to positively influence some risk factors for cardiovascular disease (CVD), to improve endothelial function, and to directly affect cardiac function. For these reasons incretins are considered not only antidiabetic drugs, but also cardiovascular effective. The first clinical trials aimed to demonstrate the safety of DPP4 inhibitors have been recently published: their clinical significance will be discussed in light of the prior experimental findings.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Inflammation; Lipid Metabolism; Male; Myocytes, Cardiac; Receptors, Glucagon

Insulin resistance and the metabolic syndrome are associated with fasting and postprandial dyslipidemia. This involves the hepatic and intestinal overproduction of very low density lipoproteins (VLDL) and chylomicron particles, respectively, which give rise to atherogenic remnants upon lipolysis in the circulation. Recently, the insulin secretagogue glucagon-like peptide-1 (GLP-1) has received attention not only as an anti-diabetic therapy for regulating glycaemia, but also as a regulator of lipid and lipoprotein metabolism. In fact, agents that raise endogenous bioactive levels of GLP-1 (dipeptidyl peptidase 4 inhibitors) and agents that directly stimulate GLP-1 receptors (GLP-1 receptor agonists) have been assessed in both preclinical and clinical trials for their ability to modulate plasma lipid parameters. Here we describe current evidence supporting a role for GLP-1 in preventing elevated intestinal chylomicron output and postprandial hypertriglyceridemia--an independent predictor of cardiovascular risk. Furthermore, we examine a role for GLP-1 in regulating fasting hepatic VLDL production and hindering the development of a potentially devastating comorbidity, hepatic steatosis. Possible mechanisms of action of GLP-1 are discussed including a reduction in intestinal absorption of dietary lipid and enhanced hepatic fatty acid oxidation or autophagy. Finally, we discuss the current controversy over whether these effects could occur via direct receptor stimulation or alternative, indirect pathways. We conclude that GLP- 1-based therapies appear promising in the management of diabetic dyslipidemia, and further studies are warranted to elucidate their mechanisms of action in both the intestine and liver.

Topics: Animals; Cardiovascular Diseases; Chylomicrons; Dyslipidemias; Fasting; Fatty Liver; Glucagon-Like Peptide 1; Humans; Insulin Resistance; Intestinal Mucosa; Lipid Metabolism; Lipoproteins; Liver; Postprandial Period; Risk Factors; Triglycerides

Cardiovascular (CV) disease remains the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial, and includes abnormalities in endothelial cells, vascular smooth muscle cells, myocardium, platelets, and the coagulation cascade. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of agents that act by potentiating the action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This review summarizes CV disease pathophysiology in T2DM and the potential effect of DPP-4 inhibitors on CV risk in patients with T2DM. Preclinical and small observational studies and post hoc analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Some effects of DPP-4 inhibitors are GLP-1 dependent, whereas others may be due to GLP-1-independent actions of DPP-4 inhibitors. Analyses of major adverse CV events occurring during clinical development of DPP-4 inhibitors found no increased risk of CV events or mortality and even a potential reduction in CV events. Two large CV outcome trials have been completed and report that saxagliptin and alogliptin did not increase or decrease adverse CV outcomes in patients with T2DM and CV disease or at high risk for adverse CV events. More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure, and there was a similar numerically increased risk of hospitalization for heart failure with alogliptin; however, the risk was not significantly greater compared with placebo. Dipeptidyl peptidase-4 inhibitors may affect some of the pathologic processes involved in the increased CV risk inherent in T2DM.

Topics: Animals; Blood Platelets; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Endothelial Cells; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Lipoproteins; Muscle, Smooth, Vascular; Myocardium; Risk Factors

Dipeptidylpeptidase-4 (DPP-4) is a ubiquitously expressed transmembrane protein that removes NH2-terminal dipeptides from various substrate hormones, chemokines, neuropeptides, and growth factors. Two known substrates of DPP-4 include the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide, which are secreted by enteroendocrine cells in response to postprandial hyperglycemia and account for 60–70% of postprandial insulin secretion. DPP-4 inhibitors (DPP-4i) block degradation of GLP-1 and gastric inhibitory peptide, extend their insulinotropic effect, and improve glycemia. Since 2006, several DPP-4i have become available for treatment of type 2 diabetes mellitus. Clinical trials confirm that DPP-4i raises GLP-1 levels in plasma and improves glycemia with very low risk for hypoglycemia and other side effects. Recent studies also suggest that DPP-4i confers cardiovascular and kidney protection, beyond glycemic control, which may reduce the risk for further development of the multiple comorbidities associated with obesity/type 2 diabetes mellitus, including hypertension and cardiovascular disease (CVD) and kidney disease. The notion that DPP-4i may improve CVD outcomes by mechanisms beyond glycemic control is due to both GLP-1-dependent and GLP-1-independent effects. The CVD protective effects by DPP-4i result from multiple factors including insulin resistance, oxidative stress, dyslipidemia, adipose tissue dysfunction, dysfunctional immunity, and antiapoptotic properties of these agents in the heart and vasculature. This review focuses on cellular and molecular mechanisms mediating the CVD protective effects of DPP-4i beyond favorable effects on glycemic control.

Topics: Animals; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Incretins; Metabolic Diseases

Adipose tissue (AT) was long perceived as a passive lipid storage depot but it is now considered as an endocrine organ that produces a large number of mediators that affect metabolism, inflammation and coagulation. In obesity, the increased size of adipocytes and chronic low-grade inflammation within AT alter its normal physiological function. AT dysfunction results in altered production and secretion of adipokines, which in turn affect several tissues, e.g. the liver, skeletal muscles and vasculature, in a para- or endocrine manner. Numerous circulating proinflammatory mediators involved in the development of cardiovascular disease (CVD) are directly released from adipocytes, thereby linking obesity to an increased cardiovascular risk. In the current chapter, we focus, on the one hand, on a small selection of novel adipokines with a potentially strong link to CVD: soluble dipeptidyl peptidase-4, visfatin and lipocalin-2. On the other hand, we summarize the most recent findings on the novel cardioprotective adipokines omentin and apelin.

Topics: Acute-Phase Proteins; Adipocytes; Adipokines; Adipose Tissue; Apelin; Cardiovascular Diseases; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; GPI-Linked Proteins; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Lectins; Lipocalin-2; Lipocalins; Nicotinamide Phosphoribosyltransferase; Obesity; Proto-Oncogene Proteins; Risk Factors

As cardiovascular (CV) disease remains the major cause of mortality and morbidity in type 2 diabetes mellitus, reducing macrovascular complications has been a major target of antiglycemic therapies. Emerging evidence suggests that incretin-based therapies are safe and may provide CV and cerebrovascular (CBV) benefits beyond those attributable to glycemic control, making the class an attractive therapeutic option. However, the mechanisms whereby the various classes of incretin-based therapies exert CV and CBV benefits may be distinct and may not necessarily lead to similar outcomes. In this chapter, we will discuss the potential mechanisms and current understanding of CV and CBV benefits of native glucagon-like peptide (GLP)-1, GLP-1 receptor agonists and analogues, and of dipeptidyl peptidase-4 inhibitor therapies as a means to better understand differences in safety and efficacy.

Topics: Blood Glucose; Blood Pressure; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Incretins; Peptide Fragments; Receptors, Glucagon

Glucagon-like peptide 1 (GLP-1) is an intestinal hormone secreted after the ingestion of various nutrients. The main role of GLP-1 is to stimulate insulin secretion in a glucose-dependent manner. However, the expression of GLP-1 receptor was found to be expressed in a variety of tissues beyond pancreas such as lung, stomach, intestine, kidney, heart and brain. Beyond pancreas, a beneficial effect of GLP-1 on body weight reduction has been shown, suggesting its role for the treatment of obesity. In addition, GLP-1 has been demonstrated to reduce cardiovascular risk factors and to have a direct cardioprotective effect, fostering heart recovery after ischemic injury. Further, data from both experimental animal models and human studies have shown beneficial effect of GLP-1 on bone metabolism, either directly or indirectly on bone cells.. We review here the recent findings of the extra-pancreatic effects of GLP-1 focusing on both basic and clinical studies, thus opening future perspectives to the use of GLP-1 analogs for the treatment of disease beyond type 2 diabetes.. Finally, the GLP-1 has been demonstrated to have a beneficial effect on both vascular, degenerative diseases of central nervous system and psoriasis.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Obesity; Pancreas; Risk Factors

The cardiovascular safety of many glucagon-like peptide-1 agents (GLP-1 agents) is unclear. In this study, we assess the effects of the GLP-1 agents on left ventricular function in patients with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD).. PubMed, EMBASE, and the Cochrane Library were searched for the relevant publications up to May 2013 without restriction by language. All clinical controlled trials assessing left ventricular function and cardiovascular outcomes with the GLP-1 agents were selected for eligibility. Fourteen trials (415 patients) were identified as eligible between 1966 and 2013. Twelve of the studies were randomized controlled trials (RCT).. The results showed that GLP-1 agent treatment in patients with T2DM and/or CVD led to significantly improved regional left ventricular contractile parameters (including peak left systolic tissue velocity and strain) and global left ventricular performance (including stroke volume, ejection fraction, and left ventricular chambers) compared with patients receiving placebo.. GLP-1 agent treatment in T2DM and/or CVD patients is associated with a modest but significant increase in the odds of left ventricular contractile parameters and left ventricular performance compared with patients having received placebo, which may be indicative of additional cardiovascular benefits for these patients.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Hemodynamics; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Ventricular Function, Left

In this paper we discuss pathogenetic mechanisms of cardiovascular risk reduction in patients with type 2 diabetes mellitus by glucagon-like peptide 1 (GLP-1) receptor agonists. Results of experimental studies and randomized clinical studies are presented, and perspectives for using GLP-1 agonists in patients with diabetic cardiovascular complications are described.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduces body weight without inducing hyperglycemia. In addition, coagonists have demonstrated lipid lowering property, which was independent of their anorectic effect. Similarly, GLP-1 modulates cardiovascular function which is favorable for treatment of myocardial injury, cardiac dysfunction, cardiac arrhythmias, endothelial dysfunction, and blood pressure, while glucagon has a positive impact on heart rate, cardiac output, ventricular contraction and enhances cardiac performance in animals and humans. Hence, researchers focused on combining these attributes of GLP-1 and glucagon in a single molecule, which was termed as a coagonist. Oxyntomodulin is the naturally occurring coagonist of GLP-1 and glucagon. This review focusses on the coagonists under clinical development discussing activities affecting cardiovascular functions, lipid modulation, direct effect on cardiac functions or other related functions. A comparative analysis of the in vitro and in vivo properties of GLP-1, glucagon and the coagonists is also carried out. This review discusses potential of GLP-1 and glucagon coagonists in treatment of cardiovascular and hemodynamic diseases with attention to GLP-1 or glucagon receptor specific properties as well as the interaction between other therapies.

Topics: Animals; Cardiovascular Diseases; Glucagon; Glucagon-Like Peptide 1; Humans; Oxyntomodulin

Patients with type 2 diabetes have a several-fold increased risk of developing cardiovascular disease when compared with nondiabetic controls. Myocardial infarction and stroke are responsible for 75% of all death in patients with diabetes, who present a 2-4× increased incidence of death from coronary artery disease. Patients with diabetes are considered for cardiovascular disease secondary prevention because their risk level is similar to that reported in patients without diabetes who have already suffered a myocardial infarction. More recently, with a better risk factors control, mainly in intensive LDL cholesterol targets with statins, a significant decrease in acute cardiovascular events was observed in population with diabetes. Together with other major risk factors, type 2 diabetes must be considered as an important cause of cardiovascular disease.Glucagon like peptide-1 receptor agonists represent a novel class of anti-hyperglycemic agents that have a cardiac-friendly profile, preserve neuronal cells and inhibit neuronal degeneration, an anti-inflammatory effect in liver protecting it against steatosis, increase insulin sensitivity, promote weight loss, and increase satiety or anorexia.This review is intended to rationally compile the multifactorial cardiovascular effects of glucagon-like peptide-1 receptor agonists available for the treatment of patients with type 2 diabetes.

Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Receptors, Glucagon

Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes (T2DM) based on randomized controlled trials (RCTs) including data describing complete blood pressure (BP) changes from baseline.. We searched the major databases for published or unpublished RCTs that had been performed in patients with T2DM and compared the effects of exenatide and liraglutide to those of other common drugs used to treat T2DM. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis.. A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of -5.24 and -3.46 mmHg, respectively, and with 95% confidence intervals (CI) of -6.88 to -3.59, p < 0.00001 and -3.63 to -3.29, p < 0.00001, respectively. Meanwhile, in the exenatide-treated group, diastolic blood pressure (DBP) was reduced by -5.91 mmHg, with a 95% CI of -7.53 to -4.28, p < 0.00001 compared with the placebo group, and -0.99 mmHg with a 95% CI of -1.12 to -0.87, p < 0.00001 compared with the sitagliptin group. SBP changes in this meta-analysis were assessed in the groups treated with 1.2 or 1.8 mg liraglutide per day. In the 1.2 mg-treated group, liraglutide treatment reduced SBP compared with placebo and glimepiride treatment, with mean differences of -5.60 and -2.38 mmHg, and 95% CIs of -5.84 to -5.36, p < 0.00001 and -4.75 to -0.01, p = 0.05, respectively. In the 1.8-mg-treated group, liraglutide also reduced SBP compared with placebo and glimepiride treatment with mean differences of -4.49 and -2.62 mmHg, and a 95% CI of -4.73 to -4.26, p < 0.00001, and -2.91 to -2.33, p < 0.00001, respectively.. Treatment with the GLP-1 RAs exenatide and liraglutide reduced SBP and DBP by 1 to 5 mmHg compared with some other anti-diabetic drugs including insulin, glimepiride and placebo for patients with T2DM. GLP-1 RAs may offer an alternative therapy for these patients and will help provide extra cardiovascular benefits.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypertension; Hypoglycemic Agents; Insulin; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Sulfonylurea Compounds; Treatment Outcome; Venoms

Glucagon-like peptide-1 (GLP-1) is a member of the proglucagon incretin family implicated in the control of appetite and satiety. GLP-1 has insulinotropic, insulinomimetic, and glucagonostatic effects, thereby exerting multiple complementary actions to lower blood glucose in subjects with type 2 diabetes mellitus. A major advantage over conventional insulin is the fact that the insulinotropic actions of GLP-1 are dependent upon ambient glucose concentration, mitigating the risks of hypoglycemia. Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested in both preclinical and clinical studies. The experimental data indicate GLP-1 and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. Clinically, beneficial effects of GLP-1 have also been demonstrated in patients with myocardial ischemia and heart failure. GLP-1 has recently been demonstrated to be a more effective alternative in treating myocardial injury. This paper provides a review on the current evidence supporting the use of GLP-1 in experimental animal models and human trials with the ischemic and non-ischemic heart and discusses their molecular mechanisms and potential as a new therapeutic approach.

Topics: Animals; Anti-Obesity Agents; Antihypertensive Agents; Cardiotonic Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart; Humans; Receptors, Glucagon

Cardiovascular diseases are major killers in all developed societies and rapidly becoming the leading cause of morbidity and mortality in the developing world. Patients with diabetes mellitus are at particular risk of developing cardiovascular diseases. The present treatment options for management of diabetes have expanded since the development of glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. There is a growing body of evidence that these agents may have cardioprotective effects even in patients who do not have diabetes. Here, we discuss this evidence as well as pathways that DPP-4 inhibitors target in the cardiovascular system. These agents over time will find an appropriate place in the management of cardiovascular diseases.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Complications; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease-related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide are incretin-based antidiabetes agents. This review examines CV-associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP-1 RAs in reducing hyperglycemia. Further, GLP-1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Receptors, Glucagon; Risk Factors; Treatment Outcome; Venoms

The rising rate of overweight/obesity among the ever-growing ageing population is imposing massive and rapidly changing burdens of ill health. The observation that the BMI value associated with the lowest relative mortality is slightly higher in older than in younger adults, mainly through its reduced impact on coronary heart disease, has often been misinterpreted that obesity is not as harmful in the elderly, who suffer a large range of disabling consequences of obesity. All medical consequences of obesity are multi-factorial and most alleviated by modest, achievable weight loss (5-10 kg) with an evidence-based maintenance strategy. But severe obesity, e.g. BMI >40 may demand greater weight loss e.g. >15 kg to reverse type 2 diabetes. Since relatively reduced physical activity and reduced muscle mass (sarcopenic obesity) are common in the elderly, combining exercise and modest calorie restriction optimally reduces fat mass and preserves muscle mass - age presents no obstacle and reducing polypharmacy is a valuable outcome. The currently licensed drug orlistat has no age-related hazards and is effective in a low fat diet, but the risks from bariatric surgery begin to outweigh benefits above age 60. For the growing numbers of obese elderly with diabetes, the glucagon-like peptide-1 (GLP-1) receptor analogue liraglutide appears a safe way to promote and maintain substantial weight loss. Obesity and sarcopenia should be prevented from younger age and during life-transitions including retiral to improve future health outcomes and quality of life, with a focus on those in "obese families".

Topics: Adult; Aged; Bariatric Surgery; Body Composition; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Europe; Glucagon-Like Peptide 1; Humans; Life Style; Liraglutide; Male; Metabolic Syndrome; Middle Aged; Morbidity; Obesity; Prevalence; Quality of Life; Sarcopenia; Waist Circumference; Weight Loss

Recent suggestions that glucagon-like peptide-1 (GLP-1)-based therapies could cause pancreatitis, and even pancreatic cancer, are based on:. The worrying histological changes are not reproduced in all studies and are unexpectedly variable with different GLP-1-based therapies.. Singh's findings that pancreatitis is doubled with GLP-1-based therapies could relate to their use in obese patients who are prone to pancreatitis risk factors--gallstones and hypertriglyceridaemia. The other observational studies do not find an association between GLP-1-based therapies and pancreatitis.. The increased reports of pancreatitis and pancreatic cancer are likely to be attributable to 'notoriety bias'.. Butler's findings for those on GLP-1-based therapies vs. those not, could have other explanations. Meanwhile: META ANALYSIS: Randomized control trials with GLP-1-based therapies do not find increased pancreatitis risk. Meta-analysis of 53 randomized controlled trials including 20 212 dipeptidyl peptidase-4 inhibitor-treated patients found a significantly reduced risk of major adverse cardiovascular events [odds ratio 0.689 (0.528-0.899), P = 0.006] for dipeptidyl peptidase-4 inhibitors compared with control subjects.. The evidence suggests that there is more than a possibility that some of the GLP-1 receptor agonists, and possibly also some dipeptidyl peptidase-4 inhibitors, may be associated with reduced cardiovascular events. Eight ongoing long-term cardiovascular randomized controlled trials will report from September 2013 onwards. These trials should resolve the issue of pancreatitis risk and substantiate the extent of benefit.. Whilst we should remain vigilant, currently the balance of evidence is strongly in support of GLP-1-based therapy, with benefits far outweighing potential risks.

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Male; Pancreatic Neoplasms; Pancreatitis; Patient Selection; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Assessment; Risk Factors; Venoms

Topics: Allylamine; Animals; Blood Glucose; Bromocriptine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Gastrins; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Islet Amyloid Polypeptide; Leptin; Metformin; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds; Thiazolidinediones; United States

The presence of cardiovascular disease (CVD) in Type 1 diabetes largely impairs life expectancy. Hyperglycemia leading to an increase in oxidative stress is considered to be the key pathophysiological factor of both micro- and macrovascular complications. In Type 1 diabetes, the presence of coronary calcifications is also related to coronary artery disease. Cardiac autonomic neuropathy, which significantly impairs myocardial function and blood flow, also enhances cardiac abnormalities. Also hypoglycemic episodes are considered to adversely influence cardiac performance. Intensive insulin therapy has been demonstrated to reduce the occurrence and progression of both micro- and macrovascular complications. This has been evidenced by the Diabetes Control and Complications Trial (DCCT) / Epidemiology of Diabetes Interventions and Complications (EDIC) study. The concept of a metabolic memory emerged based on the results of the study, which established that intensified insulin therapy is the standard of treatment of Type 1 diabetes. Future therapies may also include glucagon-like peptide (GLP)-based treatment therapies. Pilot studies with GLP-1-analogues have been shown to reduce insulin requirements.

Topics: Antihypertensive Agents; Autonomic Nervous System Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Neuropathies; Drug Therapy, Combination; Exenatide; Exercise Therapy; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Insulin; Oxidative Stress; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

Recent years have seen an enormous increase in the number of therapeutic agents available for lowering blood glucose levels in people with type 2 diabetes. Among these agents, the incretin mimetics glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors have received particular attention for the potential of these interventions to positively impact on cardiovascular outcomes. Although the results of large-scale cardiovascular outcome trials eagerly are anticipated, an increasing body of literature from preclinical and early phase clinical studies has indicated that both GLP-1R agonists and DPP4 inhibitors may exert glucose-independent cardiovascular effects. Despite its role in glucose homeostasis, the GLP-1R is surprisingly widely distributed throughout the body, including in the heart. GLP-1 may exert its effects through both receptor-dependent and receptor-independent mechanisms and through the actions of both the intact peptide and its metabolites. In addition, DPP4 inhibition not only augments the circulating levels of incretin hormones, but it also holds the capacity to augment the activity of other biologically important substrates, most notably the small protein stromal cell-derived factor 1 alpha. Whether these collective functions will act to reduce cardiovascular events in patients remains to be determined.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Male; Myocytes, Cardiac; Peptides; Treatment Outcome; Venoms

Although there have been major advances in the understanding of the molecular mechanisms that contribute to the development of diabetic nephropathy, current best practice still leaves a significant treatment gap. The incidence of diabetes and associated nephropathy is increasing, with the main cause of mortality being related to cardiovascular causes. Novel therapies which are both 'cardio-renal'-protective seem the logical way forward. In the present review, we discuss the GLP-1 (glucagon-like peptide-1) receptor agonists and DPP-4 (dipeptidyl peptidase-4) inhibitors (incretin-based therapies), which are novel antidiabetic agents used in clinical practice and their role in diabetic nephropathy with specific focus on renoprotection and surrogate markers of cardiovascular disease. We discuss the pleiotropic effects of the incretin-based therapies apart from glucose-lowering and highlight the non-GLP-1 effects of DPP (dipeptidyl peptidase) inhibition. Large-scale clinical studies with cardiovascular end points are underway; however, studies with renal end points are lacking but much needed.

Topics: Biomarkers; Cardiovascular Diseases; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Inflammation; Mice

Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon- like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice daily (ExBID) reduced mean HbA1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA1c by -1.3% to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Mice; Mice, Knockout; Models, Animal; Nausea; Peptides; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Loss

To examine whether widespread tissue expression of the glucagon-like peptide (GLP)-1 receptor supports the possibility of differential effects of GLP-1-based therapeutics on cardiac function, blood pressure, food intake, gastric emptying, and other regulatory activities. GLP-1 receptor agonists (RAs) have demonstrated pleiotropic effects on overweight/obesity, hypertension, dyslipidemia, and cardiovascular (CV) disease. Food-regulatory effects have been demonstrated in preclinical and clinical trials, including reduced gastric motility and food intake leading to body weight reductions. Native GLP-1 and GLP-1 RAs have demonstrated cardioprotective effects in preclinical models.. Using PubMed, we performed a search of the recent literature on GLP-1 and GLP-1 RAs.. Preliminary clinical data indicate native GLP-1 has beneficial effects on endothelial cell function and vascular inflammation. Native GLP-1 and GLP-1 RAs have demonstrated renoprotective and antihypertensive effects, and reductions in lipid parameters. The GLP-1 RA liraglutide has also demonstrated positive effects on such markers of endothelial dysfunction as tumor necrosis factor-α and plasminogen activator inhibitor-1.. Preliminary data suggest GLP-1 RAs could benefit type 2 diabetes patients at risk for CV comorbidities. Additional studies are needed to confirm the extraglycemic and extrapancreatic effects and determine whether outcomes will translate into beneficial effects for patient care.

Topics: Anti-Inflammatory Agents; Antihypertensive Agents; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Gastric Emptying; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Receptors, Glucagon; Risk Factors; Treatment Outcome; Weight Loss

Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue.

Topics: Blood Glucose; Brain; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Liraglutide; Liver; Meta-Analysis as Topic; Obesity; Peptides; Risk; Venoms; Weight Loss

Topics: Blood Glucose; Cardiovascular Diseases; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Humans; Peptides; Receptors, Cell Surface; Signal Transduction; Venoms

The incidence of type 2 diabetes (T2DM) is increasing rapidly worldwide and is a strong risk factor for cardiovascular disease (CVD) events. Although hyperglycemia is associated with increased CVD, intensive glycemic control with current diabetes medications has failed in recent large clinical trials to reduce macrovascular disease, demonstrating that intensive glucose control alone is insufficient to reduce major CVD events. A new approach to lowering glucose takes advantage of the incretin system and medications that raise or mimic glucagon-like peptide-1 (GLP-1). These agents not only improve glycemic control by mechanisms that minimize hypoglycemia, but also improve lipoprotein profiles, blood pressure control and weight loss. There is also increasing evidence that at least pharmacologic concentrations of GLP-1 or GLP-1 mimetics may improve endothelial function and have direct vascular-protective effects. Importantly, these benefits transpired even before the improvements in weight and overall glucose control occurred. It remains to be seen whether the chronic effects of GLP-1 activity on glucose, CVD risk factors and vascular function will lead to lasting beneficial effects on CVD risk. If preliminary findings on the vasculoprotective effects of GLP-1 agents are validated and confirmed in longitudinal clinical trials, this class of drugs may represent a paradigm shift in the treatment of vascular disease in both patients with diabetes and in non-diabetic individuals at high risk for CVD. Recent patents regarding GLP-1 agents are discussed in this review article.

Topics: Animals; Biomimetic Materials; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Glucagon-Like Peptide 1; Humans; Longitudinal Studies; Randomized Controlled Trials as Topic

Glucagon-like peptide 1 (GLP-1) is an incretin hormone responsible for amplification of insulin secretion when nutrients are given orally, as opposed to intravenously, and it retains its insulinotropic activity in patients with type 2 diabetes mellitus. GLP-1-based therapies, such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase 4, an enzyme that degrades endogenous GLP-1, have established effectiveness in lowering glucose levels and are routinely used to treat patients with type 2 diabetes. These agents regulate glucose metabolism through multiple mechanisms and have several effects on cardiovascular parameters. These effects, possibly independent of the glucose-lowering activity, include changes in blood pressure, endothelial function, body weight, cardiac metabolism, lipid metabolism, left ventricular function, atherosclerosis, and the response to ischemia-reperfusion injury. Thus, GLP-1-based therapies could potentially target both diabetes and cardiovascular disease. This Review highlights the mechanisms targeted by GLP-1-based therapies, and emphasizes current developments in incretin research that are relevant to cardiovascular risk and disease, as well as treatment with GLP-1 receptor agonists.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Receptors, Glucagon; Risk Assessment; Risk Factors; Treatment Outcome

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that enhances glucose-stimulated insulin secretion and exerts direct and indirect actions on the cardiovascular system. GLP-1 and its related incretin hormone, glucose-dependent insulinotropic polypeptide, are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4), a key determinant of incretin bioactivity. Two classes of medications that enhance incretin action, GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors, are used for the treatment of type 2 diabetes mellitus. We review herein the cardiovascular biology of GLP-1R agonists and DPP-4 inhibitors, including direct and indirect effects on cardiomyocytes, blood vessels, adipocytes, the control of blood pressure, and postprandial lipoprotein secretion. Both GLP-1R activation and DPP-4 inhibition exert multiple cardioprotective actions in preclinical models of cardiovascular dysfunction, and short-term studies in human subjects appear to demonstrate modest yet beneficial actions on cardiac function in subjects with ischemic heart disease. Incretin-based agents control body weight, improve glycemic control with a low risk of hypoglycemia, decrease blood pressure, inhibit the secretion of intestinal chylomicrons, and reduce inflammation in preclinical studies. Nevertheless, there is limited information on the cardiovascular actions of these agents in patients with diabetes and established cardiovascular disease. Hence, a more complete understanding of the cardiovascular risk to benefit ratio of incretin-based therapies will require completion of long-term cardiovascular outcome studies currently underway in patients with type 2 diabetes mellitus.

Topics: Animals; Cardiovascular Diseases; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Randomized Controlled Trials as Topic; Receptors, Glucagon

Glucagon-like peptide (GLP)-1 agonists and dipeptidyl peptidase-4 inhibitors are two classes of drugs that have been approved for treatment of Type 2 diabetes mellitus, based upon the glucose-lowering actions of the gastrointestinal hormone GLP-1. However, GLP-1 receptors are also present in cardiovascular tissues. Data from animal and in vitro studies suggest that GLP-1 may have cardioprotective effects and improve myocardial and endothelial dysfunction. Clinical data demonstrating cardiovascular effects are more limited, and there is some evidence that incretin-based therapies may be associated with improvements in cardiovascular risk factors. Large prospective cardiovascular outcome trials are underway to examine the cardiovascular safety of incretin-based therapies, and may reveal whether these agents are associated with any reduction in cardiovascular adverse events in patients with Type 2 diabetes mellitus.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Risk Factors

The two classes of incretin-related therapies, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have become important treatment options for patients with type 2 diabetes. Sitagliptin, saxagliptin, vildagliptin and linagliptin, the available DPP-4 inhibitors, are oral medications, whereas the GLP-1 RAs-twice-daily exenatide, once-weekly exenatide and once-daily liraglutide-are administered subcutaneously. By influencing levels of GLP-1 receptor stimulation, these medications lower plasma glucose levels in a glucose-dependent manner with low risk of hypoglycaemia, affecting postprandial plasma glucose more than most other anti-hyperglycaemic medications. Use of GLP-1 RAs has been shown to result in greater glycaemic improvements than DPP-4 inhibitors, probably because of higher levels of GLP-1 receptor activation. GLP-1 RAs can also produce significant weight loss and may reduce blood pressure and have beneficial effects on other cardiovascular risk factors. Although both classes are well tolerated, DPP-4 inhibitors may be associated with infections and headaches, whereas GLP-1 RAs are often associated with gastrointestinal disorders, primarily nausea. Pancreatitis has been reported with both DPP-4 inhibitors and GLP-1 RAs, but a causal relationship between use of incretin-based therapies and pancreatitis has not been established. In clinical trials, liraglutide has shown efficacy and tolerability and resulted in certain significant benefits when compared with exenatide and sitagliptin.

Topics: Administration, Oral; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Venoms; Weight Loss

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel drugs for the treatment of type 2 diabetes mellitus. They exert their action through inhibition of the catabolism of locally secreted incretins such as glucagon-like peptide-4 (GLP-4) and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting enzyme DPP-4. GLP-1 and GIP are secreted from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the small intestine and colon, whereas GIP is secreted from K cells of the jejunum. These 2 incretins lower blood glucose levels and postprandial hyperglycemia by stimulating insulin release from b cells of the pancreas, thus increasing insulin sensitivity, delaying gastrointestinal emptying, decreasing food intake through early satiety, and causing weight loss in the long term. However, their action is short-lived (2 to 3 minutes) because of catabolism by the DPP-4 enzyme. The importance of DPP-4 inhibitors lies in their blockade of the DPP-4 enzyme leading to the prevention of their catabolism and thus increasing their blood levels, extending the duration of their action, and improving their blood glucose-lowering effect. In addition to their antidiabetic action, recent experimental and clinical studies have demonstrated a pleiotropic cardiovascular protective effect of these agents independent of their antidiabetic action. They prevent atherosclerosis, improve endothelial dysfunction, lower blood pressure, and prevent myocardial injury. All these actions are discussed in this concise review. In conclusion, DPP-4 inhibitors are novel antidiabetic agents with pleiotropic cardiovascular protective effects in addition to their antidiabetic action.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelium, Vascular; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Incretins; Receptors, Glucagon

Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP4) inhibitors are currently used as glucose-lowering agents in type 2 diabetes, due to their effects on insulin and glucagon secretion. These agents, which are effective in improving glucose control, could also have a beneficial effect on the incidence of cardiovascular events. The analysis of major cardiovascular events reported during trials with metabolic endpoints shows a significant reduction of risk with both classes of drugs. Longer-term trials specifically designed to assess the effects of GLP-1 receptor agonists and DPP4 inhibitors on major cardiovascular events are currently ongoing.. In order to elucidate potential mechanisms of cardiovascular protection with incretin-based therapies, a Medline search (any date up to December 15th, 2011) was performed using the terms 'cardiovascular' and ('DPP-4' or 'GLP-1' or any single name of incretin-based drugs); papers which were considered relevant for the aim of this review were selected by the authors, on the basis of their judgment.. Incretin-based drugs have beneficial effects on cardiovascular risk factors, such as blood pressure and, to a lesser extent, cholesterol and triglyceride. GLP-1 receptor agonists also reduce body weight. A number of experimental studies has suggested that GLP-1 has direct, beneficial effects on myocardial and endothelial cells, but some of these actions could be mediated via GLP-1 receptor-independent pathways. Available experimental evidence, together with a few pilot studies in humans, shows that GLP-1 receptor agonists and DPP4 inhibitors are capable of ameliorating myocardial function and protect myocardiocytes from ischemic damage, independent of their glucose-lowering effects. Furthermore, both classes of drugs enhance endothelial function. In addition, DPP4 inhibitors increase the availability of endothelial progenitor cells, via a GLP-1 receptor-independent pathway.. Taken together, available data suggest that incretin-based therapies could prevent cardiovascular disease via multiple mechanisms.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Myocytes, Cardiac; Pilot Projects; Receptors, Glucagon

The active incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) is a 30-amino acid peptide that exerts glucoregulatory and insulinotropic actions by functioning as an agonist for the GLP-1 receptor (GLP-1R). In addition to its anti-diabetic effects, GLP-1 has demonstrated cardioprotective actions. Here we review the cardiovascular effects of the GLP-1 analogues currently approved for the treatment of type 2 diabetes, namely exenatide and liraglutide. We discuss their anti-hyperglycaemic efficacy, and offer a clinical perspective of their effects on cardiovascular risk factors such as body weight, blood pressure, heart rate and lipid profiles, as well as their potential consequences on cardiovascular events, such as arrhythmias, heart failure, myocardial infarction and death. Lastly, we briefly review additional GLP-1R agonists in clinical development.

Topics: Animals; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Design; Evidence-Based Medicine; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Receptors, Glucagon; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venoms

The management of type 2 diabetes continues to evolve as new data emerge. Although glycaemic control is still important, other risk factors--such as hypertension, dyslipidaemia and obesity--must also be addressed in order to reduce the long-term risks of cardiovascular complications and mortality. In this context, targeting the incretin system, and glucagon-like peptide-1 (GLP-1) in particular, has generated much interest. GLP-1 is released from the gut in response to food ingestion and plays a crucial role in glucose homeostasis. GLP-1 receptors are expressed in the heart and vasculature, prompting evaluation of their physiological role and pharmacological stimulation, both in healthy and disease states. These studies indicate that GLP-1 and GLP-1-based therapies appear to have direct, beneficial effects on the cardiovascular system, in addition to their glucose-lowering properties, such as modulation of blood pressure, endothelial function, and myocardial contractility. Intriguingly, some of these effects appear to be independent of GLP-1 receptor signalling. Data from clinical studies of the GLP-1 receptor agonists, exenatide and liraglutide on cardiovascular risk factors, in patients with type 2 diabetes are also promising and the results from prospective studies to assess cardiovascular outcomes are eagerly awaited.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Endothelium, Vascular; Exenatide; Glucagon-Like Peptide 1; Humans; Incretins; Liraglutide; Mice; Peptides; Prospective Studies; Risk Factors; Treatment Outcome; Venoms

Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre-clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease.

Topics: Animals; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Glucagon-Like Peptide 1; Humans; Incretins; Myocardium

Recently, the crucial role of GLP-1 in cardiovascular disease has been suggested by both preclinical and clinical studies. In vivo and in vitro studies have demonstrated cardio-protective effects of GLP-1 by activating cell survival signal pathways, which have greatly reduced ischemia/reperfusion injury and also cardiac dysfunction in various congestive heart failure animal models. Clinically, beneficial effects of GLP-1 have been shown in patients with myocardial infarction, hypertension, and heart failure, and 2 classes of incretin enhancers, GLP-1 receptor agonists and DPP-4 inhibitors, are currently available for the treatment of type 2 diabetes mellitus. In this review, we will summarize the role of incretins in various cardiovascular events such as hypertension and heart failure and postprandial lipoprotein secretion, and discuss their molecular mechanisms and potentials as a new therapeutic as well as preventive drug type for reducing cardiovascular events in both diabetic and nondiabetic patients.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon

The mechanisms for hyperglycemia-mediated harm in the hospitalized cardiac patient are poorly understood. Potential obstacles in the inpatient management of hyperglycemia in cardiac patients include rapidly changing clinical status, frequent procedures and interruptions in carbohydrate exposure, and short hospital length of stay. A patient's preadmission regimen is rarely suitable for inpatient glycemic control. Instead, an approach to a flexible, physiologic insulin regimen is described, which is intended to minimize glycemic excursions. When diabetes or hyperglycemia is addressed early and consistently, the hospital stay can serve as a potential window of opportunity for reinforcing self-care behaviors that reduce long-term complications.

Topics: Acute Disease; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Insulin; Risk

The global epidemic of diabetes mellitus (~95% type 2 diabetes) has been fueled by a parallel increase in obesity and overweight. Together, these metabolic disease epidemics have contributed to the increasing incidence and prevalence of cardiovascular disease. The accumulation of metabolic and cardiovascular risk factors in patients with type 2 diabetes--risk factors that may exacerbate one another--complicates treatment. Inadequate treatment, treatment that fails to achieve goals, increases the risk for cardiovascular morbidity and mortality. From a clinical perspective, type 2 diabetes is a cardiovascular disease, an observation that is supported by a range of epidemiologic, postmortem, and cardiovascular imaging studies. Vascular wall dysfunction, and particularly endothelial dysfunction, has been posited as a "common soil" linking dysglycemic and cardiovascular diseases. Vascular wall dysfunction promoted by environmental triggers (e.g., sedentary lifestyle) and metabolic triggers (chronic hyperglycemia, obesity) has been associated with the upregulation of reactive oxygen species and chronic inflammatory and hypercoagulable states, and as such with the pathogenesis of type 2 diabetes, atherosclerosis, and cardiovascular disease. Glucagon-like peptide-1 (GLP)-1, an incretin hormone, and synthetic GLP-1 receptor agonists represent promising new areas of research and therapeutics in the struggle not only against type 2 diabetes but also against the cardiovascular morbidity and mortality associated with type 2 diabetes. In a number of small trials in humans, as well as in preclinical and in vitro studies, both native GLP-1 and GLP-1 receptor agonists have demonstrated positive effects on a range of cardiovascular disease pathologies and clinical targets, including such markers of vascular inflammation as high-sensitivity C-reactive protein, plasminogen activator inhibitor-1, and brain natriuretic peptide. Reductions in markers of dyslipidemia such as elevated levels of triglycerides and free fatty acids have also been observed, as have cardioprotective functions. Larger trials of longer duration will be required to confirm preliminary findings. In large human trials, GLP-1 receptor agonists have been associated with significant reductions in both blood pressure and weight.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Incretins; Treatment Outcome

Type 2 diabetes mellitus is a well-established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developed recently based on the incretin phenomenon, such as the degradation-resistant incretin mimetic exenatide and the glucagon-like peptide-1 (GLP-1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)-4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increase the circulating bioactive GLP-1. GLP-1 exerts its glucose-regulatory action via stimulation of insulin secretion and glucagon suppression by a glucose-dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions are mediated through GLP-1 receptors (GLP-1Rs), although GLP-1R-independent pathways have been reported. Except for the pancreatic islets, GLP-1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature, suggesting a pleiotropic activity of GLP-1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP-1 and its metabolites on myocardium, endothelium and vasculature, as well as potential anti-inflammatory and antiatherogenic actions. Growing lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP-4 inhibitors compared with placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo-controlled trials. This review discusses the role of GLP-1 on the cardiovascular system and addresses the impact of GLP-1-based therapies on CVD outcomes.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Receptors, Glucagon

Glucose homeostasis is regulated by a complex interaction of hormones, principally including insulin, glucagon, amylin, and the incretins. Glucagon, cortisol, catecholamines, and growth hormone serve as the classic glucose counterregulatory hormones. The incretins are hormones released by enteroendocrine cells in the intestine in response to a meal. Classically, type 2 diabetes mellitus (T2DM) has been considered to be a triad of insulin resistance, increased hepatic gluconeogenesis, and progressive β-cell exhaustion/failure. However, disordered enteroendocrine physiology, specifically the reduced activity of glucagon-like peptide-1 (GLP-1), is also a principal pathophysiologic abnormality of the disease. Glucagon-like peptide-1 receptor agonists that have been studied include exenatide and liraglutide, which have been approved by the US Food and Drug Administration for use in patients with T2DM. Sitagliptin and saxagliptin, both approved for use in the United States, modulate incretin physiology by inhibiting degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4). Modulators of incretin physiology have been shown to improve glycemic control with a low risk for hypoglycemia and beneficially affect β-cell function. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produces weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The GLP-1 receptor agonists have also demonstrated beneficial effects on cardiovascular risk factors other than hyperglycemia and excess body weight, such as lipid concentrations and blood pressure. This article describes incretin physiology and studies of pharmacologic therapy designed to address the blunted incretin response in patients with T2DM. Information was obtained by a search of the PubMed and MEDLINE databases for articles published from January 1, 1995 to June 1, 2009.

Topics: Adamantane; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Obesity is common and associated with a high rate of morbidity and mortality; therefore, treatment is of great interest. At present, bariatric surgery is the only truly successful treatment of severe obesity. Mimicking one of the effects of bariatric surgery, namely the increased secretion of glucagon-like peptide (GLP)-1, by artificially increasing the levels of GLP-1 might prove successful as obesity treatment. Recent studies have shown that GLP-1 is a physiological regulator of appetite and food intake. The effect on food intake and satiety is preserved in obese subjects and GLP-1 may therefore have a therapeutic potential. The GLP-1 analogues result in a moderate average weight loss, which is clinically relevant in relation to reducing the risk of type 2 diabetes and cardiovascular disease. Inspired by the hormone profile after gastric bypass, a future strategy in obesity drug development could be to combine several hormones, and thereby produce a superior appetite suppressing hormone profile that may result in a weight loss exceeding that seen in single-agent trials. In conclusion, with the GLP-1 analogues combining a moderate weight loss with beneficial effects on metabolic and cardiovascular risk factors, it seems that we are on the right track for future treatment of obesity.

Topics: Animals; Appetite; Bariatric Surgery; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Eating; Glucagon-Like Peptide 1; Humans; Obesity; Risk Factors; Satiation; Weight Loss

Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases is partly associated with hyperglycaemia as well as dyslipidaemia. Pharmacological treatment of diabetic hyperglycaemia involves the use of the older oral antidiabetic drugs [OADs: biguanides, sulphonylureas (SUs), α-glucosidase inhibitors and thiazolidinediones], insulin (human and analogues) and/or incretin-based therapies (glucagon-like peptide-1 analogues and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to improve lipid profiles in patients with diabetes. These effects may have benefits on cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of OADs, insulins and incretin-based therapies on lipid variables along with the possible mechanisms and clinical implications of these findings. The effects of intensive versus conventional antihyperglycaemic therapy on cardiovascular outcomes and lipid profiles are also discussed. A major conclusion of this review is that agents within the same class of OADs can have different effects on lipid variables and that contrary to the findings in experimental models, insulin has been shown to have beneficial effects on lipid variables in clinical trials. Further studies are needed to understand the precise effect and the mechanisms of these effects of insulin on lipids.

Topics: Biguanides; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Insulin; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones

Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists.. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events.. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50-1.08), P = .12 (0.85 (0.50-1.45), P = .55, and 0.69 (0.40-1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25-0.83), P = .009, and 1.05 (0.63-1.76), P = .84, respectively.. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.

Topics: Algorithms; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Venoms

Diabetes accounts for millions of office visits each year to primary care offices in the United States. Successful care of the patient with type 2 diabetes requires not only focus on glucose management but also on comorbidities such as hypertension, dyslipidemia and obesity which are closely linked to microvascular and macrovascular complications. Primary care clinicians must stay abreast of frequently published diabetes literature and new treatments to care for these increasingly complex patients. Metformin and its effect on B12 absorption continues to be an issue encountered by clinicians in daily clinical practice. There has also been recent discussion regarding the increased risk of diabetes with statins; data to date on this issue have been conflicting. Rosiglitazone continues to face public scrutiny and there are now Food and Drug Administration regulations regarding its increased risk of cardiovascular disease. Liraglutide and saxagliptin represent new treatment options for type 2 diabetes, increasing the available options for treating this complex disease. A review of the primary literature involving these topics is provided.

Topics: Adamantane; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Incretins; Liraglutide; Metformin; Primary Health Care; Rosiglitazone; Thiazolidinediones; Vitamin B 12 Deficiency

Incretins, which are insulinotropic gastrointestinal hormones, are produced mainly in K and L cells of the small intestine under the influence of nutritional stimuli. The best known incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones perform several functions: they stimulate insulin secretion in the pancreatic beta cells; they inhibit glucagon release from the alpha cells of the pancreas (GIP not in humans); they slow down gastric emptying and may directly suppress appetite; and, moreover, they indirectly increase peripheral glucose tolerance/insulin sensitivity. The insulinotropic and glucagonostatic effects of GLP-1 are glucose dependent. The incretins also have numerous other properties which are still being discovered and introduced in different branches of medicine. The patents mentioned in this work concern the use of incretins in diabetology, cardiology, gastroenterology and nuclear medicine. The pleiotropic effects of incretins offer therapeutic possibilities in numerous fields of medicine.

Topics: Animals; Carbohydrate Metabolism; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Humans; Incretins; Patents as Topic; Radionuclide Imaging

The glucagon-like peptide-1 (GLP-1) is a 30 amino acid incretin hormone synthesized by L cells of ileum and colon in response to a meal. Once secreted, it is rapidly inactivated by specific enzymes called dipeptidyl dipeptidase 4. The main actions of GLP-1 are (i) to stimulate insulin secretion; (ii) to inhibit glucagon secretion; (iii) to elicit a delay of gastric emptying time; and (iv) to stimulate neogenesis of insulin-secreting cells. Patients with type 2 diabetes show low GLP-1 concentrations in response to a meal, making treatment with incretin mimetics specifically indicated in this patient subset. Besides these effects on intermediary metabolism, GLP-1 also plays an important role in the cardiovascular system by reducing blood pressure, improving endothelial function, and increasing myocardial contractility. These mechanisms of action will be discussed in detail in this article.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Clinical Trials as Topic; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Endothelium, Vascular; Evidence-Based Medicine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Myocardial Contraction; Randomized Controlled Trials as Topic; Receptors, Glucagon; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is a worldwide public health challenge. Despite the availability of many antidiabetes agents and pharmacotherapies targeting cardiovascular risk factors, the morbidity, mortality and economic consequences of T2DM are still a great burden to patients, society, health care systems and the economy. The need for new therapies for glycaemic control is compounded by the fact that existing treatments have limitations either because of their side effects (particularly weight gain and hypoglycaemia) or contraindications that limit their use. Furthermore, none of the current therapies have a significant impact on disease progression. Incretin-based therapies offer a new therapeutic approach to the management of T2DM, and there are also several even newer therapies in development. There are two groups of incretin-based therapies currently available; dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 analogues/mimetics. The former are given orally while the latter subcutaneously. These drugs result in glucose-dependent insulin secretion and glucose-dependent glucagon suppression, with consequent low risk of hypoglycaemia when used as mono- or combination therapy (except when used with sulphonylureas). In addition, they are either weight neutral in the case of DPP-4 inhibitors or cause weight loss in the case of incretin mimetics/analogues. Furthermore, animal studies have shown that these agents prolong beta cell survival which offers the theoretical possibility of slowing the progression to T2DM. In this article we will review the currently available antidiabetes agents with particular emphasis on incretin-based and future therapies. In addition, we will review and discuss the evidence relating to glycaemic control and cardiovascular disease.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Routes; Drug Interactions; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Type 2 diabetes (T2D) is associated with increased cardiovascular disease and mortality. Most diabetes treatments have not proven to reduce this risk and may be associated with worsening of specific cardiovascular risk factors. GLP-1 receptor agonists (GLP-1R agonists) are new incretin-based therapies for the treatment of T2D. They improve glucose control by stimulating insulin secretion and suppressing glucagon release, both in a glucose-dependent manner. There are two GLP-1R agonists approved for the treatment of T2D: once daily liraglutide and twice daily exenatide, both administered by sc injection. Based on recent clinical trials, GLP-1R agonists suggest having a protective role in cardiovascular risk factors besides improving glycemic control, compared to placebo and to standard diabetes therapies. Both liraglutide and exenatide have demonstrated to induce clinically significant weight loss and to reduce systolic blood pressure. Liraglutide also has a positive effect on the lipid profile and cardiovascular risk biomakers. Furthermore, recent data shows a direct effect of GLP-1 and its metabolites in the vascular endothelium and the myocardium, leading to vasodilator effects and improved cardiac function in humans with acute myocardial infarction or congestive heart failure. GLP-1R agonists have a positive impact on cardiovascular risk factors otherwise not addressed by most standard diabetes therapies. Whether these new compounds actually decrease cardiovascular disease and mortality remains to be demonstrated in outcome studies.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Models, Biological; Molecular Sequence Data; Receptors, Glucagon; Risk Factors

To describe Phase 1 and 2 clinical trials of liraglutide with a focus on clinical pharmacology.. In early clinical trials of liraglutide, 0.05-1.9 mg daily improved multiple aspects of glycaemic control and beta-cell function. Early trials demonstrated typical reductions in glycated haemoglobin (HbA(1c) ) and fasting plasma glucose (FPG) of up to 1.5% and 3.3-3.9 mmol/l, respectively, at daily doses of 1.25-1.9 mg, with 45-50% of patients reaching HbA(1c) < 7%. The effects of liraglutide in restoring beta-cell response to fasting and postprandial hyperglycaemia and in reinstating near-normal insulin secretion under hyperglycaemic conditions suggest a beta-cell-protective effect. By delaying gastric emptying and promoting satiety, liraglutide is weight sparing at low doses and causes clinically meaningful weight loss at higher doses and in combination with other anti-diabetes therapies with weight-modifying benefits, such as metformin. Significant improvements in other cardiovascular risk factors, including blood pressure, lipids and cardiovascular risk biomarkers, were also evident. Adverse effects of liraglutide were primarily gastrointestinal; dose-dependent nausea was the most commonly reported effect, but was typically mild-to-moderate in severity and transient in nature.. Early clinical trials of liraglutide indicate the ability to improve glycaemic control in a glucose-dependent manner, with low risk of hypoglycaemia. Promotion of weight loss, along with improvements in multiple cardiovascular risk factors, suggests that liraglutide may offer a novel and clinically valuable approach to disease management for patients with type 2 diabetes.

Topics: Blood Glucose; Body Weight; Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Disease Management; Drug Therapy, Combination; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Metformin

Cardiovascular disease is a leading cause of death in the United States and across the world, and better therapies are constantly being sought to improve patient outcomes. Recent studies have brought our attention to the mechanisms of glucagon-like peptide 1 (GLP-1). Not only does it demonstrate beneficial effects in regard to cardiovascular risk factors (i.e., diabetes, lipid management, and weight control), but it also has been shown in animal studies to have positive cardiac effects irrespective of its effects on glucose control and weight loss. This review discusses the biology of GLP-1 and its effects on cardiovascular risk factors, and it also elaborates on the positive direct cardiovascular outcomes of GLP-1 in animal studies.

Topics: Animals; Cardiovascular Diseases; Glucagon-Like Peptide 1; Hypoglycemic Agents

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.

Topics: Animals; Blood Glucose; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Receptors, Glucagon

Recently, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorization for liraglutide for the treatment of type 2 diabetes mellitus. Liraglutide is the first human glucagon-like peptide-1 (GLP-1) analog, based on the structure of native GLP-1, with pharmacokinetic properties suitable for once-daily dosing. In the phase III Liraglutide Effect and Action in Diabetes (LEAD) program, liraglutide has been shown to lower glycated hemoglobin to the same extent or more than other antidiabetic drugs including insulin. Liraglutide determines favorable changes in the global cardiovascular risk profile because its use is associated with weight loss, blood pressure reduction, as well as improvements of several cardiovascular risk biomarkers. Liraglutide is generally well tolerated, the most frequently reported adverse effect is transient nausea, and it does not seems to have significant interactions with medications commonly used for cardiovascular prevention. This article reviews, for the practicing cardiologist, the results of the LEAD program and explores liraglutide potentials for cardiovascular prevention in type 2 diabetes mellitus.

Topics: Algorithms; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Glucagon-Like Peptide 1; Humans; Hypertension; Hypoglycemic Agents; Liraglutide; Obesity; Practice Guidelines as Topic; Risk Factors; Treatment Outcome

The prevalence of type 2 diabetes mellitus, which is directly associated with overweight/obesity and increased cardiovascular disease risk, is projected to continue to increase during the next few decades. Traditionally, treatment has focused primarily on glycemic control, but accumulating evidence suggests that the clinical management of patients with type 2 diabetes requires a more comprehensive approach to minimize associated morbidity and mortality. Because the majority (80%-90%) of patients with type 2 diabetes are overweight or obese, effective glucose control and weight loss are the cornerstones of initial management. Both effective glucose control and therapy to reduce cardiovascular risk factors, including overweight/obesity, are needed to prevent the complications of type 2 diabetes. Most conventional antidiabetes agents, including sulfonylureas, thiazolidinediones, and insulin, improve glycemic control but are associated with weight gain or, as with metformin, are weight-neutral or weight-sparing. The incretin-based therapies, such as the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 inhibitors, have been shown to be safe and effective in lowering glucose while eliciting favorable effects on weight (ie, weight-reducing and weight-neutral, respectively). The effects of these agents on other parameters of cardiovascular risk are also being studied. Advances in GLP-1 receptor agonist therapy include development of agents with longer durations of activity allowing for more convenient dosing of therapies for patients with type 2 diabetes, which should lead to better patient compliance, adherence, and overall clinical outcomes.

Topics: Algorithms; Caloric Restriction; Cardiovascular Diseases; Comorbidity; Delayed-Action Preparations; Diabetes Complications; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Metabolic Syndrome; Obesity; Peptides; Prevalence; Receptors, Glucagon; Risk Factors; Risk Reduction Behavior; Venoms

Patients with type 2 diabetes, approximately 85% of whom are overweight or obese, often have an increased incidence of cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia. Both type 2 diabetes and obesity are independent risk factors for CVD. Unfortunately, many therapies aimed at maintaining and improving glucose control are associated with weight gain. Among the older antidiabetes agents, most, including the insulin secretagogues and sensitizers, can lead to weight gain, except for metformin, which is weight-neutral. Among the newer agents, the dipeptidyl peptidase-4 inhibitors generally are weight-neutral in addition to lowering glucose, while the glucagon-like peptide-1 receptor agonists lead to weight reduction. Patients with type 2 diabetes are at an increased risk for both diabetes- and CV-related outcomes, and weight reduction is an important component of diabetes management. Weight gain in patients with type 2 diabetes can contribute to patient frustration and may negatively impact their compliance to therapeutic regimens. The selection of antidiabetes agents that not only improve glucose control but reduce or have a neutral effect on weight with beneficial effects on lipids are ideal options for managing patients with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Carbohydrate-Restricted; Exenatide; Glucagon-Like Peptide 1; Health Knowledge, Attitudes, Practice; Humans; Hypoglycemic Agents; Incretins; Motivation; Obesity; Patient Compliance; Peptides; Risk Management; Self Care; Venoms; Weight Gain

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety - which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor-dependent and -independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Weight Loss

The management of type 2 diabetes mellitus (T2DM) typically focuses on correcting dysglycaemia to reduce risk for microvascular and macrovascular complications, possibly by reducing glucose-mediated oxidative stress. However, other cardiometabolic risk factors, including abdominal obesity and dyslipidaemia are often overlooked in the quest for perfect glucose control. The currently used antidiabetic agents, including insulin, metformin, sulphonylureas and thiazolidinediones, have limited efficacy on these risk factors. A number of new therapeutic agents are undergoing clinical development, including glucagon-like peptide 1 mimetics (exenatide and liraglutide) and dipeptidyl peptidase 4 inhibitors (sitagliptin and vildagliptin), which target the incretin system, and the cannabinoid-1 receptor antagonists (rimonabant), which target the endocannabinoid system, may hold some promise for meeting these unmet needs. In this review, the clinical properties of these agents and potential treatment pathways to best use these agents are discussed for improving the management of T2DM and cardiovascular risk.

Topics: Cannabinoid Receptor Antagonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Obesity; Weight Gain

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Postprandial Period

Glucagon-like peptide-1 (GLP-1), a gastrointestinal hormone mainly produced in the post-prandial state, reduces blood glucose through the stimulation of insulin secretion and the inhibition of glucagon release. Long-acting GLP-1 receptor agonists, and dipeptidyl-peptidase-4 (DPP-4) inhibitors which increase GLP-1 levels, are used as hypoglycemic treatments in type 2 diabetes. This paper aims at reviewing the potential benefit of those treatments in the prevention of cardiovascular risk in type 2 diabetic patients.. Experimental studies have shown that GLP-1 has several potentially beneficial actions on cardiovascular risk. Some of those, such as protection from myocardial ischemic damage and improvement of cardiac function, have also been demonstrated in humans. However, the equivalence of GLP-1 agonists and DPP-4 inhibitors with GLP-1, with respect to cardiovascular risk profile, cannot be assumed or taken for granted. Drugs of those two classes have been shown to effectively reduce glycated hemoglobin and to have a specific effect on post-prandial glucose; furthermore, they seem to reduce blood pressure and to have some favorable effects on lipid profiles. Additionally, GLP-1 agonists induce weight loss in diabetic patients.. The profile of action of GLP-1 receptor agonists and DPP-4 inhibitors suggests the possibility of an actual reduction in cardiovascular risk, which needs to be confirmed by large long-term clinical trials.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart Rate; Humans; Incretins; Insulin Resistance; Myocardial Contraction; Myocardial Ischemia; Risk Factors

Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. Exenatide is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1). Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA(1c)) levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions in body weight in patients with type 2 diabetes may have a positive impact on disease progression and potentially decrease the risk of associated long-term complications.

Topics: Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Molecular Mimicry; Obesity; Peptides; Treatment Outcome; Venoms

Type 2 diabetes is reaching epidemic proportions worldwide, fueled by the increasing prevalence of obesity as many populations adopt a western lifestyle. Secondary complications affecting both the microvascular and macrovascular systems are responsible for premature mortality in Type 2 diabetes, with two thirds or more dying of cardiovascular disease. Two interacting metabolic defects, insulin resistance and beta-cell dysfunction are present in Type 2 diabetes. It is now recognised that insulin resistance is central to a cluster of metabolic abnormalities--called the insulin resistance syndrome--that are responsible for the excess of cardiovascular disease. Older antidiabetic agents such as the sulfonylureas, metformin and insulin are more effective than lifestyle modification in reducing microvascular complications of Type 2 diabetes, but overall do not reduce cardiovascular risk. Metformin, although no more effective as a glucose-lowering agent than sulfonylureas or insulin, does significantly reduce cardiovascular disease, probably as a result of its weak insulin-sensitising action. The newly-marketed thiazolidinedione insulin-sensitising antidiabetic agents also improve multiple biomarkers of cardiovascular risk, suggesting that novel approaches to insulin sensitisation will not only provide effective long-term glycaemic control but improve cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within the insulin signalling cascade are being explored, together with follow-up compounds to the first generation thiazolidinediones. These initiatives, together with developments in beta(3)-adrenoceptor agonists, 11 beta-hydroxysteroid dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1 axis, all of which also potentially enhance insulin sensitivity, are critically evaluated.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adrenergic beta-3 Receptor Agonists; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Like Peptide 1; Humans; Hydroxysteroid Dehydrogenases; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Metformin; Peptide Fragments; Protein Precursors; Randomized Controlled Trials as Topic; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thiazoles; Transcription Factors

Dietary intake of pulses is associated with beneficial effects on body weight management and cardiometabolic health, but some of these effects are now known to depend on integrity of plant cells, which are usually disrupted by flour milling. Novel cellular flours preserve the intrinsic dietary fiber structure of whole pulses and provide a way to enrich preprocessed foods with encapsulated macronutrients.. This study aimed to determine the effects of replacing wheat flour with cellular chickpea flour on postprandial gut hormones, glucose, insulin, and satiety responses to white bread.. We conducted a double-blind randomized crossover study in which postprandial blood samples and scores were collected from healthy human participants (n = 20) after they consumed bread enriched with 0%, 30%, or 60% (wt/wt) cellular chickpea powder (CCP, 50 g total starch per serving).. Bread type significantly affected postprandial glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) responses (time × treatment, P = 0.001 for both). The 60% CCP breads elicited significantly elevated and sustained release of these anorexigenic hormones [between 0% and 60% CPP-GLP-1: mean difference incremental area under the curve (iAUC), 3101 pM/min; 95% CI: 1891, 4310; P-adjusted < 0.001; PYY: mean difference iAUC, 3576 pM/min; 95% CI: 1024, 6128; P-adjusted = 0.006] and tended to increase fullness (time × treatment, P = 0.053). Moreover, bread type significantly influenced glycemia and insulinemia (time × treatment, P < 0.001, P = 0.006, and P = 0.001 for glucose, insulin, and C-peptide, respectively), with 30% CCP breads eliciting a >40% lower glucose iAUC (P-adjusted < 0.001) than the 0% CCP bread. Our in vitro studies revealed slow digestion of intact chickpea cells and provide a mechanistic explanation for the physiologic effects.. The novel use of intact chickpea cells to replace refined flours in a white bread stimulates an anorexigenic gut hormone response and has potential to improve dietary strategies for prevention and treatment of cardiometabolic diseases. This study was registered at clinicaltrials.gov as NCT03994276.

Topics: Blood Glucose; Bread; Cardiovascular Diseases; Cicer; Cross-Over Studies; Flour; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Glucose; Humans; Insulin; Peptide YY; Postprandial Period; Triticum

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Outcome Assessment, Health Care; Overweight; Randomized Controlled Trials as Topic; Weight Loss

Albiglutide is a long-acting glucagon-like peptide-1 receptor agonist that improves glycemic control in patients with type 2 diabetes mellitus (T2DM). Harmony Outcomes is a randomized, double-blind, placebo-controlled trial of the effect of albiglutide on major adverse cardiovascular (CV) events in patients with T2DM and established CV disease.. The trial was designed to recruit 9,400 patients aged ≥40 years with T2DM, prior atherosclerotic CV disease, and suboptimal glycemic control. Participants were assigned in a 1:1 ratio to albiglutide 30 mg (potentially increasing to 50 mg) or matching placebo administered once weekly by subcutaneous injection. The trial will continue until ≥611 confirmed primary outcome events (CV death, myocardial infarction, or stroke) occur over a median follow-up of at least 1.5 years.. A total of 9,463 patients were enrolled at 611 sites in 28 countries between July 2015 and December 2016. The mean age was 64.1 years; duration of T2DM, 13.8 years; and glycated hemoglobin, 8.7%. The percentage of patients with prior coronary artery disease was 70.5%; peripheral arterial disease, 25.0%; stroke, 17.7%; heart failure, 20.2%; and chronic kidney disease, 22.6%.. Harmony Outcomes will assess the CV safety of albiglutide in patients with T2DM and CV disease. Trials of other agents in the glucagon-like peptide-1 receptor agonist class have shown CV benefit for only some of these medications, possibly due to differences in trial design or instead due to differences in drug structure or metabolism. Harmony Outcomes will provide information critical to our understanding of this heterogenous class of glucose-lowering agents.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Incretins; Italy; Male; Middle Aged; Ontario; Survival Rate; Treatment Outcome; United Kingdom; United States

Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.. We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30-50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.. Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68-0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.. In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.. GlaxoSmithKline.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Stroke; Treatment Outcome

Epicardial adipose tissue (EAT), the visceral fat depot of the heart, is a modifiable cardiovascular risk factor and emerging therapeutic target. Liraglutide, an analog of glucagon-like peptide-1, is indicated for the treatment of type 2 diabetes mellitus. Liraglutide has recently been shown to reduce cardiovascular risk. Nevertheless, whether liraglutide could reduce EAT is unknown.. To test the hypothesis, a 6-month randomized, open-label, controlled study was performed in 95 type 2 diabetic subjects with body mass index (BMI) ≥27 kg/m. In the liraglutide group, EAT decreased from 9.6 ± 2 to 6.8 ± 1.5 and 6.2 ± 1.5 mm (P < 0.001), accounting for a -29% and -36% of reduction at 3 and 6 months, respectively, whereas there was no EAT reduction in the metformin group; BMI and hemoglobinA1c improved only in the liraglutide group after 6 months.. Liraglutide causes a substantial and rapid EAT reduction. Liraglutide cardiometabolic effects may be EAT-mediated.

Topics: Adipose Tissue; Adult; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Liraglutide; Male; Metformin; Middle Aged; Pericardium; Risk Factors

A multifunctional diet (MFD) was previously shown to reduce blood lipids, CRP and blood pressure in a 4-week intervention under weight-maintenance conditions. Here, MFD effects were evaluated in an 8-week intervention with no restriction for weight changes.. Healthy subjects consumed MFD (23 subjects) or a control diet (CD) devoid of the functional components (24 subjects) in a "free-living" randomized controlled experiment. MFD included several functional concepts: low-glycemic-impact meals, antioxidant-rich foods, oily fish, viscous dietary fibers, soybean and whole barley kernel products, almonds and plant stanols. Measured outcomes were fasting blood values of lipids, glucose, insulin, GGT, CRP, HbA1c, PAI-1, GLP-1, GLP-2, body weight, blood pressure and breath hydrogen.. At baseline, participants were 51-72 years old, with BMI between 25 and 34 and fasting glycemia  ≤ 6.1 mmol/L. Consumption of both diets resulted in similar weight loss after 8 weeks (-4 %; P  <  0.001). Compared to baseline, consumption of MFD reduced total serum cholesterol (-26 %; P  <  0.0001), LDL cholesterol (-35 %; P  <  0.0001), triglycerides (-16 %; P  < 0.05), LDL/HDL (-27 %; P  <  0.0001) and ApoB/ApoA1 (-15 %; P  <  0.0001). There were important net differences between diets, which remained significant after adjustment for body weight. Reduced systolic blood pressure, circulating GGT, HbA1c and insulin concentrations were observed with both MFD and CD with no difference between diets. The Reynolds cardiovascular risk score was decreased by 36 % (P  <  0.0001) with MFD. MFD increased breath hydrogen levels (120 %; P  <  0.05).. Consumption of MFD decreased blood lipids and improved several other aspects of the cardiometabolic risk profile. This effect was not dependent on weight loss.

Topics: Aged; Biomarkers; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cross-Over Studies; Diet; Female; gamma-Glutamyltransferase; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glycated Hemoglobin; Humans; Insulin; Lipids; Male; Metabolic Syndrome; Middle Aged; Obesity; Overweight; Plasminogen Activator Inhibitor 1; Risk Factors; Waist Circumference

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1,360 confirmed primary composite cardiovascular end points, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, have occurred. The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular end point. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once-weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI is <1.30. EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT01144338.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; China; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incidence; Injections, Subcutaneous; Italy; Male; Microspheres; Middle Aged; Ontario; Peptides; Prognosis; Risk Assessment; Risk Factors; Survival Rate; Time Factors; United Kingdom; United States; Venoms

The role of the different factors associated with fatty liver is still poorly defined. We evaluated the relationships between liver fat content (LF) and metabolic, inflammatory and nutritional factors in a homogeneous cohort of individuals at high cardio-metabolic risk.. In 70 individuals with high waist circumference and at least one more criterion for metabolic syndrome enrolled in a nutritional intervention study, LF was evaluated at baseline by hepatic/renal echo intensity ratio (H/R), together with dietary habits (7-day dietary record), insulin sensitivity and β-cell function (fasting and OGTT-derived indices), fasting and postprandial plasma GLP-1 and lipoproteins, and plasma inflammatory markers. H/R correlated positively with fasting and OGTT plasma glucose and insulin concentrations, HOMA-IR and β-cell function, and IL-4, IL-17, IFN-γ, TNF-α, FGF and GCSF plasma concentrations (p < 0.05 for all), and negatively with insulin sensitivity (OGIS), dietary, polyphenols and fiber (p < 0.05 for all). By multiple stepwise regression analysis, the best predictors of H/R were OGIS (β = -0.352 p = 0.001), postprandial GLP-1 (β = -0.344; p = 0.001), HDL-cholesterol (β = -0.323; p = 0.002) and IFN-γ (β = 0.205; p = 0.036).. A comprehensive evaluation of factors associated with liver fat, in a homogeneous population at high cardio-metabolic risk, indicated a pathogenic combination of the same pathways underlying the atherosclerotic process, namely whole body insulin sensitivity and inflammation. The higher predictive value of postprandial variables suggests that liver fat is essentially a postprandial phenomenon, with a relevant role possibly played by GLP-1.. NCT01154478.

Topics: Adaptive Immunity; Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diet Records; Feeding Behavior; Female; Glucagon-Like Peptide 1; Humans; Inflammation Mediators; Insulin; Insulin Resistance; Interferon-gamma; Italy; Liver; Male; Metabolic Syndrome; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Nutritional Status; Postprandial Period; Regression Analysis; Risk Assessment; Risk Factors; Time Factors

The prevalence of type 2 diabetes (T2DM) in younger adults is growing. Compared to the late onset T2DM, it is well recognized that the disease tends to behave more aggressively in the younger age group with evidence of premature micro and macrovasular diseases and shorter life span. This increased mortality is largely attributed to cardiovascular complications. In a recent pilot study, young adults with T2DM were found to have significantly lower peak diastolic strain rate (PEDSR) on cardiac MRI (CMR), a forerunner of diabetic cardiomyopathy. Liraglutide, a glucagon like peptide-1 (GLP-1) analogue, is one of the new classes of glucose lowering therapies licensed to be used in management of T2DM. In randomised controlled trials, liraglutide improves glycaemic control by 1-1.5 % with an added benefit of weight loss of 2-3 kg. In addition, there is emerging evidence elucidating the cardioprotective effects of GLP-1 analogues independent of glycaemic control. In a small study, liraglutide has also been shown to improve cardiac function in patients with coronary ischaemia or congestive heart failure.. This is a prospective, randomised, open-label, blind end-point (PROBE) active-comparator trial. A total of 90 obese eligible participants with T2DM (18-50 years) will be randomised to either liraglutide 1.8 mg once daily or sitagliptin 100 mg once daily for 26 weeks. The primary aim is to assess whether liraglutide improves diastolic function compared to sitagliptin as measured by PEDSR using CMR.. Although newer classes of GLP-1 analogues are made available in recent years, there are very few published studies demonstrating the beneficial effect of GLP-1 analogues on cardiovascular endpoints. In a recently published LEADER study, liraglutide has shown superiority to placebo in a population of type 2 diabetes with high risk of cardiovascular disease. To the best of our knowledge, there are no published studies establishing the effect of liraglutide on cardiac function in younger patients with T2DM on a larger scale. The LYDIA study will comprehensively describe changes in various parameters of cardiac structure and function in patients treated with liraglutide aiming to provide new evidence on effect of liraglutide on diastolic function in young obese people with T2DM. Trial Registration ClinicalTrials.gov identifier: NCT02043054.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Pilot Projects; Young Adult

Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.. We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.. At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.. In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Kaplan-Meier Estimate; Male; Middle Aged

Intake of sugar-sweetened beverages (SSB) may contribute to cardiovascular risk. The aim of this study was to investigate whether functional sugars with low compared to high glycemic index (GI) have beneficial effects on arterial stiffness during a period of low-physical activity. In a controlled cross-over dietary intervention (55% CHO, 30% fat, 15% protein), 13 healthy men (age: 23.7 ± 2.2 years, body mass index: 23.6 ± 1.9 kg/m²) completed 2 × 1 week of low physical activity following 1 week of normal physical activity (2363 ± 900 vs. 11,375 ± 3124 steps/day). During inactive phases participants consumed either low-GI (isomaltulose) or high-GI SSB (maltodextrin-sucrose), providing 20% of energy requirements. Postprandial vasodilatation (augmentation index, AIx), insulin sensitivity (IS) and Glucagon-like-peptide 1 (GLP-1) responses were measured during a meal test before and after SSB-intervention. Compared to maltodextrin-sucrose-SSB, postprandial vasodilatation was prolonged (AIx after 120 min: 9.9% ± 4.3% vs. 11.4% ± 3.7%,

Topics: Adult; Beverages; Cardiovascular Diseases; Cross-Over Studies; Dietary Carbohydrates; Dietary Sucrose; Exercise; Germany; Glucagon-Like Peptide 1; Glucose Intolerance; Glycemic Index; Humans; Insulin Resistance; Isomaltose; Male; Polysaccharides; Postprandial Period; Risk Factors; Sedentary Behavior; Single-Blind Method; Vascular Stiffness; Vasodilation

Polycystic ovary syndrome (PCOS) is associated with obesity and increased cardiovascular (CV) risk markers. In this study our aim was to assess the effects of six months treatment with liraglutide 1.8 mg od on obesity, and CV risk markers, particularly platelet function, in young obese women with PCOS compared to controls of similar age and weight.. Carotid intima-media wall thickness (cIMT) was measured by B-mode ultrasonography, platelet function by flow cytometry, clot structure/lysis by turbidimetric assays and endothelial function by ELISA and post-ischaemic reactive hyperemia (RHI). Data presented as mean change (6-month - baseline) ± standard deviation.. Nineteen obese women with PCOS and 17 controls, of similar age and weight, were recruited; baseline atherothrombotic risk markers did not differ between the two groups. Twenty five (69.4%) participants completed the study (13 PCOS, 12 controls). At six months, weight was significantly reduced by 3.0 ± 4.2 and 3.8 ± 3.4 kg in the PCOS and control groups, respectively; with no significant difference between the two groups, P = 0.56. Similarly, HOMA-IR, triglyceride, hsCRP, urinary isoprostanes, serum endothelial adhesion markers (sP-selectin, sICAM and sVCAM), and clot lysis area were equally significantly reduced in both groups compared to baseline. Basal platelet P-selectin expression was significantly reduced at six months in controls -0.17 ± 0.26 but not PCOS -0.12 ± 0.28; between groups difference, 95% confidence interval = -0.14 - 0.26, P = 0.41. No significant changes were noted in cIMT or RHI.. Six months treatment with liraglutide (1.8 mg od) equally affected young obese women with PCOS and controls. In both groups, liraglutide treatment was associated with 3-4% weight loss and significant reduction in atherothrombosis markers including inflammation, endothelial function and clotting. Our data support the use of liraglutide as weight loss medication in simple obesity and suggest a potential beneficial effect on platelet function and atherothrombotic risk at 6 months of treatment.. Clinical trial reg. no. ISRCTN48560305. Date of registration 22/05/2012.

Topics: Adolescent; Adult; Blood Platelets; Cardiovascular Diseases; Carotid Intima-Media Thickness; Female; Fibrinolysis; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Middle Aged; Polycystic Ovary Syndrome; Risk Factors; Young Adult

Dietary polyphenols and long chain n-3 polyunsaturated fatty acids (LCn3) are associated with lower cardiovascular risk. This may relate to their influence on glucose metabolism and diabetes risk. We evaluated the effects of diets naturally rich in polyphenols and/or LCn3 of marine origin on glucose metabolism in people at high cardiometabolic risk.. According to a 2 × 2 factorial design, individuals with high waist circumference and at least one more component of the metabolic syndrome were recruited at the obesity outpatient clinic. Eighty-six participants were randomly assigned by MINIM software to an isoenergetic diet: (1) control, low in LCn3 and polyphenol (analysed n = 20); (2) rich in LCn3 (n = 19); (3) rich in polyphenols (n = 19); or (4) rich in LCn3 and polyphenols (n = 19). The assigned diets were known for the participants and blinded for people doing measurements. Before and after the 8 week intervention, participants underwent a 3 h OGTT and a test meal with a similar composition as the assigned diet for the evaluation of plasma glucose, insulin and glucagon-like peptide 1 (GLP-1) concentrations, and indices of insulin sensitivity and beta cell function.. During OGTT, polyphenols significantly reduced plasma glucose total AUC (p = 0.038) and increased early insulin secretion (p = 0.048), while LCn3 significantly reduced beta cell function (p = 0.031) (two-factor ANOVA). Moreover, polyphenols improved post-challenge oral glucose insulin sensitivity (OGIS; p = 0.05 vs control diet by post hoc ANOVA). At test meal, LCn3 significantly reduced GLP-1 total postprandial AUC (p < 0.001; two-factor ANOVA).. Diets naturally rich in polyphenols reduce blood glucose response, likely by increasing early insulin secretion and insulin sensitivity. These effects may favourably influence diabetes and cardiovascular risk. The implications of the decrease in insulin secretion and postprandial GLP-1 observed with diets rich in marine LCn3 need further clarification.. ClinicalTrials.gov NCT01154478.. The trial was funded by European Community's Seventh Framework Programme FP7/2009-2012 under grant agreement FP7-KBBE-222639, Etherpaths Project and 'Ministero Istruzione Università e Ricerca' PRIN 2010-2011 - 2010JCWWKM.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diet; Fatty Acids, Omega-3; Female; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Metabolic Diseases; Middle Aged; Obesity; Patient Compliance; Polyphenols; Waist Circumference

Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated.. ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy.. Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m(2), and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events.. ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk.

Topics: Acute Coronary Syndrome; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Peptides; Placebos; Protein Kinase Inhibitors; Research Design

The effects of twice-daily GLP-1 analogue injections added on continuous subcutaneous insulin infusion (CSII) in patients with poorly controlled type 2 diabetes (T2DM) were unknown. After optimization of blood glucose in the first 3 days by CSII during hospitalization, patients with poorly controlled T2DM were randomized to receive CSII combined with injections of exenatide or placebo for another 3 days. A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11% were studied. There was no difference in mean glucose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51 ± 2.43 vs. 41.49 ± 3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin 0-peak/ Glucose 0-peak) in 75 g oral glucose tolerance test was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 ± 0.32 vs. -1.62 ± 0.97 μg/mL, in exenatide and placebo groups, respectively, p = 0.045). In conclusion, the add-on of GLP-1 analogue to CSII increased glucose variability and the β - cell response in patients with poorly controlled T2DM.

Topics: Adiponectin; Biomarkers; Blood Glucose; C-Peptide; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endpoint Determination; Exenatide; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin-Secreting Cells; Male; Middle Aged; Peptides; Risk Factors; Venoms

The goal of this study was to investigate the effects of linagliptin compared with glimepiride on alpha and beta cell function and several vascular biomarkers after a standardized test meal.. Thirty-nine patients on metformin alone (age, 64 ± 7 years; duration of type 2 diabetes mellitus, 7.8 ± 4.5years, 27 male, 12 female; HbA1c , 57.2 ± 6.9 mmol/mol; mean ± SD) were randomized to receive linagliptin 5 mg (n = 19) or glimepiride (n = 20) for a study duration of 12 weeks. Glucagon-like peptide 1, blood glucose, insulin, intact proinsulin, glucagon, plasminogen activator inhibitor-1 (PAI-1), cyclic guanosinmonophosphat and asymetric dimethylarginin levels were measured in the fasting state and postprandial at 30-min intervals for a duration of 5 h. The areas under the curve (AUC0-300 min ) were calculated for group comparisons.. HbA1c , fasting and postprandial glucose levels improved in both groups. An increase in postprandial insulin (22595 ± 5984 pmol/L*min), postprandial intact proinsulin (1359 ± 658 pmol/L*min), postprandial glucagon (317 ± 1136 pg/mL*min) and postprandial PAI-1 levels (863 ± 467 ng/mL*min) could be observed during treatment with glimepiride, whereas treatment with linagliptin was associated with a decrease in postprandial insulin (-8007 ± 4204 pmol/L*min), intact proinsulin (-1771 ± 426 pmol/L*min), postprandial glucagon (-1597 ± 1831 pg/mL*min) and PAI-1 levels (-410 ± 276 ng/mL*min).. Despite an improvement in blood glucose control in both groups, linagliptin reduced postprandial insulin, proinsulin, glucagon and PAI-levels. These results indicate an improvement in postprandial alpha and beta cell function, as well as a reduced postprandial vascular risk profile during treatment with linagliptin.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Linagliptin; Male; Metformin; Middle Aged; Plasminogen Activator Inhibitor 1; Postprandial Period; Proinsulin; Purines; Quinazolines; Risk Factors; Sulfonylurea Compounds

Until recently, very few intervention studies have investigated the effects of whole-grain cereals on postprandial glucose, insulin and lipid metabolism, and the existing studies have provided mixed results. The objective of this study was to evaluate the effects of a 12-week intervention with either a whole-grain-based or a refined cereal-based diet on postprandial glucose, insulin and lipid metabolism in individuals with metabolic syndrome.. Sixty-one men and women age range 40-65 years, with the metabolic syndrome were recruited to participate in this study using a parallel group design. After a 4-week run-in period, participants were randomly assigned to a 12-week diet based on whole-grain products (whole-grain group) or refined cereal products (control group). Blood samples were taken at the beginning and end of the intervention, both fasting and 3 h after a lunch, to measure biochemical parameters. Generalized linear model (GLM) was used for between-group comparisons. Overall, 26 participants in the control group and 28 in the whole-grain group completed the dietary intervention. Drop-outs (five in the control and two in the whole-grain group) did not affect randomization. After 12 weeks, postprandial insulin and triglyceride responses (evaluated as average change 2 and 3 h after the meal, respectively) decreased by 29% and 43%, respectively, in the whole-grain group compared to the run-in period. Postprandial insulin and triglyceride responses were significantly lower at the end of the intervention in the whole-grain group compared to the control group (p = 0.04 and p = 0.05; respectively) whereas there was no change in postprandial response of glucose and other parameters evaluated.. A twelve week whole-grain cereal-based diet, compared to refined cereals, reduced postprandial insulin and triglycerides responses. This finding may have implications for type 2 diabetes risk and cardiovascular disease.

Topics: Adult; Aged; Apolipoproteins A; Apolipoproteins B; Blood Glucose; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet; Edible Grain; Fatty Acids, Nonesterified; Female; Glucagon-Like Peptide 1; Glycemic Index; Humans; Insulin; Linear Models; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Nutrition Assessment; Patient Compliance; Postprandial Period; Triglycerides

In type 2 diabetes, acute hyperglycemia worsens endothelial function and inflammation,while resistance to GLP-1 action occurs. All these phenomena seem to be related to the generation of oxidative stress. A Mediterranean diet, supplemented with olive oil, increases plasma antioxidant capacity, suggesting that its implementation can have a favorable effect on the aforementioned phenomena. In the present study, we test the hypothesis that a Mediterranean diet using olive oil can counteract the effects of acute hyperglycemia and can improve the resistance of the endothelium to GLP-1 action.. Two groups of type 2 diabetic patients, each consisting of twelve subjects, participated in a randomized trial for three months, following a Mediterranean diet using olive oil or a control low-fat diet. Plasma antioxidant capacity, endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels were evaluated at baseline and at the end of the study. The effect of GLP-1 during a hyperglycemic clamp, was also studied at baseline and at the end of the study.. Compared to the control diet, the Mediterranean diet increased plasma antioxidant capacity and improved basal endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. The Mediterranean diet also reduced the negative effects of acute hyperglycemia, induced by a hyperglycemic clamp, on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels. Furthermore, the Mediterranean diet improved the protective action of GLP-1 on endothelial function, nitrotyrosine, 8-iso-PGF2a, IL-6 and ICAM-1 levels, also increasing GLP-1-induced insulin secretion.. These data suggest that the Mediterranean diet, using olive oil, prevents the acute hyperglycemia effect on endothelial function, inflammation and oxidative stress, and improves the action of GLP-1, which may have a favorable effect on the management of type 2 diabetes, particularly for the prevention of cardiovascular disease.

Topics: Adult; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diet, Mediterranean; Drug Resistance; Endothelium, Vascular; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Inflammation; Male; Middle Aged; Oxidative Stress

To demonstrate the efficacy of exenatide versus insulin glargine on endothelial functions and cardiovascular risk markers.. Thirty-four insulin and incretin-naive patients with type 2 diabetes mellitus (body mass index 25-45 kg/m(2)) who received metformin for at least two months were randomized to exenatide or insulin glargine treatment arms and followed-up for 26 weeks. Measurements of endothelial functions were done by ultrasonography, cardiovascular risk markers by serum enzyme-linked immunosorbent assay, and total body fat mass by bioimpedance.. Levels of high sensitivity-C-reactive protein and endothelin-1 decreased (27.5% and 18.75%, respectively) in the exenatide arm. However, in the insulin glargine arm, fibrinogen, monocyte chemoattractant protein-1, leptin and endothelin-1 levels (13.4, 30.2, 47.5, and 80%, respectively) increased. Post-treatment flow mediated dilatation and endothelium independent vascular responses were significantly higher in both arms (p=0.0001, p=0.0001). Positive correlation was observed between the changes in body weight and endothelium-independent vasodilatation, leptin, plasminogen activator inhibitor type 1 and endothelin-1 in both arms (r=0.376, r=0.507, r=0.490, r=0.362, respectively).. Insulin glargine improved endothelial functions, without leading to positive changes in cardiovascular risk markers. Exenatide treatment of 26 weeks resulted in reduced body weight and improvement in certain cardiovascular risk markers and endothelial functions.

Topics: Biomarkers; Blood Glucose; Brachial Artery; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Peptides; Prognosis; Risk Factors; Ultrasonography; Vasodilation; Venoms

Postprandial triglyceridaemia is a risk factor for cardiovascular disease (CVD). This study investigated the effects of steady-state liraglutide 1.8 mg versus placebo on postprandial plasma lipid concentrations after 3 weeks of treatment in patients with type 2 diabetes mellitus (T2DM).. In a cross-over trial, patients with T2DM (n = 20, 18-75 years, BMI 18.5-40 kg/m²) were randomized to once-daily subcutaneous liraglutide (weekly dose escalation from 0.6 to 1.8 mg) and placebo. After each 3-week period, a standardized fat-rich meal was provided, and the effects of liraglutide on triglyceride (primary endpoint AUC(0-8h)), apolipoprotein B48, non-esterified fatty acids, glycaemic responses and gastric emptying were assessed. ClinicalTrials.gov ID: NCT00993304.. Novo Nordisk A/S.. After 3 weeks, mean postprandial triglyceride (AUC(0-8h) liraglutide/placebo treatment-ratio 0.72, 95% CI [0.62-0.83], p = 0.0004) and apolipoprotein B48 (AUC(0-8h) ratio 0.65 [0.58-0.73], p < 0.0001) significantly decreased with liraglutide 1.8 mg versus placebo, as did iAUC(0-8h) and C(max) (p < 0.001). No significant treatment differences were observed for non-esterified fatty acids. Mean postprandial glucose and glucagon AUC(0-8h) and C(max) were significantly reduced with liraglutide versus placebo. Postprandial gastric emptying rate [assessed by paracetamol absorption (liquid phase) and the ¹³C-octanoate breath test (solid phase)] displayed no treatment differences. Mean low-density lipoprotein and total cholesterol decreased significantly with liraglutide versus placebo.. Liraglutide treatment in patients with T2DM significantly reduced postprandial excursions of triglyceride and apolipoprotein B48 after a fat-rich meal, independently of gastric emptying. Results indicate liraglutide's potential to reduce CVD risk via improvement of postprandial lipaemia.

Topics: Aged; Body Mass Index; Cardiovascular Diseases; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Diet, High-Fat; Double-Blind Method; Female; Gastric Emptying; Germany; Glucagon-Like Peptide 1; Half-Life; Humans; Hyperlipidemias; Hypoglycemic Agents; Hypolipidemic Agents; Lipids; Liraglutide; Male; Middle Aged; Obesity; Postprandial Period; Risk Factors

Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM).. To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.. LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Research Design; Treatment Outcome

The purpose of this study was to determine the effects of consuming raisins, increasing steps walked, or a combination of these interventions on lipoprotein metabolism and appetite hormones by assessing plasma apolipoprotein concentrations, cholesterol ester transfer protein activity, low-density lipoprotein (LDL) receptor messenger RNA (mRNA) abundance, and plasma ghrelin and leptin concentrations. Thirty-four subjects (17 men and 17 postmenopausal women) were matched for weight and sex and randomly assigned to consume 1 cup raisins per day (RAISIN), increase the amount of steps walked per day (WALK), or a combination of both interventions (RAISIN + WALK). The subjects completed a 2-week run-in period, followed by a 6-week intervention. Ribonucleic acid was extracted from mononuclear cells, and LDL receptor mRNA abundance was quantified by use of reverse transcriptase polymerase chain reaction. Plasma apolipoproteins were measured by Luminex (Austin, TX) technology. Apoproteins A-1, B, C-II, and E and cholesterol ester transfer protein activity were not altered for any of the groups. In contrast, apolipoprotein C-III was significantly decreased by 12.3% only in the WALK group (P < .05). Low-density lipoprotein receptor mRNA abundance was increased for all groups after the intervention (P < .001). There was a significant group effect for plasma leptin (P = .026). Plasma concentrations increased for RAISIN and RAISIN + WALK. Similarly, plasma ghrelin concentrations were elevated postintervention for both groups consuming raisins (P < .05). These data suggest that walking and raisin consumption decrease plasma LDL cholesterol by up-regulating the LDL receptor and that raisin consumption may reduce hunger and affect dietary intake by altering hormones influencing satiety.

Topics: Aged; Apolipoproteins; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Female; Ghrelin; Glucagon-Like Peptide 1; Humans; Leptin; Lipoproteins; Male; Middle Aged; Peptide YY; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation; Vitis; Walking

Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin-angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort).. In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs.. We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found.. Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulins; Renal Insufficiency, Chronic; Retrospective Studies

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology suggests starting with a sodium-glucose cotransprter-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RAs are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Liraglutide

Type 2 diabetes (T2D) is a well-recognised cardiovascular disease (CVD) risk factor, and recent guidelines for the management of T2D include consideration of CVD risk.. To assess whether contemporary clinical management of Australians with T2D is in accord with recent national and international guidelines.. This Australia-specific analysis of the CAPTURE study, a non-interventional, cross-sectional study included adults diagnosed with T2D ≥180 days prior to providing informed consent and visiting primary or specialist care. Main outcome measures were the use of blood glucose-lowering medications (BGLMs), BGLMs with proven cardiovascular benefits and other CVD medications, stratified by CVD status and care setting.. Of 824 Australian participants in the CAPTURE sample, 332 (40.3%) had CVD. Oral BGLMs were used by 83.9% of all participants, most commonly metformin (76.0%), dipeptidyl peptidase-4 inhibitors (28.8%), sodium-glucose cotransporter-2 inhibitors (SGLT2is; 21.8%) and sulfonylureas (21.7%). Insulin was used by 29.2% of participants. BGLMs with proven CV benefit were used by 22.6%; glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were less commonly used than SGLT2is in all CVD groups, but these drug classes were more often prescribed in specialist than primary care (SGLT2is 25.4 vs 20.7%, GLP-1 RAs 3.2 vs 0.8% respectively). Use of non-BGLMs for CVD risk reduction appeared consistent with guidelines.. Use of BGLMs with CVD benefits appears low in Australia, irrespective of CVD status. This likely reflects the delay in translation of clinical evidence into contemporary care and prescribing restrictions.

Topics: Adult; Australia; Blood Glucose; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

To assess the potential gain in the number of life-years free of a (recurrent) cardiovascular disease (CVD) event with optimal cardiovascular risk management (CVRM) and initiation of glucose-lowering agents with proven cardiovascular benefit in people with type 2 diabetes (T2D).. 9,416 individuals with T2D from the CAPTURE study, a non-interventional, cross-sectional, multinational study, were included. The diabetes lifetime-perspective prediction model was used for calculating individual 10-year and lifetime CVD risk. The distribution of preventive medication use was assessed according to predicted CVD risk and stratified for history of CVD. For the estimation of absolute individual benefit from lifelong preventive treatment, including optimal CVRM and the addition of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is), the model was combined with treatment effects from current evidence.. GLP-1 RA or SGLT-2i use did not greatly differ between patients with and without CVD history, while use of blood pressure-lowering medication, statins and aspirin was more frequent in patients with CVD. Mean (standard deviation [SD]) lifetime benefit from optimal CVRM was 3.9 (3.0) and 1.3 (1.9) years in patients with and without established CVD, respectively. Further addition of a GLP-1 RA and an SGLT-2i in patients with CVD gave an added mean (SD) lifetime benefit of 1.2 (0.6) years.. Life-years gained free of (recurrent) CVD by optimal CVRM and the addition of a GLP-1 RA or aSGLT-2i is dependent on baseline CVD status. These results aid individualizing prevention and promote shared decision-making in patients with T2D.

Topics: Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors

Recent national guidelines recommend sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD); yet, there are limited data on the use of these agents in contemporary community practice.. To evaluate the use of SGLT2i and GLP-1 RA in adults with T2D and ASCVD across a diverse sample of health care systems in the US.. This multicenter, retrospective cohort study used electronic health record data from 88 US health care systems participating in Cerner Real World Data between January 2018 to March 2021. Adults with ASCVD and T2D taking at least 1 glucose-lowering medication, had end-stage kidney disease, or had stage 5 chronic kidney disease were excluded.. Treatment with SGLT2i or GLP-1 RA.. A total of 321 304 patients were identified with T2D and ASCVD ASCVD (130 280 female [40.5%]; median [IQR] age, 70.9 [62.9-78.0] years) who were potentially eligible for SGLT2i and/or GLP-1 RA, including 37 754 Black individuals (11.8%), 51 522 Hispanic individuals (16.0%), and 256 008 White individuals (11.8%). From January 2018 to March 2021, the use of SGLT2i increased from 5.8% (11 285 of 194 264) to 12.9% (11 058 of 85 956), GLP-1 RA increased from 6.9% (13 402 of 194 264) to 13.8% (11 901 of 85 956), and use of either agent increased from 11.4% (22 069 of 194 264) to 23.2% (19 909 of 85 956). Those taking an SGLT2i or GLP-1 RA were younger, less frequently hospitalized in the year prior, and more likely to be taking additional secondary prevention medications. Treated and nontreated populations were similar in terms of race, ethnicity, and outpatient health care utilization. Sulfonylureas and dipeptidyl peptidase 4 inhibitors remained more commonly used than SGLT2i or GLP-1 RA through 2021.. In this study, uptake of SGLT2i and GLP-1 RA in adults with T2D and ASCVD increased modestly after guideline recommendations, although less than a quarter of persons with ASCVD and T2D receiving medical therapy were taking either. Further efforts are necessary to maximize the potential population benefit of these therapies in this high-risk population.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Peptides; Retrospective Studies; Sodium; Sodium-Glucose Transporter 2 Inhibitors

To examine the association of race/ethnicity and socioeconomic deprivation with initiation of guideline-recommended diabetes medications with cardiovascular benefit (glucagon-like peptide 1 receptor agonists [GLP1-RA] and sodium-glucose cotransporter 2 inhibitors [SGLT2i]) among older adults with type 2 diabetes (T2D) and either incident atherosclerotic cardiovascular disease (ASCVD) or congestive heart failure (CHF).. Using Medicare data (2016-2019), we identified 4,057,725 individuals age >65 years with T2D and either incident ASCVD or CHF. We estimated incidence rates and hazard ratios (HR) of GLP1-RA or SGLT2i initiation within 180 days by race/ethnicity and zip code-level Social Deprivation Index (SDI) using adjusted Cox proportional hazards models.. Incidence rates of GLP1-RA or SGLT2i initiation increased over time but remained low (<0.6 initiations per 100 person-months) in all years studied. Medication initiation was less common among those of Black or other race/ethnicity (HR 0.81 [95% CI 0.79-0.84] and HR 0.84 [95% CI 0.75-0.95], respectively) and decreased with increasing SDI (HR 0.96 [95% CI 0.96-0.97]). Initiation was higher in ASCVD than CHF (0.35 vs. 0.135 initiations per 100 person-months). Moderate (e.g., nephropathy, nonalcoholic fatty liver disease) but not severe (e.g., advanced chronic kidney disease, cirrhosis) comorbidities were associated with higher probability of medication initiation.. Among older adults with T2D and either ASCVD or CHF, initiation of GLP1-RA or SGLT2i was low, suggesting a substantial deficit in delivery of guideline-recommended care or treatment barriers. Individuals of Black and other race/ethnicity and those with higher area-level socioeconomic deprivation were less likely to initiate these medications.

Topics: Aged; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Medicare; United States

Whether sodium-glucose co-transporter 2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are cost-effective based solely on their cardiovascular and kidney benefits is unknown. We projected the health and economic outcomes due to myocardial infarction (MI), stroke, heart failure (HF) and end-stage kidney disease (ESKD) among people with type 2 diabetes, with and without CVD, under scenarios of widespread use of these drugs.. We designed a microsimulation model using real-world data that captured CVD and ESKD morbidity and mortality from 2020 to 2040. The populations and transition probabilities were derived by linking the Australian Diabetes Registry (1.1 million people with type 2 diabetes) to hospital admissions databases, the National Death Index and the ESKD Registry using data from 2010 to 2019. We modelled four interventions: increase in use of SGLT2is or GLP-1 RAs to 75% of the total population with type 2 diabetes, and increase in use of SGLT2is or GLP-1 RAs to 75% of the secondary prevention population (i.e. people with type 2 diabetes and prior CVD). All interventions were compared with current use of SGLT2is (20% of the total population) and GLP-1 RAs (5% of the total population). Outcomes of interest included quality-adjusted life years (QALYs), total costs (from the Australian public healthcare perspective) and the incremental cost-effectiveness ratio (ICER). We applied 5% annual discounting for health economic outcomes. The willingness-to-pay threshold was set at AU$28,000 per QALY gained.. The numbers of QALYs gained from 2020 to 2040 with increased SGLT2i and GLP-1 RA use in the total population (n=1.1 million in 2020; n=1.5 million in 2040) were 176,446 and 200,932, respectively, compared with current use. Net cost differences were AU$4.2 billion for SGLT2is and AU$20.2 billion for GLP-1 RAs, and the ICERs were AU$23,717 and AU$100,705 per QALY gained, respectively. In the secondary prevention population, the ICERs were AU$8878 for SGLT2is and AU$79,742 for GLP-1 RAs.. At current prices, use of SGLT2is, but not GLP-1 RAs, would be cost-effective when considering only their cardiovascular and kidney disease benefits for people with type 2 diabetes.

Topics: Australia; Cardiovascular Diseases; Cost-Effectiveness Analysis; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Incidence; Kidney; Sodium-Glucose Transporter 2 Inhibitors

There is limited research using real-world data to evaluate protective cardiovascular effects of glucagon-like peptide-1 (GLP-1) agonists among adults with type 2 diabetes (T2D) early in treatment.. We conducted a retrospective, active comparator cohort study using 2011-2015 administrative claims data to compare cardiovascular disease (CVD) event rates following initiation of exenatide extended-release (E-ER), exenatide immediate-release (E-IR) or liraglutide in T2D adults who previously received no other antidiabetic medication (ADM) except metformin. The primary outcome was time to first major adverse CVD event (ischaemic heart disease, stroke, congestive heart failure or peripheral arterial disease) after starting GLP-1. Cox proportional hazards regression was used to model the association between index GLP-1 and CVD events, adjusting for baseline patient, prescriber and plan characteristics. Primary analyses included all patients with ≥2 prescription fills for the index GLP-1, regardless of subsequent refill adherence or initiation of other ADM after index date.. Compared with liraglutide, neither E-ER nor E-IR was associated with risk of composite major CVD events (hazard ratios [HRs] for E-ER and E-IR: 1.33 [95% C.I. 0.73-2.39] and 1.30 [0.81-2.09]). No associations were observed between event rates for individual CVD components. The HR for an ischaemic event with E-IR relative to liraglutide was 1.85 (95% C.I. 0.97-3.53). Adjusting for time-varying exposure to other ADM and CVD medications after index date produced similar results.. Initiating either immediate or extended-release exenatide rather than liraglutide was not associated with significant differences in CVD risk in this observational real-world study.

Topics: Adult; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Retrospective Studies

Sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor (GLP-1) agonists are recommended for patients with type two diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) to reduce cardiovascular-related mortality. The objective of this study was to evaluate a telehealth targeted medication review (TMR) program to identify patients for uptake of these evidence-based medications.. This was an observational descriptive study of a TMR program for Medicare-enrolled, Medication Therapy Management-eligible patients in one insurance plan. Prescription claims and patient interviews identified individuals who would benefit from SGLT-2 inhibitors or GLP-1 agonists. Facsimiles were sent to providers of patients with educational information about the targeted medications. Descriptive statistics described characteristics and proportion of patients prescribed targeted medications after 120 days. Bivariate statistical tests evaluated associations between age, sex, number of medications, number of providers, and poverty level with adoption of targeted medications.. A total of 1106 of 1127 had a facsimile sent to their provider after a conversation with the patient. Among patients with a provider facsimile, 69 (6%) patients filled a prescription for a targeted medication after 120 days. There was a significant difference in age between individuals who started a targeted medication (67 ± 10 years) compared with patients who did not (71 ± 10 years) (. A TMR efficiently identified patients with T2D and ASCVD or HF who would benefit from evidence-based medications. Although younger patients were more likely to receive these medications, the overall uptake of these medications within four months of the intervention was lower than expected.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Medicare; Middle Aged; Telemedicine; United States

To determine whether glucagon-like peptide 1 receptor agonists (GLP-1RAs) have cardiovascular and renal protective effects in patients with advanced diabetic kidney disease (DKD) with an estimated glomerular filtration rate (eGFR) < 30 mL/min per 1.73 m. In this cohort study, patients with type 2 diabetes mellitus and eGFR < 30 mL/min per 1.73 m. A total of 8922 participants [mean (SD) age 68.4 (11.5) years; 4516 (50.6%) males; GLP-1RAs, n = 759; DPP-4is, n = 8163] were eligible for this study. During a mean follow-up of 2.1 years, 78 (13%) and 204 (13.8%) patients developed composite cardiovascular events in the GLP-1RA and DPP-4i groups, respectively [hazard ratio (HR) 0.88, 95% confidence interval CI 0.68-1.13]. Composite kidney events were reported in 134 (38.2%) and 393 (44.2%) patients in the GLP-1RA and DPP-4i groups, respectively (subdistribution HR 0.72, 95% CI 0.56-0.93).. GLP-1RAs had a neutral effect on the composite cardiovascular outcomes but reduced composite kidney events in the patients with advanced DKD compared with DPP-4is.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Kidney; Male

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up.. Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed.. Median duration of follow-up was 5.0 years (0.25-10.8) in primary prevention and 3.6 years (0-10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0-10.8) and 2.5 years (0-10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03-1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82-6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46-5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up.. In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Retrospective Studies

Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology.. This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations.. We sequenced GLP1R in 8642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cyclic adenosine monophosphate (cAMP) formation and β-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330 566 unrelated White exome-sequenced participants in the UK Biobank cohort.. We identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1-induced cAMP signaling compared to wild-type. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on glycated hemoglobin A1c.. Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

Topics: Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Phenotype

To describe glucose-lowering drugs prescribing pattern in a large population of older diabetics from 2010 to 2021.. Using linkable administrative health databases, we included patients aged 65-90 years treated with glucose-lowering drugs. Prevalence rate of drugs was collected within each study year. A stratified analysis by gender, age and coexistence of cardiovascular disease (CVD) was conducted.. A total of 251 737 and 308 372 patients were identified in 2010 and 2021, respectively. Use of metformin (68.4% to 76.6%), DPP-4i (1.6% to 18.4%), GLP-1-RA (0.4% to 10.2%), SGLT2i (0.6% to 11.1%) increased, while sulfonylureas (53.6% to 20.7%) and glinides (10.5% to 3.5%) decreased over time. Metformin, glitazones, GLP1-RA, SGLT2i and DPP4i (except for 2021) usage decreased with aging, in contrast to sulfonylureas, glinides and insulin. The coexistence of CVD was associated with a higher prescription of glinides, insulin, DPP-4i, GLP1-RA and SGLT2i, particularly in 2021.. We found a significant increase in the prescriptions of GLP-1 RA and SGLT2i in older diabetics, mainly in those with CVD. However, drugs without CV benefits including sulfonylureas and DPP-4i continued to be highly prescribed in older patients. There is still room to improve the management in this population according to recommendations.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Metformin; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

The latest guidelines continue to recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). Despite this, overall use of these 2 drug classes has been suboptimal.. To assess the association of high out-of-pocket (OOP) costs and the initiation of an SGLT2 inhibitor or GLP-1 RA among adults with T2D and established CVD who are treated with metformin-treated.. This retrospective cohort study used 2017 to 2021 data from the Optum deidentified Clinformatics Data Mart Database. Each individual in the cohort was categorized into quartiles of OOP costs for a 1-month supply of SGLT2 inhibitor and GLP-1 RA based on their health plan assignment. Data were analyzed from April 2021 to October 2022.. OOP cost for SGLT2 inhibitors and GLP-1 RA.. The primary outcome was treatment intensification, defined as a new dispensing (ie, initiation) of either an SGLT2 inhibitor or GLP-1 RA, among patients with T2D previously treated with metformin monotherapy. For each drug class separately, Cox proportional hazards models were used to adjust for demographic, clinical, plan, clinician, and laboratory characteristics to estimate the hazard ratios of treatment intensification comparing the highest vs the lowest quartile of OOP costs.. Our cohort included 80 807 adult patients (mean [SD] age, 72 [9.5] years, 45 129 [55.8%] male; 71 128 [88%] were insured with Medicare Advantage) with T2D and established CVD on metformin monotherapy. Patients were followed for a median (IQR) of 1080 days (528 to 1337). The mean (SD) of OOP costs in the highest vs lowest quartile was $118 [32] vs $25 [12] for GLP-1 RA, and $91 [25] vs $23 [9] for SGLT2 inhibitors. Compared with patients in plans with the lowest quartile (Q1) of OOP costs, patients in plans with the highest quartile (Q4) of costs were less likely to initiate a GLP-1 RA (adjusted HR, 0.87 [95% CI, 0.78 to 0.97]) or an SGLT2 inhibitor (adjusted HR, 0.80 [95% CI, 0.73 to 0.88]). The median (IQR) number of days to initiating a GLP-1 RA was 481 (207-820) days in Q1 and 556 (237-917) days in Q4 of OOP costs and 520 (193-876) days in Q1 vs 685 (309-1017) days in Q4 for SGLT2 inhibitors.. In this cohort study of more than 80 000 older adults with T2D and established CVD covered by Medicare Advantage and commercial plans, those in the highest quartile of OOP cost were 13% and 20% less likely to initiate a GLP-1 RA or SGLT2 inhibitor, respectively, when compared with those in the lowest quartile of OOP costs.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Health Expenditures; Humans; Male; Medicare; Metformin; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors; United States

Type 2 diabetes (T2D) is linked to metabolic, mitochondrial and inflammatory alterations, atherosclerosis development and cardiovascular diseases (CVDs). The aim was to investigate the potential therapeutic benefits of GLP-1 receptor agonists (GLP-1 RA) on oxidative stress, mitochondrial respiration, leukocyte-endothelial interactions, inflammation and carotid intima-media thickness (CIMT) in T2D patients.. Type 2 diabetic patients (255) and control subjects (175) were recruited, paired by age and sex, and separated into two groups: without GLP-1 RA treatment (196) and treated with GLP-1 RA (59). Peripheral blood polymorphonuclear leukocytes (PMNs) were isolated to measure reactive oxygen species (ROS) production by flow cytometry and oxygen consumption with a Clark electrode. PMNs were also used to assess leukocyte-endothelial interactions. Circulating levels of adhesion molecules and inflammatory markers were quantified by Luminex's technology, and CIMT was measured as surrogate marker of atherosclerosis.. Treatment with GLP-1 RA reduced ROS production and recovered mitochondrial membrane potential, oxygen consumption and MPO levels. The velocity of leukocytes rolling over endothelial cells increased in PMNs from GLP-1 RA-treated patients, whereas rolling and adhesion were diminished. ICAM-1, VCAM-1, IL-6, TNFα and IL-12 protein levels also decreased in the GLP-1 RA-treated group, while IL-10 increased. CIMT was lower in GLP-1 RA-treated T2D patients than in T2D patients without GLP-1 RA treatment.. GLP-1 RA treatment improves the redox state and mitochondrial respiration, and reduces leukocyte-endothelial interactions, inflammation and CIMT in T2D patients, thereby potentially diminishing the risk of atherosclerosis and CVDs.

Topics: Atherosclerosis; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Endothelial Cells; Endothelium; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Inflammation; Leukocytes; Reactive Oxygen Species

An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs.. Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates.. Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo.. GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Obesity; Overweight

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have proven cardiovascular benefits, are recommended in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). However, there is limited real-world evidence comparing the effects of once-weekly (OW) GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP-4is). This observational cohort study (1/1/2017-9/30/2021) used data from the Optum Clinformatics. Time to occurrence of ischemic stroke, myocardial infarction (MI), or their composite and ASCVD-related and all-cause HCRU and medical costs were investigated. Baseline characteristics were balanced using inverse probability of treatment weighting. Survival analyses were conducted to compare risks during exposure.. OW GLP-1 RA users (weighted N = 25,287) had 26%, 22%, and 24% lower risk of ischemic stroke, MI, and their composite, respectively, compared with DPP-4i users (weighted N = 39,684; all P < 0.01). Compared with DPP-4i users, OW GLP-1 RA users had 25% and 26% lower ASCVD-related and all-cause hospitalization costs, 19% and 23% lower ASCVD-related and all-cause medical costs, 23% and 27% fewer ASCVD-related and all-cause hospitalizations, 13% and 8% fewer ASCVD-related and all-cause outpatient visits, and 8% fewer all-cause ER visits (all P < 0.01).. In adults with T2D and ASCVD, OW GLP-1 RAs are associated with reduced stroke and MI risks and ASCVD-related and all-cause HCRU and costs vs DPP-4is.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Ischemic Stroke; Myocardial Infarction; Risk Factors

Including pharmacists on care teams of patients with type 2 diabetes (T2D) has been shown to promote guideline-based prescribing and improve glycemic control, lowering risks of adverse cardiovascular outcomes. Evidence is lacking regarding whether including pharmacists on the care team is associated with the prescribing of GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) recommended for use in patients with T2D and atherosclerotic cardiovascular disease (ASCVD).. To assess the association between having a pharmacist on the primary care team of patients with T2D and ASCVD and being prescribed a guideline-recommended GLP-1 RA or SGLT-2i.. A cross-sectional analysis of patients with T2D and ASCVD seen by primary care providers at an academic medical center between June 2019 and May 2020 was completed. Patients with prescriptions for GLP-1 RA or SGLT-2i with evidence of cardiovascular benefit were identified and compared between those with pharmacist care vs usual care using multivariable log-binominal regression analyses.. Of 1,497 included patients, 1,283 (85.7%) were in the usual care group (mean age 68.9 years, hemoglobin A1c 7.6%) and 214 (14.3%) in the pharmacist care group (mean age 64.5 years, A1c 9.0%). Of the pharmacist care group, 50.5% were prescribed a GLP-1 RA or SGLT-2i with cardiovascular benefit vs 17.9% in the usual care group (. These data provide preliminary evidence that integrating pharmacists into patient care teams is associated with increased prescribing of guideline-recommended treatment with GLP-1 RA and SGLT-2i in patients with T2D and ASCVD, yet there is room for improvement in prescribing these agents to patients with T2D and ASCVD.

Topics: Aged; Atherosclerosis; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Middle Aged; Pharmacists; Sodium-Glucose Transporter 2 Inhibitors

In 2020, the American Diabetes Association (ADA) Standards of Medical Care in Diabetes Guidelines newly recommended adding a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist in patients with both type 2 diabetes and atherosclerotic cardiovascular disease, regardless of hemoglobin A1c (HbA1c) levels. In this study, the primary objective was to assess the pharmacist's role in the therapeutic optimization of patients with both type 2 diabetes and atherosclerotic cardiovascular disease relative to the new recommendations. The secondary objectives were to assess other factors affecting therapeutic optimization and clinician familiarity with the recommendations. This study, conducted at the East Hawai.i Health Clinic, included 60 patients with type 2 diabetes and atherosclerotic cardiovascular disease. Anonymous surveys were sent to clinicians at the clinic to assess recommendation familiarity. Patients seen by a pharmacist were significantly more likely to be therapeutically optimized per the 2020 ADA guidelines than those not seen by a pharmacist. HbA1c and age also influenced SGLT-2/GLP-1 therapy use. All clinicians were more likely to prescribe SGLT-2/GLP-1 therapy for patients with uncontrolled HbA1c but were less likely to prescribe additional therapy for patients with controlled HbA1c, even in patients with previous atherosclerotic events.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Pharmacists; Sodium-Glucose Transporter 2 Inhibitors; United States

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Glucose; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Male; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Kidney Diseases; Practice Guidelines as Topic; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors

Kanie T, Mizuno A, Takaoka Y, et al.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

The prevalence of type 2 diabetes (T2D) in Italy is increasing and cardiovascular disease (CVD) represents the leading cause of death in this population. CAPTURE was a multinational, multicentre, non-interventional, cross-sectional study assessing the prevalence of CVD, atherosclerotic CVD (AsCVD) and CVD subtypes among patients with T2D, across 13 countries. Here we report the results from Italy.. Overall, 816 patients with T2D (median age, 69 years [interquartile range: 62-75]; median duration of diabetes, 11.2 years [interquartile range: 5.7-18.7]) were recruited during routine clinical visits at secondary care centres in Italy between December 2018-September 2019. The prevalence of CVD was estimated at 38.8%, largely accounted for by AsCVD (33.1%). The most prevalent CVD subtype was coronary heart disease (20.8%), followed by carotid artery disease (13.2%). Most patients (85.9%) were prescribed oral glucose-lowering agents (GLAs), particularly biguanide (76.7%). Insulin use was higher in patients with CVD (41.3%) than in patients without CVD (32.9%). Sodium-glucose co-transporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were prescribed to 20.2% vs 14.6%, and 14.5% vs 16.6% of patients with CVD compared to those without CVD, respectively.. The results show that, in Italy, more than one in three patients with T2D attending secondary care centres have CVD, 85% of whom have AsCVD, yet only a minority are treated with SGLT2is and GLP-1 RAs, in discordance with the recommendations of current national and international guidelines.

Topics: Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Middle Aged; Prevalence; Sodium-Glucose Transporter 2 Inhibitors

We assessed the effect of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on ischemic stroke prevention in the Asian population with type 2 diabetes (T2D) without established cardiovascular disease.. This retrospective cohort study examined data obtained from the Taiwan National Health Insurance Research Database for the period from 1998 to 2018. The follow-up ended upon the occurrence of hospitalization for ischemic stroke. The median follow-up period was 3 years. The effect of GLP-1RA exposure time on the development of hospitalization for ischemic stroke was assessed.. The GLP-1RA and non-GLP-1RA user groups both included 6,534 patients. Approximately 53% of the patients were women, and the mean age was 49 ± 12 years. The overall risk of ischemic stroke hospitalization for GLP-1RA users was not significantly lower than that for GLP-1RA nonusers (adjusted hazard ratio [HR] 0.69 [95% CI 0.47-1.00]; P = 0.0506), but GLP-1RA users with a >251-day supply during the study period had a significantly lower risk of ischemic stroke hospitalization than GLP-1RA nonusers (adjusted HR 0.28 [95% CI 0.11-0.71]). Higher cumulative dose of GLP-1 RAs (>1,784 mg) was associated with significantly lower risk of ischemic stroke hospitalization. The subgroup analyses defined by various baseline features did not reveal significant differences in the observed effect of GLP-1RAs.. Longer use and higher dose of GLP-1 RAs were associated with a decreased risk of hospitalization for ischemic stroke among Asian patients with T2D who did not have established atherosclerotic cardiovascular diseases, but who did have dyslipidemia or hypertension.

Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Ischemia; Ischemic Stroke; Male; Middle Aged; Retrospective Studies

Current guidelines for the management of hyperglycemia recommend the use of agents with proven cardiovascular (CV) benefit in patients with type 2 diabetes (T2D) and established CV disease. Although both glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of major adverse CV events (MACE) in high-risk populations with T2D, the ideal choice between the two classes for people with coronary artery disease remains controversial. SGLT2i reduce CV risk primarily through hemodynamic effects and changes in energy metabolism, making them the first choice in cases where heart failure or chronic kidney disease predominates. On the other hand, GLP-1 RA exert powerful anti-atherogenic properties that are the main drivers of their cardioprotection, and seem to have a consistent benefit in the atherosclerotic components of MACE. However, most people with diabetes and CV disease could take advantage of the complementary effects of the two drug categories on glycemic control, body weight, and diabetic complications. Future mechanistic studies and clinical head-to-head trials are expected to shed more light on this intriguing clinical dilemma and provide clear guidance for daily practice.

Topics: Animals; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Horses; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

This study used data from the Veterans Affairs administrative and clinical dataset to evaluate determinants of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among patients with concomitant atherosclerotic cardiovascular disease and diabetes mellitus and an antecedent primary care provider visit. The prevalence of GLP-1 RA use was 8.0%. In multivariable-adjusted models, White race, hypertension, obesity, higher hemoglobin A1c, ischemic heart disease, chronic kidney disease, a higher number of primary care provider visits, and previous cardiology or endocrinology visits were directly associated with GLP-1 RA use. Older age, having a physician primary care provider, and receiving care at a teaching facility were inversely associated with GLP-1 RA use. Our data can help inform targeted interventions to promote equitable access to GLP-1 RA and incentivize the adoption of these disease-modifying agents in high-risk patient populations.

Topics: Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Veterans

To investigate the budget implications of treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus other glucose-lowering treatment (here termed 'standard of care' [SoC]) during 2012-2019.. GLP-1 RA-naïve adults with type 2 diabetes (T2D) in the IBM MarketScan database with at least one glucose-lowering medication claim within 6 months after their first cardiovascular disease (CVD) hospitalization were included (index date was the date of first claim for a GLP-1 RA for the GLP-1 RA group, and the date of the first claim, independent of medication type, for the SoC group). Monthly healthcare costs and hospitalization risk over 12 months postindex date were compared for those who initiated a GLP-1 RA posthospitalization versus those with a claim for any other glucose-lowering medication.. Postindex date, mean observed total costs were lower for patients receiving a GLP-1 RA compared with SoC ($3853 vs. $4288). In adjusted analysis, both groups had similar total healthcare costs (P = .56). This was driven by significantly lower inpatient and outpatient costs and higher drug costs in the GLP-1 RA group compared with SoC (P < .001). Risks of all-cause (adjusted hazard ratio: 0.85) and CVD-related hospitalization (0.76) were significantly lower in the GLP-1 RA group compared with SoC (P < .001). Similar results were observed in a subgroup with atherosclerotic CVD.. These findings suggest that, in US patients with T2D and a CVD-related hospitalization, the added medical cost of treatment with GLP-1 RAs is offset by lower inpatient and outpatient care costs, resulting in budget neutrality against SoC.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Health Care Costs; Hospitalization; Humans; Hypoglycemic Agents; Retrospective Studies

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Uric Acid

Topics: Anti-Inflammatory Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

The availability of newer glucose-lowering drugs has created opportunities for comprehensive diabetes care. Two classes of drugs, GLP1RA (glucagon-like peptide 1 receptor agonists), and SGLT2i (sodium glucose cotransporter 2 inhibitors) have demonstrated their efficacy in glucose control as well as cardiovascular risk reduction. While both can be used together, there is an ongoing debate regarding their relative advantages and limitations. We present a clinical perspective to compare and control these two classes of drugs, and promote rational prescription in diabetes praxis.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Symporters

To report on the use of antihyperglycemic agents (AHAs) by age (i.e. <65, ≥65 years) in patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) or cardiovascular risk (CV risk) factors in the United States.. Patients with T2D and CVD (CVD cohort) or T2D and an additional CV risk factor without pre-existing CVD (CV risk cohort) were identified from 2015 to 2019 in a claims database. Patients were followed from their first observed CVD diagnosis or CV risk factor for each year they were continuously enrolled or until occurrence of a CVD diagnosis (CV risk cohort only). Classes of AHAs received were reported by year, cohort, and age group.. From 2015 to 2019, the percentage of patients <65 years on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increased (CVD: 9-17%, CV risk: 9-17%) and was approximately twice that of those ≥65 years (CVD: 4-8%, CV risk: 4-8%); the percentage of patients <65 years on sodium-glucose cotransporter-2 (SGLT2) inhibitors increased (CVD: 11-16%, CV risk: 11-17%) and was approximately triple that of those ≥65 years (CVD: 3-6%, CV risk: 4-7%).. The use of GLP-1 RAs and SGLT2 inhibitors increased during the study period; however, most patients did not receive these medications. Patients aged ≥65 years were particularly disadvantaged.

Topics: Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Risk Factors; United States

Glucagon-like peptide-1 (GLP-1) receptor agonists mimic the action of the endogenous GLP-1 incretin hormone, improving glycaemic control in type 2 diabetes mellitus (T2DM) by increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. However, as cardiovascular (CV) morbidity and mortality is common in patients with T2DM, several trials with the use of GLP-1 receptor agonists (RAs) have been performed focusing on endpoints related to cardiovascular disease rather than metabolic control of T2DM. Following the positive cardiovascular effects of liraglutide, dulaglutide and semaglutide observed in these trials, major changes in T2DM management guidelines have occurred. This document from a Eastern and Southern European Diabetes Expert Group discusses the results of GLP-1 RA CV outcomes trials, their impact on recent clinical guidelines for the management of T2DM, and some selected combination regimens utilising GLP-1 RAs. We also propose an algorithm for guiding GLP-1 RA-based treatment according to patients' characteristics, which can be easily applied in every day clinical practice.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide

GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) have shown to reduce the risk of major adverse cardiovascular events (MACE), death and worsening nephropathy when added to standard of care. However, these two dug classes differ in efficacy and safety. We compared the effectiveness and safety profile of GLP-1 RA and SGLT-2i in a large and unselected cohort of patients with type 2 diabetes resident in Lombardy from 2015 to 2020.. Using linkable administrative health databases, we included patients aged 50 years and older initiating GLP-1 RA or SGLT-2i. Clinical events were: death, hospital admission for myocardial infarction (MI), stroke, heart failure (HF), and renal disease as individual and composite outcomes (MACE-3: all cause-death, non-fatal MI, non-fatal stroke; MACE-4: MACE-3 plus unstable angina). Outcomes were evaluated separately in subjects with and without previous cardiovascular (CV) diseases. Treatments were compared using Cox proportional hazards regression model after Propensity Score Matching (PSM) in both intention-to-treat (ITT) and per protocol (PP) analyses. Serious adverse events were also evaluated.. The analysis comprised 20,762 patients per cohort. The ITT analysis showed a significant risk reduction for non-fatal MI (HR 0.77; CI 95% 0.66-0.90), MACE-3 (HR 0.91; CI 95% 0.84-0.98), and MACE-4 (HR 0.92; CI 95% 0.86-0.99) in GLP-1RA compared with SGLT-2i users, while no difference was reported in the incidence of HF hospitalization and stroke between the two cohorts. Similar benefits were found in the subgroup of patients without previous CV diseases only. PP analysis largely confirmed the main results. The incidence of serious adverse events was low in both cohorts (< 1%).. GLP-1RA showed to be equally safe and more effective than SGLT-2i in reducing the risk of MACE-3, MACE-4 and MI. This study adds to the growing body of real-world evidence addressing the specific clinical properties of GLP-1RA and SGLT-2i in everyday practice to tailor treatment to the individual patient.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors; Stroke

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents

Guidelines from 2016 onwards recommend early use of SGLT2i or GLP-1 RA for patients with type 2 diabetes (T2D) and cardiovascular disease (CVD), to reduce CV events and mortality. Many eligible patients are not treated accordingly, although data are lacking for Central and Eastern Europe (CEE).. The CORDIALLY non-interventional study evaluated the real-world characteristics, modern antidiabetic treatment patterns, and the prevalence of CVD and chronic kidney disease (CKD) in adults with T2D at nonhospital-based practices in CEE. Data were retrospectively collated by medical chart review for patients initiating empagliflozin, another SGLT2i, DPP4i, or GLP-1 RA in autumn 2018. All data were analysed cross-sectionally, except for discontinuations assessed 1 year ± 2 months after initiation.. Patients (N = 4055) were enrolled by diabetologists (56.7%), endocrinologists (40.7%), or cardiologists (2.5%). Empagliflozin (48.5%) was the most prescribed medication among SGLT2i, DPP4i, and GLP-1 RA; > 3 times more patients were prescribed empagliflozin than other SGLT2i (10 times more by cardiologists). Overall, 36.6% of patients had diagnosed CVD. Despite guidelines recommending SGLT2i or GLP-1 RA, 26.8% of patients with CVD received DPP4i. Patients initiating DPP4i were older (mean 66.4 years) than with SGLT2i (62.4 years) or GLP-1 RA (58.3 years). CKD prevalence differed by physician assessment (14.5%) or based on eGFR and UACR (27.9%). Many patients with CKD (≥ 41%) received DPP4i, despite guidelines recommending SGLT2is owing to their renal benefits. 1 year ± 2-months after initiation, 10.0% (7.9-12.3%) of patients had discontinued study medication: 23.7-45.0% due to 'financial burden of co-payment', 0-1.9% due to adverse events (no patients discontinued DPP4i due to adverse events). Treatment guidelines were 'highly relevant' for a greater proportion of cardiologists (79.4%) and endocrinologists (72.9%) than diabetologists (56.9%), and ≤ 20% of physicians consulted other physicians when choosing and discontinuing treatments.. In CORDIALLY, significant proportions of patients with T2D and CVD/CKD who initiated modern antidiabetic medication in CEE in autumn 2018 were not treated with cardioprotective T2D medications. Use of DPP4i instead of SGLT2i or GLP-1 RA may be related to lack of affordable access, the perceived safety of these medications, lack of adherence to the latest treatment guidelines, and lack of collaboration between physicians. Thus, many patients with T2D and comorbidities may develop preventable complications or die prematurely. Trial registration NCT03807440.

Topics: Adult; Benzhydryl Compounds; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucosides; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors

Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.

Topics: Adipose Tissue; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metabolic Diseases; Sodium-Glucose Transporter 2 Inhibitors

Topics: Cardiovascular Diseases; Diabetes Mellitus; Expert Testimony; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Poland

Randomized clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause significant weight loss and reduce cardiovascular events in patients with type 2 diabetes (T2D). Black patients have a disproportionate burden of obesity and cardiovascular disease and have a higher rate of cardiovascular-related mortality. Racial and ethnic disparities in health outcomes are largely attributable to the pervasiveness of structural racism, and patients who are marginalized by racism have less access to novel therapeutics.. To evaluate GLP-1 RA uptake among a commercially insured population of patients with T2D; identify associations of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use; and specifically examine its use among the subgroup of patients with atherosclerotic cardiovascular disease (ASCVD) because of the known benefit of GLP-1 RA use for this population.. This was a retrospective cohort analysis using data from OptumInsight Clinformatics Data Mart of commercially insured adult patients with T2D (with or without ASCVD) in the US. Data from October 1, 2015, to June 31, 2019, were included, and the analyses were performed in July 2020. We estimated multivariable logistic regression models to identify the association of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use.. A prescription for a GLP-1 RA.. Of the 1 180 260 patients with T2D (median [IQR] age, 69 [59-76] years; 50.3% female; 57.7% White), 90 934 (7.7%) were treated with GLP-1 RA during the study period. From 2015 to 2019, the percentage of T2D patients treated with an GLP-1 RA increased from 3.2% to 10.7%. Among patients with T2D and ASCVD, use also increased but remained low (2.8%-9.4%). In multivariable analyses, lower rates of GLP-1 RA use were found among Asian (aOR, 0.59; 95% CI, 0.56-0.62), Black (adjusted odds ratio [aOR] 0.81; 95% CI, 0.79-0.83), and Hispanic (aOR, 0.91; 95% CI, 0.88-0.93) patients with T2D. Female sex (aOR, 1.22; 95% CI, 1.20-1.24) and higher zip code-linked median household incomes (>$100 000 [OR, 1.13; 95% CI, 1.11-1.16] and $50 000-$99 999 [OR, 1.07; 95% CI, 1.05-1.09] vs <$50 000) were associated with higher GLP-1 RA use. These results were similar to those found among patients with ASCVD.. In this cohort study of US patients with T2D, GLP-1 RA use increased, but remained low overall for treatment of T2D, particularly among patients with ASCVD who are likely to derive the most benefit. Asian, Black, and Hispanic patients and those with low income were less likely to receive treatment with a GLP-1 RA. Strategies to lower barriers to GLP-1 RA use, such as lower cost, are needed to prevent the widening of well-documented inequities in cardiovascular disease outcomes in the US.

Topics: Adult; Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Ethnicity; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Retrospective Studies; Socioeconomic Factors

Fralick M, Kim SC, Schneeweiss S, et al.

Topics: Aged; Amputation, Surgical; Canagliflozin; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Retrospective Studies; Risk Factors

Diabetes mellitus remains one of the most common and disabling diseases in the world. Patients with diabetes tend to have more cardiovascular complications, regardless of their prior cardiac history. Tight glycemic control has been shown to prevent microvascular complications as it relates to nephropathy and retinopathy; however, it hasn't been proven beneficial in patients with macrovascular diseases, i.e., cardiovascular disease. In fact, two groups of diabetic medications, dual peroxisome-proliferator-activated receptor - agonists and sulfonylurea, are known to worsen cardiovascular disease. Patients using this group of medications have shown increased heart failure readmission rates and increased risk for cardiovascular death. Insulin and Metformin have been the gold standard treatment for diabetes management to prevent worsening cardiac outcomes, and now a newer class of medications have demonstrated similar results. These drug classes includes sodium glucose cotransporter 2(SGLT 2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon like peptide-1 (GLP 1) analogues.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors

Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction.. In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients.. In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.

Topics: Biomarkers; Cardiovascular Diseases; Glucagon-Like Peptide 1; Heart Disease Risk Factors; Humans; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Risk Factors

Topics: Biomarkers; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Myocardial Infarction; Risk Factors

Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk.. GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD.. In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10. In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

Topics: Adult; Aged; Cardiovascular Diseases; Female; Gastric Inhibitory Polypeptide; Genotype; Glucagon-Like Peptide 1; Glucose; Humans; Male; Middle Aged; Prospective Studies; Receptors, Gastrointestinal Hormone

The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting.. Cox regression models were constructed to analyze 20 years of data from the Danish National Patient Registry with respect to effect of the antihyperglycemic therapies on the three end points.. A total of 66,807 people with type 2 diabetes were treated with metformin (MET) plus a combination of second- and third-line therapies. People on MET plus sulfonylurea (SU) had the highest risk of all end points, except for severe hypoglycemia, for which people on MET plus basal insulin (BASAL) had a higher risk. The lowest risk of major adverse cardiovascular events was seen for people on a regimen including a glucagon-like peptide 1 (GLP-1) receptor agonist. People treated with MET, GLP-1, and BASAL had a lower risk of all three end points than people treated with MET and BASAL, especially for severe hypoglycemia. The lowest risk of all three end points was, in general, seen for people treated with MET, sodium-glucose cotransporter 2 inhibitor, and GLP-1.. Findings from this study do not support SU as the second-line treatment choice for patients with type 2 diabetes. Moreover, the results indicate that adding a GLP-1 in people treated with MET and BASAL could be considered, especially if those people suffer from severe hypoglycemia.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Registries; Risk Factors; Severity of Illness Index; Sulfonylurea Compounds; Treatment Outcome

Molecular mechanism underlying glucagon-like peptide-1 exertion of cardioprotective effects in glucagon-like peptide-1 receptor-dependent and -independent manners. Glucagon-like peptide-1 (28-36a) enters coronary artery endothelial cells through macropinocytosis and binds to mitochondrial trifunctional protein-α, shifting substrate utilization to increase adenosine triphosphate production and modulating a adenosine triphosphate-sensor soluble adenylyl cyclase, thereby producing cyclic adenosine monophosphate and activating protein kinase A to exert cytoprotection from oxidative injury.

Topics: Adenosine Triphosphate; Cardiotonic Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peptide Fragments; Prognosis; Signal Transduction

To estimate the rate of lower limb amputation among adults newly prescribed canagliflozin according to age and cardiovascular disease.. Population based, new user, cohort study.. Two commercial and Medicare claims databases, 2013-17.. Patients newly prescribed canagliflozin were propensity score matched 1:1 with patients newly prescribed a glucagon-like peptide-1 (GLP-1) receptor agonist. Hazard ratios and rate differences per 1000 person years were computed for the rate of lower limb amputation in the following four groups: group 1, patients aged less than 65 years without baseline cardiovascular disease; group 2, patients aged less than 65 with baseline cardiovascular disease; group 3, patients aged 65 or older without baseline cardiovascular disease; group 4, patients aged 65 or older with baseline cardiovascular disease. Within each group, pooled hazard ratio and rate difference per 1000 person years were calculated by meta-analysis.. Canagliflozin versus a GLP-1 agonist.. Lower limb amputation requiring surgery.. Across the three databases, 310 840 propensity score matched adults who started canagliflozin or a GLP-1 agonist were identified. The hazard ratio and rate difference per 1000 person years for amputation in adults receiving canagliflozin compared with a GLP-1 agonist for each group was: group 1, hazard ratio 1.09 (95% confidence interval 0.83 to 1.43), rate difference 0.12 (-0.31 to 0.55); group 2, hazard ratio 1.18 (0.86 to 1.62), rate difference 1.06 (-1.77 to 3.89); group 3, hazard ratio 1.30 (0.52 to 3.26), rate difference 0.47 (-0.73 to 1.67); and group 4, hazard ratio 1.73 (1.30 to 2.29), rate difference 3.66 (1.74 to 5.59).. The increase in rate of amputation with canagliflozin was small and most apparent on an absolute scale for adults aged 65 or older with baseline cardiovascular disease, resulting in a number needed to treat for an additional harmful outcome of 556 patients at six months (that is, 18 more amputations per 10 000 people who received canagliflozin). These results help to contextualize the risk of amputation with canagliflozin in routine care.

Topics: Age Distribution; Aged; Amputation, Surgical; Canagliflozin; Cardiovascular Diseases; Cardiovascular System; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Longitudinal Studies; Male; Middle Aged; Propensity Score; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; United States

Topics: Cardiology; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Metformin; Prediabetic State; Scotland; Sodium

Cardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.. This cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m. A greater GLP-1 response was associated with lower central systolic and diastolic BP of - 1.17 mmHg (95% confidence interval (CI) - 2.07 to - 0.27 mmHg, P = 0.011) and - 0.74 mmHg (95% CI - 1.29 to - 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of - 1.27 mmHg (95% CI - 2.20 to - 0.33 mmHg, P = 0.008) and - 1.00 (95% CI - 1.56 to - 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: - 4.94 (95% CI - 8.56 to - 1.31) mmHg, central diastolic BP: - 3.05 (95% CI - 5.29 to - 0.80) mmHg, brachial systolic BP: - 5.18 (95% CI - 8.94 to - 1.42) mmHg, and brachial diastolic BP: - 2.96 (95% CI - 5.26 to - 0.67) mmHg).. Greater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality. Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005.

Topics: Aged; Biomarkers; Blood Pressure; Brachial Artery; Cardiovascular Diseases; Cross-Sectional Studies; Denmark; Diabetes Mellitus; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Male; Middle Aged; Pulse Wave Analysis; Risk Assessment; Risk Factors; Vascular Stiffness

The biochemical response to food intake must be precisely regulated. Because ingested sugars and fats can feed into many anabolic and catabolic pathways

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Disease Models, Animal; Disease Progression; Eating; Enterocytes; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Integrin beta Chains; Intestine, Small; Intraepithelial Lymphocytes; Male; Metabolic Syndrome; Mice

Glucagon-like peptide-1 (GLP-1) is an enteroendocrine hormone that controls insulin secretion, intestinal function, and food intake. Recently in Nature, He et al. (2019) reported that gut intraepithelial T cells regulate GLP-1 bioavailability by capturing it on GLP-1 receptors and impacting L-cell numbers. This study delineates a novel endocrine-immune axis through which intestinal immune cells regulate whole-body metabolism.

Topics: Cardiovascular Diseases; Enteroendocrine Cells; Glucagon-Like Peptide 1; Humans; Intestines; Intraepithelial Lymphocytes; Male

Topics: Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Intraepithelial Lymphocytes

Previous research overstated the generalizability of the Exenatide Study of Cardiovascular Event Lowering trial results by omitting the restriction on the percentage of patients without a prior cardiovascular event.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment.. To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD.. Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.. Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.. Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Biomarkers; Body Weight; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Inflammation; Liver; Male; Middle Aged; Multicenter Studies as Topic; Non-alcoholic Fatty Liver Disease; Obesity; Randomized Controlled Trials as Topic; Retrospective Studies; Weight Reduction Programs; Young Adult

Metabolic syndrome increases the risk of cardiovascular disease. Recently glucagon-like peptide 1 (GLP-1) agonists proved to be effective in preventing cardiovascular disease (CVD) in patients with type 2 diabetes. We investigated the association of blood incretin levels with metabolic syndrome in patients with type 2 diabetes.. This is a cross-sectional study involving 334 people with type 2 diabetes. Intact GLP-1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 min after ingestion of a standard mixed meal. Metabolic syndrome was diagnosed based on the criteria of the International Diabetes Federation.. Two hundred twenty-five (69%) of the subjects have metabolic syndrome. The fasting iGLP-1 level was no different between groups. Thirty-min postprandial iGLP-1 was non-significantly lower in the subjects who had metabolic syndrome. Incremental iGLP-1 (ΔiGLP-1, the difference between 30-min postmeal and fasting iGLP-1 levels) was significantly lower in those with metabolic syndrome. There were no significant differences in fasting iGIP, postprandial iGIP, and ΔiGIP between groups. The ΔiGLP-1, but not ΔiGIP levels decreased significantly as the number of metabolic syndrome components increased. In hierarchical logistic regression analysis, the ΔiGLP-1 level was found to be a significant contributor to metabolic syndrome even after adjusting for other covariates.. Taken together, the iGLP-1 increment in the 30 min after meal ingestion is inversely associated with metabolic syndrome in patients with type 2 diabetes. This suggests that postmeal iGLP-1 increment could be useful in assessing cardiovascular risk in type 2 diabetes.

Topics: Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Male; Metabolic Syndrome; Middle Aged; Postprandial Period; Risk

Combining a GLP-1 receptor agonist (GLP-1RA) with insulin is often an effective treatment strategy for overweight patients with type 2 diabetes (T2D), but little is known about the longer-term effects on cardiovascular and mortality outcomes in routine clinical practice in the United Kingdom. We therefore compared the times to a major nonfatal cardiovascular (CV) event and all-cause mortality among overweight patients with T2D treated with insulin alone versus insulin+GLP-1RA in a large UK database.. A retrospective cohort study was conducted in 18,227 patients with insulin-treated T2D from UK General Practices using The Health Improvement Network database. The 5-year risk of mortality and a 3-point composite of all-cause mortality and nonfatal CV outcomes (myocardial infarction or stroke) was compared between a propensity score-matched cohort of those on insulin alone (n=1,793) and insulin+GLP-1RA (n=1,793), irrespective of other diabetes therapies, providing a total of 12,682 person-years of follow-up. Cox proportional hazard models were used to estimate the hazard ratios of the outcomes.. Hemoglobin A1c reduction was similar between both groups (-0.42 vs -0.33%, P=.089 at 12 months). Overall, 3-point composite events of all-cause mortality and CV events (major adverse cardiovascular even) were 98 versus 55 for the insulin alone versus insulin+GLP-1RA groups, respectively (14.7 vs 9.2 per 1,000 person-years; adjusted hazard ratio [aHR]: 0.64; 95% CI: 0.42-0.98; P=.038). Corresponding composite nonfatal CV events were 33 versus 28 (6.0 vs 5.6 per 1,000 person-years; aHR: 0.76; 95% CI: 0.41-1.42; P=.393), whereas all-cause mortality events were 49 versus 13 (6.9 vs 2.0 per 1,000 person-years; aHR: 0.35; 95% CI: 0.17-0.73; P=.005).. Based on a large UK cohort in routine clinical practice, adding a GLP-1RA to insulin therapy is associated with a reduction in risk of composite CV events and all-cause mortality but a nonsignificant higher risk of hospitalization for heart failure in overweight patients with T2D.

Topics: Adult; Aged; Body Mass Index; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Overweight; Propensity Score; Proportional Hazards Models; Retrospective Studies; Severity of Illness Index; Survival Analysis; United Kingdom

Topics: Anti-Inflammatory Agents; Cardiovascular Diseases; Diabetes Mellitus; Fibrinolytic Agents; Glucagon-Like Peptide 1; Humans; Hyperlipidemias; Inflammation; PCSK9 Inhibitors; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Thrombosis

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Glucagon-Like Peptide 1; Humans

Understanding cardiovascular outcomes of initiating second-line antidiabetic medications (ADMs) may help inform treatment decisions after metformin alone is not sufficient or not tolerated. To date, no studies have compared the cardiovascular effects of all major second-line ADMs during this early decision point in the pharmacologic management of type 2 diabetes.. To examine the association of second-line ADM classes with major adverse cardiovascular events.. Retrospective cohort study among 132 737 insured adults with type 2 diabetes who started therapy with a second-line ADM after taking either metformin alone or no prior ADM. This study used 2011-2015 US nationwide administrative claims data. Data analysis was performed from January 2017 to October 2018.. Dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, thiazolidinediones (TZDs), basal insulin, and sulfonylureas or meglitinides (both referred to as sulfonylureas hereafter). The DPP-4 inhibitors served as the comparison group in all analyses.. The primary outcome was time to first cardiovascular event after starting the second-line ADM. This composite outcome was based on hospitalization for the following cardiovascular conditions: congestive heart failure, stroke, ischemic heart disease, or peripheral artery disease.. Among 132 737 insured adult patients with type 2 diabetes (men, 55%; aged 45-64 years, 58%; white, 63%), there were 3480 incident cardiovascular events during 169 384 person-years of follow-up. Patients were censored after the first cardiovascular event, discontinuation of insurance coverage, transition from International Classification of Diseases, Ninth Revision (ICD-9) to end of ICD-9 coding, or 2 years of follow-up. After adjusting for patient, prescriber, and health plan characteristics, the risk of composite cardiovascular events after starting GLP-1 receptor agonists was lower than DPP-4 inhibitors (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96), but this finding was not significant in all sensitivity analyses. Cardiovascular event rates after starting treatment with SGLT-2 inhibitors (HR, 0.81; 95% CI, 0.57-1.53) and TZDs (HR, 0.92; 95% CI, 0.76-1.11) were not statistically different from DPP-4 inhibitors. The comparative risk of cardiovascular events was higher after starting treatment with sulfonylureas (HR, 1.36; 95% CI, 1.23-1.49) or basal insulin (HR, 2.03; 95% CI, 1.81-2.27) than DPP-4 inhibitors.. Among insured adult patients with type 2 diabetes initiating second-line ADM therapy, the short-term cardiovascular outcomes of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors were similar. Higher cardiovascular risk was associated with use of sulfonylureas or basal insulin compared with newer ADM classes. Clinicians may consider prescribing GLP-1 receptor agonists, SGLT-2 inhibitors, or DPP-4 inhibitors more routinely after metformin rather than sulfonylureas or basal insulin.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Middle Aged; Retrospective Studies; Risk Factors; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

The glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting.. We conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015. Patients with T2DM exposed to GLP1a (n=8345) were compared to age, gender, body mass index, duration of T2DM and smoking status-matched patients with T2DM unexposed to GLP1a (n=16,541).. Patients with diabetes receiving GLP1a were significantly less likely to die from any cause compared to matched control patients with diabetes (adjusted incidence rate ratio [aIRR]: 0.64, 95% CI: 0.56-0.74, P-value<0.0001). Similar findings were observed in low-risk patients (aIRR: 0.64, 95% CI: 0.53-0.76, P -value=0.0001). No significant difference in the risk of incident CVD was detected in the low-risk patients (aIRR: 0.93, 95% CI: 0.83-1.12). Subgroup analyses suggested that effect is persistent in the elderly or across glycated haemoglobin categories.. GLP1a treatment in a real-world setting may confer additional mortality benefit in patients with T2DM irrespective of their baseline CVD risk, age or baseline glycated haemoglobin and was sustained over the observation period.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Retrospective Studies

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Liraglutide; Neoplasms; Randomized Controlled Trials as Topic

Topics: Adaptive Immunity; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Postprandial Period; Risk Factors

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents

Topics: Adaptive Immunity; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Postprandial Period; Risk Factors

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide

Preventing type 2 diabetes in a real-world setting remains challenging. The present study aimed to assess the effectiveness of a lifestyle-based programme for individuals at high risk of developing type 2 diabetes as assessed by achieved weight loss, cardiovascular risk factors and glucagon-like peptide-1 (GLP-1).. Sixty-six obese individuals with history of diabetes in first-degree relatives participated in an 8-month lifestyle programme consisting of 12 × 1.25 h group education sessions led by dietitian and a weekly exercise programme. Before and after comparisons were made of fasting blood glucose, insulin, HbA1c, lipids, GLP-1 and quality of life (QoL).. Fifty-four participants of whom the majority were women [47 females; mean (SD) body mass index 35.3 (2.8) kg m. An evidence-based lifestyle programme achieved sustained weight loss in obese first-degree relatives of individuals with type 2 diabetes associated with improvements in cardiometabolic risk factors and QoL without the 'voltage drop' of less benefit commonly seen when moving from the clinical trial experience into the real world.

Topics: Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Life Style; Middle Aged; Non-Randomized Controlled Trials as Topic; Obesity; Quality of Life; Risk Factors; Weight Loss; Young Adult

Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes.. Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation.. Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis.. Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes.

Topics: Albuminuria; Animals; Apoptosis; Cardiomegaly; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Forkhead Box Protein O3; Forkhead Transcription Factors; Glucagon-Like Peptide 1; Glycated Hemoglobin; Immunohistochemistry; Kidney; Male; Mice; NADPH Oxidases; Piperidones; Podocytes; Proto-Oncogene Proteins c-akt; Pyrimidines; Ventricular Dysfunction

Cardiovascular disease is a major threat to people with diabetes. Attempts have long been made to lower cardiovascular risk by means of glucose-lowering treatment. Initially, it seemed that was an option, but subsequent trials could not verify the original observations and there was concern that some glucose-lowering drugs can actually cause cardiovascular harm. This led medical product agencies in the United States and Europe to require major outcomes trials before accepting new glucose-lowering drugs. The least requirement was noninferiority compared with existing treatment modalities. A large number of such trials have been performed or are ongoing, including >100,000 patients. The drug classes investigated are basal insulin, glucagon-like peptide-1 agonists, dipeptidyl peptidase 4 inhibitors, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. This commentary discusses these trials and their outcomes, the reasons why several of them ended with neutral results (noninferiority), and that the likelihood for showing cardiovascular benefit was minor or even nonexistent. The surprising and highly rewarding impact of the SGLT2 inhibitor empagliflozin is described and potential mechanisms for cardiovascular benefits are discussed.

Topics: Benzhydryl Compounds; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucosides; Humans; Hypoglycemic Agents; Insulin; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU).. A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed.. Mean age was 52.8±14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p<0.0001). Insulin was associated with significant increase in weight compared with GLP-1ar (1.78 vs -3.93 kg; p<0.0001) but haemoglobin A1c reduction was similar between both treatment groups (-1.29 vs -0.98; p=0.156). In a subgroup analysis of obese patients (body mass index >30 kg/m(2)) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively.. In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cause of Death; Databases, Factual; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Kaplan-Meier Estimate; Male; Metformin; Middle Aged; Obesity; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Sulfonylurea Compounds; Time Factors; Treatment Outcome; United Kingdom

To investigate the relative safety of various glucose-lowering agents as add-on medication to metformin in type 2 diabetes in an observational study linking five national health registers.. Patients with type 2 diabetes who had been on metformin monotherapy and started another agent in addition to metformin were eligible for inclusion. The study period was 2005-2012. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality, cardiovascular disease (CVD), coronary heart disease (CHD), stroke and congestive heart failure (CHF) were estimated using Cox proportional hazards models, weighted for a propensity score.. Of the 20 422 patients included in the study, 43% started on second-line treatment with sulphonylurea (SU), 21% basal insulin, 12% thiazolidinedione (TZD), 11% meglitinide, 10% dipeptidyl peptidase-4 (DPP-4) inhibitor, 1% glucagon-like peptide-1 (GLP-1) receptor agonist and 1% acarbose. At the index date, the mean patient age was ~60 years for all groups except the GLP-1 receptor agonist (56.0 years) and SU (62.9 years) groups. Diabetes duration and glycated haemoglobin levels were similar in all groups. When compared with SU, basal insulin was associated with an 18% higher risk and TZD with a 24% lower risk of mortality [HR 1.18 (95% CI 1.03-1.36) and 0.76 (95% CI 0.62-0.94)], respectively. DPP-4 inhibitor treatment was associated with significantly lower risks of CVD, fatal CVD, CHD, fatal CHD and CHF.. This nationwide observational study showed that second-line treatment with TZD and DPP-4 inhibitor as add-on medication to metformin were associated with significantly lower risks of mortality and cardiovascular events compared with SU, whereas basal insulin was associated with a higher risk of mortality.

Topics: Aged; Blood Glucose; Cardiotoxicity; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Registries; Sulfonylurea Compounds; Sweden; Thiazolidinediones; Treatment Outcome

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin, Short-Acting; Research Personnel; Risk Factors; Sugars

Topics: Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin, Short-Acting; Research Personnel; Risk Factors; Sugars

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans

Role of GLP-1 variants on basal GLP-1 levels, body weight and cardiovascular risk factors remains unclear in patients with diabetes mellitus type 2.. Our aim was to analyze the effects of rs6923761 GLP-1 receptor polymorphism on body weight, cardiovascular risk factors, basal GLP-1 levels and serum adipokine levels in naïve patients with diabetes mellitus type 2.. A sample of 104 naïve patients with diabetes mellitus type 2 was enrolled in a prospective way. Basal fasting glucose, c-reactive protein (CRP), insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides concentration, basal GLP-1, HbA1c and adipokines (leptin, adiponectin, resistin) levels were determined. Weights, body mass index, waist circumference, fat mass by bioimpedance and blood pressure measures were measured.. Forty-nine patients (47.1%) had the genotype GG and 55 (52.9%) diabetic subjects had the next genotypes; GA (44 patients, 42.3%) or AA (11 study subjects, 10.6%) (second group). In A allele carriers, basal GLP-1 levels were higher than non-carriers (2.9 ± 2.1 ng/ml; p < 0.05). No differences were detected between both genotype groups.. Our cross-sectional study revealed an association between the rs6923761 GLP-1 receptor polymorphism (A allele carriers) and basal GLP-1 levels in naïve patients with diabetes mellitus type 2.

Topics: Adipokines; Adult; Aged; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Genetic Variation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Middle Aged; Prospective Studies; Risk Factors

Several new medicines are in development for the treatment of type 2 diabetes, and cardiovascular outcome trials are the gold standard for these medicines. This editorial demonstrates that despite being available for over 10 years, there are no cardiovascular outcome studies for any of the glucagon-like peptide-1 receptor agonists, which demonstrate cardiovascular safety or benefit in subjects with high cardiovascular risk. The author argues that the FDA should be ensuring that clinical outcome studies for subjects with type 2 diabetes and high cardiovascular risk be undertaken in a timelier manner.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Risk; Time Factors

A polymorphism (1359 G/A) of the cannabinoid receptor 1 (CNR1) gene was reported as a common polymorphism (rs1049353) with potential implications in weight loss. We decide to investigate the role of this polymorphism on metabolic changes and weight loss secondary to treatment with liraglutide.. A population of 86 patients with diabetes mellitus type 2 and obesity, unable to achieve glycemic control (hemoglobine glycate A1c >7%) with metformin alone or associated to sulfonylurea, who require initiation of liraglutide treatment in progressive dose to 1.8 mg/d subcutaneously, was analyzed.. Fifty-one patients (59.3%) had the genotype G1359G, and 35 patients (40.7%) had G1359A (28 patients, 32.6%) or A1359A (7 patients, 8.1%) (A allele carriers). In patients with both genotypes, basal glucose, HbA1c, body mass index, weight, fat mass, waist circumference, and systolic blood pressures decreased. In patients with G1359G genotype, total cholesterol and low-density lipoprotein cholesterol decreased, and in patients with A allele, homeostasis model assessment for insulin resistance decreased, too.. There is an association of the A allele with an improvement of insulin resistance secondary to weight loss after liraglutide treatment in obese patients with diabetes mellitus type 2. Noncarriers of A allele showed an improvement in cholesterol levels after weight loss.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Genetic Variation; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Prospective Studies; Receptor, Cannabinoid, CB1; Risk Factors; Treatment Outcome; Weight Loss

To evaluate the effects of liraglutide after 14 weeks of treatment on serum adipokines, insulin resistance index and cardiovascular risk biomarkers in overweight or obese T2DM patients unable to achieve glycemic control with metformin alone or in association with a sulfonylurea in daily clinical practice.. Prospective study in 59 consecutive overweight or obese (BMI≥25kg/m(2)) T2DM patients unable to achieve glycemic control (HbA1c>7%, 53mmol/mol) with metformin alone or in association with sulfonylurea that require initiation of liraglutide in progressive dose increase up to 1.8mg/day subcutaneously. Weight, body composition, blood pressure, glucose, HbA1c, C-peptide, insulin, plasma lipids, adipokines (leptin, adiponectin, resistin and visfatin) as well as cardiovascular biomarkers (IL-6 and TNF-a) levels were measured fasting at baseline and 14 weeks after liraglutide initiation.. 14 weeks of liraglutide treatment significantly reduced HbA1c, BMI and total body fat mass by 0.9%, 1.4kg/m(2) and 0.5% respectively. Statistically significant lower insulin resistance and higher insulin secretion was found by HOMA-IR 8.4 (1.6) vs 4.6 (0.9)molmIU/L(2) and HOMA-B 48.2 (9.0) vs 87.6 (16.3)μIU/mmol. Statistically significantly higher levels of visfatin 6.3 (2.1) vs 6.8 (2.1)ng/ml and resistin 3.6 (2.0) vs 4.3 (2.3)ng/ml were also observed after treatment. Baseline visfatin was negatively correlated with basal fasting plasma glucose r=-0.360 (p<0.05).. Liraglutide treatment for 14 weeks in daily clinical practice led to reduction of BMI and improvement of glucose control and insulin sensitivity and resistance parameters. Additionally, circulating levels of adipokines and pro-inflammatory factors could play an important role in GLP-1 treatment response.

Topics: Adipokines; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Male; Middle Aged; Obesity; Prospective Studies; Risk Factors

The covariate-balancing propensity score (CBPS) extends logistic regression to simultaneously optimize covariate balance and treatment prediction. Although the CBPS has been shown to perform well in certain settings, its performance has not been evaluated in settings specific to pharmacoepidemiology and large database research. In this study, we use both simulations and empirical data to compare the performance of the CBPS with logistic regression and boosted classification and regression trees. We simulated various degrees of model misspecification to evaluate the robustness of each propensity score (PS) estimation method. We then applied these methods to compare the effect of initiating glucagonlike peptide-1 agonists versus sulfonylureas on cardiovascular events and all-cause mortality in the US Medicare population in 2007-2009. In simulations, the CBPS was generally more robust in terms of balancing covariates and reducing bias compared with misspecified logistic PS models and boosted classification and regression trees. All PS estimation methods performed similarly in the empirical example. For settings common to pharmacoepidemiology, logistic regression with balance checks to assess model specification is a valid method for PS estimation, but it can require refitting multiple models until covariate balance is achieved. The CBPS is a promising method to improve the robustness of PS models.

Topics: Bias; Cardiovascular Diseases; Comorbidity; Computer Simulation; Confounding Factors, Epidemiologic; Diabetes Mellitus; Glucagon-Like Peptide 1; Humans; Likelihood Functions; Logistic Models; Pharmacoepidemiology; Propensity Score; Sulfonylurea Compounds

The wide ubiquity of GLP-1 receptors in the body has stimulated the search for different extrapancreatic actions of GLP-1 and its receptor agonists. Thus, severe cardioprotective effects directed on myocardial ischaemia and dysfunction as well as diverse antiaterogenic actions have been reported. Also, native and GLP-1 receptor agonists have demonstrated significant beneficial effects on liver steatosis and fibrosis and on neuronal protection in experimental models of Alzheimer, and Parkinson's disease as well as on cerebral ischaemia. Recent evidences suggest that these drugs may also be useful for prevention and treatment of diabetic retinopathy, nephropathy and peripheral neuropathy. Good results have also been reported in psoriasis. Despite we still need confirmation that these promising effects can be applied to clinical practice, they offer new interesting perspectives for treatment of type 2 diabetes associated complications and give to GLP-1 receptor agonists an even more integral position in diabetes therapy.

Topics: Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Cardiotonic Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Models, Animal; Endothelium, Vascular; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin Resistance; Kidney Diseases; Lipid Metabolism; Liver Diseases; Multicenter Studies as Topic; Nervous System Diseases; Neuroprotective Agents; Organ Specificity; Receptors, Glucagon; Recombinant Proteins

The rising adoption of liraglutide in clinical practice calls for an update on its long-term effectiveness and safety. The aims of this paper were to review characteristics of patients treated with liraglutide under routine clinical practice conditions, to describe therapeutic schemes, to assess the durability of liraglutide after two years of therapy, to evaluate changes in clinical parameters obtained after 20-24 months and to identify elective phenotype of patients that are able to respond better to this treatment.. One diabetes outpatient clinic in Italy systematically collected data of patients receiving liraglutide every four months during a two-year follow-up. Mean levels and changes vs. baseline of HbA1c, fasting blood glucose (FBG), body weight, body mass index, waist circumference, blood pressure and lipid profile were evaluated. Rate of treatment discontinuation and side effects were also investigated.. Overall, 205 patients were analyzed. Liraglutide was prescribed as an add-on drug in 39% of patients and as a replacement in 61%. It was used both in patients with short (21% ≤5 years) and long (32% >15 years) diabetes duration and both in obese and non-obese individuals (38% BMI≤30 Kg/m2). Liraglutide was used within many different therapeutic schemes, also including insulin (20%). On average, HbA1c levels were reduced of 1% vs. baseline at each visit, but magnitude of reduction was inversely related to diabetes duration, i.e., to the preservation of beta-cell function. However, clinically relevant improvements of glycaemic control were obtained and sustained during two years in all subgroups of patients, despite of classes of diabetes duration, BMI and antidiabetic therapeutic regimen. Durability of effectiveness on body weight and waist circumference was also documented. Liraglutide treatment was also associated with a reduction of systolic blood pressure and improvement of lipid profile. Side effects, that occurred in 20% of patients during the first four months of treatment, decreased at 2% at 20 months. The rate of drop-out was 16.1% of the patients treated.. The analysis of our clinical practice shows that treatment with liraglutide was safe, well tolerated and effective in reducing HbA1c, fasting blood glucose and body weight significantly, with positive effects on systolic blood pressure and lipid profile. Therefore, results of LEAD studies are substantially reproduced in the context of routine clinical practice. Even if the maximum effectiveness of liraglutide occurs in patients with short disease duration, preferably treated with metformin, also in patients with long duration of disease, treated with several drugs or in insulin therapy, the use of this GLP-1 analogue allows to obtain more than satisfactory results. Improvements in metabolic control and body weight are maintained after two years, suggesting durability and safety of liraglutide in the long run.

Topics: Aged; Ambulatory Care Facilities; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Liraglutide; Male; Middle Aged; Obesity; Retrospective Studies; Risk Factors; Treatment Outcome; Triglycerides; Waist Circumference

Topics: Benzhydryl Compounds; Blood Pressure; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucosides; Humans; Hyperlipidemias; Hypoglycemic Agents; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Glucagon-like peptide (GLP)-1 action involves both endocrine and neural pathways to control peripheral tissues. In diabetes the impairment of either pathway may define different subsets of patients: some may be better treated with GLP-1 receptor agonists that are more likely to directly stimulate beta-cells and extrapancreatic receptors, while others may benefit from dipeptidyl peptidase (DPP)-4 inhibitor treatments that are more likely to increase the neural gut-brain-pancreas axis. Elevated plasma concentrations of GLP-1 associated with agonist treatment or bariatric surgery also appear to exert neuroprotective effects, ameliorate postprandial and fasting lipids, improve heart physiology and protect against heart failure, thereby expanding the possible positioning of GLP-1-based therapies. However, the mechanisms behind GLP-1 secretion, the role played by proximal and distal intestinal GLP-1-producing cells as well as the molecular basis of GLP-1 resistance in diabetes are still to be ascertained. The pharmacological features distinguishing GLP-1 receptor agonists from DPP-4 inhibitors are discussed here to address their respective positions in type 2 diabetes.

Topics: Bariatric Surgery; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Female; Glucagon-Like Peptide 1; Humans; Incretins; Lipids; Male

Topics: alpha-Linolenic Acid; Cardiovascular Agents; Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans

Obesity and dyslipidemia often coexist in patients with type 2 diabetes and contribute to increase the risk of cardiovascular events. Pharmacological treatments of diabetes often result in weight gain, an undesirable event associated with a worse cardiovascular risk profile and decreased adherence to therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs have been shown to improve glycemic control without promoting weight gain and to exert beneficial effects on lipid profile by reducing total and LDL cholesterol, triglycerides, and free fatty acid levels. DPP-4 inhibitors have demonstrated to be weight neutral whereas treatment with GLP-1 analogs is associated with a significant weight loss. DPP-4 and GLP-1 analogs represent a new therapeutic option for type 2 diabetes, which offers the advantage of combining glycemic control with beneficial effects on body weight and lipid profile, thus providing greater cardiovascular protection.

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Therapy, Combination; Dyslipidemias; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Metformin; Obesity; Risk Factors; Thiazolidinediones

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Metformin; Practice Guidelines as Topic; Precision Medicine

Glucagon-like peptide-1 (GLP-1) [GLP-1 (7-36)-amide] plays a fundamental role in regulating postprandial nutrient metabolism. GLP-1 acts through a G-protein-coupled receptor present on the membranes of many tissues, including myocardium and endothelium. GLP-1 is cleaved by the dipeptidyl peptidase-4 enzyme to its metabolite GLP-1 (9-36)-amide within 1-2 min of its release into the circulation. Investigations have been done in humans and in animal models to determine whether GLP-1 has effects on the myocardium. Infusions of GLP-1 increase cardiac function in ischemic and non-ischemic cardiovascular disease. In humans and animal models, constant infusions of GLP-1 decrease the size of infarction and improve myocardial function in ischemic/reperfusion injury. In cardiomyopathy and heart failure, infusions of GLP-1 improve myocardial function. These beneficial effects of GLP-1 on cardiac function are mediated by both GLP-1 receptor activation and GLP-1 receptor independent actions. Infusions of the metabolite GLP-1 (9-36)-amide improve cardiac function in experimental animals with cardiovascular disease even though the metabolite does not bind to the GLP-1 receptor. The beneficial effects of GLP-1 on the heart occur in the presence of a GLP-1 receptor antagonist and in animals devoid of GLP-1 receptors. Preliminary data in animals with available GLP-1 receptor agonists and cardiac disease suggest that exenatide has beneficial effects in porcine models of ischemic heart disease. The animal data with liraglutide are inconclusive. Clinical trials with exenatide and liraglutide show significant improvements in weight, systolic blood pressure, lipid profiles, and other cardiovascular risk factors. Whether these will decrease cardiovascular events is currently under investigation.

Topics: Animals; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dogs; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Lipids; Liraglutide; Male; Mice; Peptides; Rats; Venoms

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Incretins

Previous studies addressing the changes of glucagon-like peptide-1 (GLP-1) concentrations in morbidly obese patients after bariatric surgery have demonstrated conflicting results. The aim of the present study was to investigate the changes in serum GLP-1 levels 9 months after biliopancreatic diversion in morbidly obese patients without diabetes mellitus.. A sample of 40 morbidly obese patients without diabetes mellitus was enrolled. Biochemical and anthropometrical evaluations were conducted at basal and 9 months after surgery.. The mean patient age was 46.6 ± 13.1 years, and the mean preoperative body mass index (BMI) was 47.1 ± 18.1. A significant decrease in BMI, weight, waist circumference, fat mass, glucose, LDL cholesterol, total cholesterol, and triglyceride levels was observed after 9 months. Serum basal GLP-1 levels did not change after surgery (0.65 ± 0.18 ng/ml vs. 0.66 ± 0.17 ng/ml; n.s.). Postsurgical correlation analysis showed a negative association between basal GLP-1 and HDL cholesterol (r = -0.57; p < 0.01).. Fasting GLP-1 concentrations did not change after massive weight loss with biliopancreatic diversion in morbidly obese patients without diabetes mellitus.

Topics: Adult; Biliopancreatic Diversion; Blood Glucose; Blood Pressure; Body Composition; Body Mass Index; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Obesity, Morbid; Prospective Studies; Risk Factors; Triglycerides; Waist Circumference; Weight Loss

We examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials. We focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005-2010. We contrasted these findings with those from 2 different groups: 1. diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2. diabetes drugs with NDAs delayed and not yet approved within the same time frame (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release). The new guidelines have had an important impact on clinical development. Review time has increased over 2-fold. The increase is seen even if a drug with the same mechanism of action has been already approved. Whereas exenatide (approved in 2005) required 10 months of regulatory review, the approval of liraglutide in 2010 required more than twice as long (21 months). In contrast, the marketing authorization of liraglutide in the EU required 14 months. Additionally, the manufacturer of vildagliptin announced in June 2008, 30 months after the NDA was filed, that a re-submission to meet FDA's demands was not planned. The drug however received marketing authorization in the EU in 2007. The number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines. The significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.

Topics: Adamantane; Allylamine; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Investigational New Drug Application; Liraglutide; Nitriles; Peptides; Piperidines; Practice Guidelines as Topic; Pyrazines; Pyrrolidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Time Factors; Triazoles; United States; United States Food and Drug Administration; Uracil; Venoms; Vildagliptin

Topics: Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins

Diabetes is an important poor prognostic factor for ischemic heart disease and other cardiovascular diseases. Various study results have previously shown that new diabetes therapeutic agents including GLP-1 agonists and DPP-4 inhibitors have been suggested to be able to not only improve the pathology of diabetes, but also improve cardiovascular risk and be useful in prognosis. This report describes the effects of incretin on the cardiovascular system and its expected efficacy in reducing cardiovascular risk.

Topics: Blood Vessels; Cardiovascular Diseases; Diabetes Complications; Glucagon-Like Peptide 1; Humans

We assessed the cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist, using existing clinical data. Patient-level results from all completed phase 2 and 3 studies from the liraglutide clinical development programme were pooled to determine rates of major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, stroke. MACE were identified by querying the study database using Medical Dictionary for Regulatory Activities (MedDRA) terms combined with serious adverse events recorded by study investigators. Broad, narrow, and custom groups of MedDRA queries were used. Candidate events from each query were independently adjudicated post hoc. In 15 studies (6638 patients; 4257 liraglutide treated), there were 114 patients with MACE identified using the broad MedDRA query. Of these, 44 were classified as serious adverse events and 39 were adjudicated as MACE. The incidence ratio for adjudicated broad/serious MACE associated with liraglutide was 0.73 (95% CI 0.38-1.41) versus all comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine, placebo), within cardiovascular safety limits defined by the United States Food & Drug Administration for diabetes therapies under current investigation.

Topics: Adult; Aged; Cardiovascular Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Evidence-Based Medicine; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incidence; Liraglutide; Male; Middle Aged; Patient Safety; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors

Topics: Blood Glucose; Body Mass Index; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Factors; Treatment Outcome; Weight Loss

Besides the insulinotropic effects of glucagon-like peptide-1 (GLP-1) mimetics, their effects on endothelial dysfunction and myocardial ischaemia are of interest. No previous study has investigated associations between plasma levels of GLP-1 and CHD.. We investigated longitudinal relationships of fasting GLP-1 with the dynamic GLP-1 response after OGTT (difference between 60 min OGTT-stimulated and fasting GLP-1 levels [DeltaGLP-1]) and CHD in a population-based cohort of 71-year-old men. In the same cohort, we also cross-sectionally investigated the association between stimulated GLP-1 levels and: (1) cardiovascular risk factors (blood pressure, lipids, urinary albumin, waist circumference and insulin sensitivity index [M/I] assessed by euglycaemic-hyperinsulinaemic clamp); and (2) impaired glucose tolerance (IGT) and type 2 diabetes mellitus.. During the follow-up period (maximum 13.8 years), of 294 participants with normal glucose tolerance (NGT), 69 experienced a CHD event (13.8 years), as did 42 of 141 with IGT and 32 of 74 with type 2 diabetes mellitus. DeltaGLP-1 did not predict CHD (HR 1.0, 95% CI 0.52-2.28). The prevalence of IGT was associated with DeltaGLP-1, lowest vs highest quartile (OR 0.3, 95% CI 0.12-0.58), with no such association for type 2 diabetes mellitus (OR 1.0, 95% CI 0.38-2.86). M/I was significantly associated with DeltaGLP-1 in the type 2 diabetes mellitus group (r = 0.38, p < 0.01), but not in the IGT (r = 0.11, p = 0.28) or NGT (r = 0.10, p = 0.16) groups.. Impaired GLP-1 secretion is associated with IGT, but not with type 2 diabetes mellitus. This finding in the latter group might be confounded by oral glucose-lowering treatment. GLP-1 does not predict CHD. Although DeltaGLP-1 was associated with insulin sensitivity in the type 2 diabetes mellitus group, GLP-1 does not seem to be a predictor of CHD in insulin-resistant patients.

Topics: Aged; Albuminuria; Blood Pressure; Cardiovascular Diseases; Cholesterol; Cohort Studies; Coronary Disease; Diabetes Mellitus, Type 2; Fasting; Follow-Up Studies; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Male; Survival Analysis; Waist Circumference

Topics: Animals; Biomarkers; Calcitonin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Approval; Drug Therapy, Combination; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Pancreatitis; Risk Factors; Rodentia; Thyroid Neoplasms; United States; United States Food and Drug Administration

Management of type 2 diabetes mellitus (T2DM) can be challenging. Patients frequently present with poor glycemic control despite therapy. Other patients may be nonadherent or resistant to continuing their treatment when confronted with undesirable adverse effects, such as weight gain, that are associated with many conventional therapies. Incretin-based therapies developed to treat patients with T2DM, including oral dipeptidyl peptidase-4 inhibitor agents or glucagon-like peptide-1 agonists, offer the potential of sustained glycemic control for many patients without the adverse events associated with other classes of antihyperglycemic medications. Available safety data from clinical trials indicate that incretin-based therapies have weight-neutral or weight-reducing effects, with no apparent adverse impact on other important safety parameters, such as cardiovascular disease. The integration of these therapies into treatment algorithms, as highlighted in three case presentations, will increase treatment options for patients with T2DM.

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Life Style; Male; Metformin; Middle Aged; Peptides; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.. To examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).. Fasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.. Circulating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Chi-Square Distribution; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Japan; Logistic Models; Male; Metabolic Syndrome; Middle Aged; Obesity, Abdominal; Odds Ratio; Risk Assessment; Risk Factors; Triglycerides; Up-Regulation; Uric Acid; Waist Circumference

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Guidelines as Topic; Humans; Hypoglycemic Agents; Insulin; Insulin Infusion Systems

Glucagon-like peptide-1 (GLP-1) receptor agonists, which have been recently introduced as a treatment for type 2 diabetes, show several features which could be useful for the prevention of cardiovascular disease. In fact, beyond reducing hyperglycemia with low hypoglycemic risk, these drugs are capable of promoting a relevant weight loss. Furthermore, in trials performed in type 2 diabetes, GLP-1 analogues determine a consistent reduction in blood pressure and a modest improvement of lipid profile. Therefore, their overall effect on cardiovascular risk appears to be very beneficial. This expectation is confirmed, up to now, by the observation that the incidence of cardiovascular events in randomized trial shows a trend towards a greater reduction than that expected on the basis of the improvement of metabolic control. Specifically designed randomized trials, which are currently ongoing, will provide greater information in the next few years.

Topics: Cardiovascular Diseases; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Risk Factors

Type 2 diabetes (T2D) is associated with a greatly increased risk of cardiovascular disease. An increasing need for glucose-lowering treatments is emphasized by the almost inevitable failure of monotherapy and occurrence of weight gain. Recently, novel classes of drugs derived from the incretin system have been introduced into the management of T2D. Recent advances in the field of incretin-based therapies in the management of T2D were discussed at the 45th Annual Meeting of the European Association for the Study of Diabetes, held from September 29 until October 2, 2009, in Vienna, Austria.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Treatment Outcome

The 64th scientific congress of the American Diabetes Association had a special session devoted to the presentation of the results from three clinical trials: 1) the first multicentre international trial of pancreatic islet transplantation according to the so-called Edmonton protocol with the primary endpoint of restoring insulin independence in type 1 diabetic patients; 2) three pivotal studies of 30 weeks testing both the efficacy and safety of exenatide (exendin-4), a new insulin secretagogue that is a long-acting analogue of glucagon-like peptide-1, in patients with type 2 diabetes treated with either metformin, or a sulfonylurea, or a metformin-sulfonylurea combination; and 3) the "Collaborative AtoRvastatin Diabetes Study" (CARDS), a placebo-controlled primary prevention trial of cardiovascular complications using atorvastatin 10 mg in 2 838 at risk patients with type 2 diabetes. The main results and conclusions of these trials are briefly presented as they open new perspectives in the management of patients with type 1 or type 2 diabetes mellitus.

Topics: Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Exenatide; Glucagon; Glucagon-Like Peptide 1; Heptanoic Acids; Humans; Islets of Langerhans Transplantation; Peptide Fragments; Peptides; Protein Precursors; Pyrroles; Venoms