glucagon-like-peptide-1 and Heart-Diseases

Recent experimental data suggest glucagon-like peptide 1 (GLP-1) and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. These direct effects may be cardioprotective, contractility augmenting, and vasorelaxant. A few preliminary clinical trials appear to support a mechanical function improvement after GLP-1 administration to patients with a weakened left ventricle. Based on animal studies, diminished lethal injury to the postischemic reperfused myocardium appears to be a particularly promising prospect, awaiting to be tested in clinical settings.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Glucagon-Like Peptide 1; Heart Diseases; Humans; Myocardial Contraction; Myocardial Reperfusion Injury; Signal Transduction; Treatment Outcome; Vasodilation; Ventricular Function, Left

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Drug Interactions; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Kidney Diseases; Pancreatitis; Receptors, Glucagon; Sulfonylurea Compounds; Thiazolidinediones; Thyroid Diseases

Various publications in 2009 showed that the treatment of type 2 diabetic (T2D) patients with macrovascular complications is still a controversial subject, whether with regard to the use of glitazones, to the best management strategy for T2D patients with stable coronary artery disease or to the use of incretin mimetic drugs in patients with heart disease. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes study (RECORD) compared cardiovascular morbidity-mortality outcomes in patients taking rosiglitazone in combination with metformin or sulfonylurea versus metformin with sulfonylurea. The results showed that rosiglitazone was not inferior to the metformin-sulfonylurea combination in terms of mortality and cardiovascular hospitalization, but caution must be used when interpreting the results, as the event rate was low. The BARI 2D study (Bypass Angioplasty Revascularization Investigation 2 Diabetes) is a cardiovascular morbidity-mortality trial with the goal of determining the best strategy for blood glucose control and revascularization in T2D patients with stable coronary artery disease. The results of this trial showed that early revascularization is not clearly beneficial, except in a subgroup of patients in whom surgical revascularization is indicated. The use of GLP-1 analogs (Glucagon-Like Peptide-1) in the acute phase of myocardial ischemia in animal models provided promising results. Some clinical studies also suggest an improvement in cardiovascular risk factors with these treatments. Results from morbidity-mortality studies are needed to better assess the long-term efficiency of these new drugs.

Topics: Animals; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Glucagon-Like Peptide 1; Heart Diseases; Humans; Hypoglycemic Agents; Risk Factors; Rosiglitazone; Thiazolidinediones

Chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is a major problem of public health. Currently, many of these patients experience progression of cardiovascular and renal disease, even when receiving optimal treatment. In previous years, several new drug classes for the treatment of type 2 DM have emerged, including inhibitors of renal sodium-glucose co-transporter-2 (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. Apart from reducing glycaemia, these classes were reported to have other beneficial effects for the cardiovascular and renal systems, such as weight loss and blood pressure reduction. Most importantly, in contrast to all previous studies with anti-diabetic agents, a series of recent randomized, placebo-controlled outcome trials showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events and all-cause mortality, as well as progression of renal disease, in patients with type 2 DM. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 analogues, analyses the potential mechanisms involved in these actions and discusses their place in the treatment of patients with CKD and DM.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemic Agents; Kidney; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Societies, Medical; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Cardiovascular complications of obesity and diabetes are major health problems. Assessing their development, their link with ectopic fat deposition and their flexibility with therapeutic intervention is essential. The aim of this study was to longitudinally investigate cardiac alterations and ectopic fat accumulation associated with diet-induced obesity using multimodal cardiovascular magnetic resonance (CMR) in mice. The second objective was to monitor cardiac response to exendin-4 (GLP-1 receptor agonist).. Male C57BL6R mice subjected to a high fat (35 %) high sucrose (34 %) (HFHSD) or a standard diet (SD) during 4 months were explored every month with multimodal CMR to determine hepatic and myocardial triglyceride content (HTGC, MTGC) using proton MR spectroscopy, cardiac function with cine cardiac MR (CMR) and myocardial perfusion with arterial spin labeling CMR. Furthermore, mice treated with exendin-4 (30 μg/kg SC BID) after 4 months of diet were explored before and 14 days post-treatment with multimodal CMR.. HFHSD mice became significantly heavier (+33 %) and displayed glucose homeostasis impairment (1-month) as compared to SD mice, and developed early increase in HTGC (1 month, +59 %) and MTGC (2-month, +63 %). After 3 months, HFHSD mice developed cardiac dysfunction with significantly higher diastolic septum wall thickness (sWtnD) (1.28 ± 0.03 mm vs. 1.12 ± 0.03 mm) and lower cardiac index (0.45 ± 0.06 mL/min/g vs. 0.68 ± 0.07 mL/min/g, p = 0.02) compared to SD mice. A significantly lower cardiac perfusion was also observed (4 months:7.5 ± 0.8 mL/g/min vs. 10.0 ± 0.7 mL/g/min, p = 0.03). Cardiac function at 4 months was negatively correlated to both HTGC and MTGC (p < 0.05). 14-day treatment with Exendin-4 (Ex-4) dramatically reversed all these alterations in comparison with placebo-treated HFHSD. Ex-4 diminished myocardial triglyceride content (-57.8 ± 4.1 %), improved cardiac index (+38.9 ± 10.9 %) and restored myocardial perfusion (+52.8 ± 16.4 %) under isoflurane anesthesia. Interestingly, increased wall thickness and hepatic steatosis reductions were independent of weight loss and glycemia decrease in multivariate analysis (p < 0.05).. CMR longitudinal follow-up of cardiac consequences of obesity and diabetes showed early accumulation of ectopic fat in mice before the occurrence of microvascular and contractile dysfunction. This study also supports a cardioprotective effect of glucagon-like peptide-1 receptor agonist.

Topics: Adiposity; Animals; Blood Glucose; Coronary Circulation; Diabetes Mellitus; Diet, High-Fat; Dietary Sucrose; Disease Models, Animal; Exenatide; Fatty Liver; Glucagon-Like Peptide 1; Heart Diseases; Liver; Magnetic Resonance Imaging, Cine; Male; Mice, Inbred C57BL; Multimodal Imaging; Multivariate Analysis; Myocardial Contraction; Myocardial Perfusion Imaging; Myocardium; Obesity; Peptides; Predictive Value of Tests; Proton Magnetic Resonance Spectroscopy; Recovery of Function; Time Factors; Triglycerides; Venoms; Ventricular Function; Weight Gain

Topics: Animals; Blood Glucose; Cardiotonic Agents; Clinical Trials, Phase II as Topic; Delayed Diagnosis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Global Health; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Heart Diseases; Humans; Hypoglycemic Agents; Incretins; Models, Animal; Receptors, Glucagon

Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.. C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet-fed mice at 16 and 32 weeks, respectively (both P<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase-dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α-activated human endothelial cells in vitro.. Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.

Topics: Animals; Blood Glucose; Cardiotonic Agents; Cell Line; Connexin 43; Coronary Vessels; Disease Models, Animal; Endoplasmic Reticulum Stress; Endothelial Cells; Gene Expression; Glucagon-Like Peptide 1; Heart Diseases; Humans; Hypercholesterolemia; Insulin Resistance; Liraglutide; Mice; Mice, Inbred C57BL; Monocytes; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Obesity; Risk Factors; Signal Transduction; Tumor Necrosis Factor-alpha

Dahl salt-sensitive (Dahl S) rats exhibit many phenotypic traits associated with salt-sensitive hypertension in man. Specifically, they are salt-sensitive, insulin-resistant and hyperlipidemic. They also develop endothelial dysfunction, cardiac injury and glomerulosclerosis. Insulin resistance is linked to hypertension, renal and cardiac damage and endothelial dysfunction. Thus, an agent that has diuretic action and can improve insulin resistance, like recombinant glucagon-like peptide-1(7-36)amide (rGLP-1), may have an antihypertensive effect.. To determine whether chronic administration of rGLP-1 attenuates the development of hypertension, endothelial dysfunction and/or hypertension-induced renal and cardiac end organ damage in Dahl S rats.. Mean arterial pressure (MAP) and urinary excretion of protein and albumin were measured in Dahl S rats before and after they were fed a 8% NaCl diet and infused with rGLP-1 (1 micro g/kg per min, i.v.) or vehicle for 14 days. At the end of the study, the degree of renal and cardiac injury was histologically assessed and endothelium-dependent relaxing function was studied using aortic rings. In other rats, the effects of rGLP-1 on sodium and water balance and plasma glucose and insulin levels for the first 3 days following a step change in sodium intake from a 0.1% NaCl diet to 7.5 mEq/day were determined.. rGLP-1 significantly attenuated the development of hypertension in Dahl S rats (136 +/- 7 versus 174 +/- 6 mmHg). This was associated with reduction in proteinuria (46 +/- 7 versus 128 +/- 15 mg/day) and albuminuria (46 +/- 7 versus 86 +/- 18 mg/day) and improvement of endothelial function and renal and cardiac damage. rGLP-1 markedly increased urine flow and sodium excretion for the first 3 days following elevation in sodium intake. It had no significant effects on plasma glucose and insulin concentrations.. rGLP-1 has antihypertensive and cardiac and renoprotective effects in Dahl S rats fed a high salt diet. The antihypertensive effect of rGLP-1 in Dahl S rats is due mainly to its diuretic and natriuretic effects, rather than an effect to improve insulin-resistance.

Topics: Animals; Antihypertensive Agents; Aorta; Blood Glucose; Diuresis; Endothelium, Vascular; Glucagon; Glucagon-Like Peptide 1; Heart Diseases; Hypertension; Insulin; Kidney Diseases; Male; Natriuresis; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred Dahl; Sodium; Sodium Chloride, Dietary; Water-Electrolyte Balance