glucagon-like-peptide-1 and Renal-Insufficiency--Chronic

Obesity is a chronic disease characterised by excess adiposity, which impairs health. The high prevalence of obesity raises the risk of long-term medical complications including type 2 diabetes and chronic kidney disease. Several studies have focused on patients with obesity, type 2 diabetes and chronic kidney disease due to the increased prevalence of diabetic kidney disease. Several randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 analogues, and bariatric surgery in diabetic kidney disease showed renoprotective effects. However, further research is critical to address the treatment of patients with obesity and chronic kidney disease to lessen morbidity.Key messageObesity is a driver of chronic kidney disease, and type 2 diabetes, along with obesity, accelerates chronic kidney disease.Several randomized controlled trials on sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 analogues, and bariatric surgery in diabetic kidney disease demonstrate the improvement of renal outcomes.There is a need to address the treatment of patients with obesity and CKD to lessen morbidity.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucagon-Like Peptide 1; Glucose; Humans; Hypoglycemic Agents; Obesity; Renal Insufficiency, Chronic; Sodium

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

There is a pandemic of obesity worldwide and in Europe up to 30% of the adult population is already obese. Obesity is strongly related to the risk of CKD, progression of CKD, and end-stage renal disease (ESRD), also after adjustment for age, sex, race, smoking status, comorbidities, and laboratory tests. In the general population, obesity increases the risk of death. In nondialysis-dependent CKD patients, the association between body mass index and weight with mortality is controversial. In ESRD patients, obesity is paradoxically associated with better survival. There are only a few studies investigating changes in weight in these patients and in most weight loss was associated with higher mortality. However, it is not clear if weight change was intentional or unintentional and this is an important limitation of these studies. Management of obesity includes life-style interventions, bariatric surgery, and pharmacotherapy. In the last 2 years, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist and GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist were shown to be effective in managing weight loss in non-CKD patients, but we are awaiting results of more definitive studies in CKD patients.

Topics: Adult; Glucagon-Like Peptide 1; Humans; Kidney Failure, Chronic; Obesity; Renal Insufficiency, Chronic; Weight Loss

Chronic kidney disease due to diabetes, or diabetic kidney disease (DKD), is a worldwide leading cause of chronic kidney disease and kidney failure and an increasingly important global public health issue. It is associated with poor quality of life, high burden of chronic diseases, and increased risk of premature death. Until recently, people with DKD had limited therapeutic options. Treatments have focused largely on glycemic and blood pressure control and renin-angiotensin system blockade, leaving patients with significant residual risk for progression of DKD. The availability of newer classes of glucose-lowering agents, namely, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, has changed the therapeutic landscape for these patients. These therapies have offered unprecedented opportunities to reduce the risk for progression of kidney disease and the risk of death that have led to recent updates to clinical guidelines. As such, the American Diabetes Association, the Kidney Disease: Improving Global Outcomes, and the European Association for the Study of Diabetes now recommend the use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists for patients with DKD to provide both kidney and cardiovascular protective benefits. This review highlights the importance of early detection of DKD and summarizes the latest recommendations in the clinical guidelines on management of patients with DKD with hope of facilitating their uptake into everyday clinical practice. An integrated approach to patient care with a multidisciplinary focus can help achieve the necessary shift in clinical care of patients with DKD.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucagon-Like Peptide 1; Health Personnel; Humans; Quality of Life; Renal Insufficiency, Chronic; Sodium

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

Diabetes mellitus affects over 20% of people aged > 65 years. With the population of older people living with diabetes growing, the condition may be only one of a number of significant comorbidities that increases the complexity of their care, reduces functional status and inhibits their ability to self-care. Coexisting comorbidities may compete for the attention of the patient and their healthcare team, and therapies to manage comorbidities may adversely affect a person's diabetes. The presence of renal or liver disease reduces the types of antihyperglycemic therapies available for use. As a result, insulin and sulfonylurea-based therapies may have to be used, but with caution. There may be a growing role for sodium-glucose co-transporter 2 (SGLT-2) inhibitors in diabetic renal disease and for glucagon-like peptide (GLP)-1 therapy in renal and liver disease (nonalcoholic steatohepatitis). Cancer treatments pose considerable challenges in glucose therapy, especially the use of cyclical chemotherapy or glucocorticoids, and cyclical antihyperglycemic regimens may be required. Clinical trials of glucose lowering show reductions in microvascular and, to a lesser extent, cardiovascular complications of diabetes, but these benefits take many years to accrue, and evidence specifically in older people is lacking. Guidelines recognize that clinicians managing patients with type 2 diabetes mellitus need to be mindful of comorbidity, particularly the risks of hypoglycemia, and ensure that patient-centered therapeutic management of diabetes is offered. Targets for glucose control need to be carefully considered in the context of comorbidity, life expectancy, quality of life, and patient wishes and expectations. This review discusses the role of chronic kidney disease, chronic liver disease, cancer, severe mental illness, ischemic heart disease, and frailty as comorbidities in the therapeutic management of hyperglycemia in patients with type 2 diabetes mellitus.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Drug Therapy, Combination; End Stage Liver Disease; Frailty; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Mental Disorders; Myocardial Ischemia; Neoplasms; Quality of Life; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

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

As the burden of diabetic kidney disease continues to expand, new therapies to preserve renal function or prevent diabetic nephropathy are urgently needed. In the past decade, a number of new hypoglycemic classes have emerged, each with a unique profile of action and benefits. Here we review the impact of glycemic control on renal outcomes and the results of the major clinical trials of glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. Both GLP-1 agonists and SGLT2 inhibitors consistently demonstrate renal benefits. Further studies of these new agents in different patient groups and in comparison to (or in combination with) other treatments are required to better define their role in combating the burden of diabetic kidney disease.

Topics: Animals; Diabetic Nephropathies; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Chronic hyperglycemia and its associated metabolic products are key factors responsible for the development and progression of diabetic chronic kidney disease (CKD). Endocrinologists are tasked with detection and management of early CKD before patients need referral to a nephrologist for advanced CKD or dialysis evaluation. Primary care physicians are increasingly becoming aware of the importance of managing hyperglycemia to prevent or delay progression of CKD. Glycemic control is an integral part of preventing or slowing the advancement of CKD in patients with diabetes; however, not all glucose-lowering agents are suitable for this patient population. The availability of the latest information on treatment options may enable physicians to thwart advancement of serious renal complication in patients suffering from diabetes. This review presents clinical data that shed light on the risk/benefit profiles of three relatively new antidiabetes drug classes, the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogs, and sodium glucose co-transporter 2 inhibitors, particularly for patients with diabetic CKD, and summarizes the effects of these therapies on renal outcomes and glycemic control for endocrinologists and primary care physicians. Current recommendations for screening and diagnosis of CKD in patients with diabetes are also discussed.

Topics: Antihypertensive Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Incretin-based drugs, i.e., glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are widely used for the treatment of type 2 diabetes. In addition to the primary role of incretins in stimulating insulin secretion from pancreatic β-cells, they have extra pancreatic functions beyond glycemic control. Indeed, recent studies highlight the potential beneficial effects of incretin-based therapy in diabetic kidney disease (DKD). Experimental studies using various diabetic models suggest that incretins protect the vascular endothelium from injury by binding to GLP-1 receptors, thereby ameliorating oxidative stress and the local inflammatory response, which reduces albuminuria and inhibits glomerular sclerosis. In addition, there is some evidence that GLP-1 receptor agonists and DPP-4 inhibitors mediate sodium excretion and diuresis to lower blood pressure. The pleiotropic actions of DPP-4 inhibitors are ascribed primarily to their effects on GLP-1 signaling, but other substrates of DPP-4, such as brain natriuretic peptide and stromal-derived factor-1α, may have roles. In this review, we summarize recent studies of the roles of incretin-based therapy in ameliorating DKD and its complications.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Receptors, Glucagon; Renal Insufficiency, Chronic; Signal Transduction

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 (GLP-1) receptor agonist use is associated with reduced mortality and improved cardiovascular outcomes in the general population with diabetes. Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used antidiabetic agents for patients with advanced-stage chronic kidney disease (CKD). The association of these 2 drug classes with outcomes among patients with diabetes and advanced-stage CKD or end-stage kidney disease (ESKD) is not well understood.. To assess whether use of GLP-1 receptor agonists in a population with diabetes and advanced-stage CKD or ESKD is associated with better outcomes compared with use of DPP-4 inhibitors.. This retrospective cohort study used data on patients with type 2 diabetes and stage 5 CKD or ESKD obtained from the National Health Insurance Research Database of Taiwan. The study was conducted between January 1, 2012, and December 31, 2018. Data were analyzed from June 2020 to July 2021.. Treatment with GLP-1 receptor agonists compared with treatment with DPP-4 inhibitors.. All-cause mortality, sepsis- and infection-related mortality, and mortality related to major adverse cardiovascular and cerebrovascular events were compared between patients treated with GLP-1 receptor agonists and patients treated with DPP-4 inhibitors. Propensity score weighting was used to mitigate the imbalance among covariates between the groups.. Of 27 279 patients included in the study, 26 578 were in the DPP-4 inhibitor group (14 443 [54.34%] male; mean [SD] age, 65 [13] years) and 701 in the GLP-1 receptor agonist group (346 [49.36%] male; mean [SD] age, 59 [13] years). After weighting, the use of GLP-1 receptor agonists was associated with lower all-cause mortality (hazard ratio [HR], 0.79; 95% CI, 0.63-0.98) and lower sepsis- and infection-related mortality (HR, 0.61; 95% CI, 0.40-0.91). Subgroup analysis demonstrated a lower risk of mortality associated with use of GLP-1 receptor agonists compared with DDP-4 inhibitors among patients with cerebrovascular disease (HR, 0.33; 95% CI, 0.12-0.86) than among those without cerebrovascular disease (HR, 0.89; 95% CI, 0.71-1.12) (P = .04 for interaction).. Treatment with GLP-1 receptor agonists was associated with lower all-cause mortality among patients with type 2 diabetes, advanced-stage CKD, and ESKD than was treatment with DPP-4 inhibitors. Additional well-designed, prospective studies are needed to confirm the potential benefit of GLP-1 receptor agonist treatment for patients with advanced CKD or ESKD.

Topics: Aged; Cohort Studies; 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; Kidney Failure, Chronic; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sepsis; Sodium-Glucose Transporter 2 Inhibitors; Taiwan

To evaluate trends in antidiabetic medication initiation patterns among patients with type 2 diabetes mellitus (T2DM) with and without chronic kidney disease (CKD).. A retrospective cohort study using the UK Clinical Practice Research Datalink (2006-2020) was conducted to evaluate the overall, first-, and second line (after metformin) medication initiation patterns among patients with CKD (n = 38,622) and those without CKD (n = 230,963) who had T2DM.. Relative to other glucose-lowering therapies, metformin initiations declined overall but remained the first-line treatment of choice for both patients with and those without CKD. Sodium-glucose cotransporter-2 (SGLT2i) use increased modestly among patients with CKD, but this increase was more pronounced among patients without CKD; by 2020, patients without CKD, compared with patients with CKD, were three (28.5% vs. 9.4%) and six (46.3% vs. 7.9%) times more likely to initiate SGLT2i overall and as second-line therapy, respectively. Glucagon-like peptide 1 receptor agonist (GLP-1RA) use was minimal regardless of CKD status (<5%), whereas both dipeptidyl peptidase-4 inhibitor (DPP4i) and sulfonylurea use remained high among patients with CKD. For instance, by 2020, and among patients with CKD, DPP4i and sulfonylureas constituted 28.3% and 20.6% of all initiations, and 57.4% and 30.3% of second-line initiations, respectively.. SGLT2i use increased among patients with T2DM, but this increase was largely driven by patients without CKD. Work is needed to identify barriers associated with the uptake of therapies with proven cardiorenal benefits (e.g., SGLT2i, GLP-1RA) among patients with CKD.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Metformin; Renal Insufficiency, Chronic; Retrospective Studies; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

People with diabetes and chronic kidney disease (CKD) are at high risk for kidney failure, atherosclerotic cardiovascular disease, heart failure, and premature mortality. Recent clinical trials support new approaches to treat diabetes and CKD. The 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease each provide evidence-based recommendations for management. A joint group of ADA and KDIGO representatives reviewed and developed a series of consensus statements to guide clinical care from the ADA and KDIGO guidelines. The published guidelines are aligned in the areas of CKD screening and diagnosis, glycemia monitoring, lifestyle therapies, treatment goals, and pharmacologic management. Recommendations include comprehensive care in which pharmacotherapy that is proven to improve kidney and cardiovascular outcomes is layered on a foundation of healthy lifestyle. Consensus statements provide specific guidance on use of renin-angiotensin system inhibitors, metformin, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist. These areas of consensus provide clear direction for implementation of care to improve clinical outcomes of people with diabetes and CKD.

Topics: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucose; Humans; Kidney; Metformin; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Sodium; Sodium-Glucose Transporter 2 Inhibitors; United States

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

The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) whose activation results in suppression of food intake and improvement of glucose metabolism. Several receptor interacting proteins regulate the signaling of GLP-1R such as G protein-coupled receptor kinases (GRK) and β-arrestins. Here we evaluated the physiological and pharmacological impact of GRK inhibition on GLP-1R activity leveraging small molecule inhibitors of GRK2 and GRK3. We demonstrated that inhibition of GRK: i) inhibited GLP-1-mediated β-arrestin recruitment, ii) enhanced GLP-1-induced insulin secretion in isolated islets and iii) has additive effect with dipeptidyl peptidase 4 in mediating suppression of glucose excursion in mice. These findings highlight the importance of GRK to modulate GLP-1R function

Topics: Amides; Animals; beta-Arrestins; Calcium; CHO Cells; Cricetulus; Diabetes Mellitus; Dipeptidyl Peptidase 4; Eating; G-Protein-Coupled Receptor Kinase 1; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Insulin; Islets of Langerhans; Mice; Obesity; Phosphorylation; Receptors, Glucagon; Renal Insufficiency, Chronic; Signal Transduction

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 diseases frequently coexist with chronic kidney disease that constitutes a major determinant of outcome in patients with heart failure. Dysfunction of both organs is related to chronic inflammation, endothelial dysfunction, oxidative stress, and fibrosis. Widespread expression of serine protease DPP4 that degrades varieties of substrates suggests its involvement in numerous physiological processes. In this study, we tested the effects of selective DPP4 inhibition on the progression of renal disease in a nondiabetic model of hypertensive heart disease using Dahl salt-sensitive rats. Chronic DPP4 inhibition positively affected renal function with a significant reduction in albuminuria and serum creatinine. DPP4 inhibition attenuated the inflammatory component by reducing the expression of NF-

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Endothelial Cells; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypertension; Inflammation; Kidney; Kidney Function Tests; Models, Biological; Nitrosative Stress; Oxidative Stress; Phenotype; Rats, Inbred Dahl; Renal Insufficiency, Chronic; Signal Transduction; Sodium Chloride, Dietary

Chronic kidney diseases are characterized by renal fibrosis with excessive matrix deposition, leading to a progressive loss of functional renal parenchyma and, eventually, renal failure. Renal microcirculation lesions, including the phenotypic conversion of vascular cells, contribute to renal fibrosis. Here, renal microcirculation lesions were established with monocrotaline (MCT, 60 mg/kg). Sitagliptin (40 mg/kg/d), a classical dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the renal microcirculation lesions by inhibiting glomerular tuft hypertrophy, glomerular mesangial expansion, and microvascular thrombosis. These effects of sitagliptin were mediated by glucagon-like peptide-1 receptor (GLP-1R), since they were blocked by the GLP-1R antagonist exendin-3 (Ex-3, 40 ug/kg/d). The GLP-1R agonist liraglutide showed a similar renal protective effect in a dose-independent manner. In addition, sitagliptin, as well as liraglutide, alleviated the MCT-induced apoptosis of renal cells by increasing the expression of survival factor glucose-regulated protein 78 (GRP78), which was abolished by the GLP-1R antagonist Ex-3. Sitagliptin and liraglutide also effectively ameliorated the conversion of vascular smooth muscle cells (SMCs) from a synthetic phenotype to contractile phenotype. Moreover, sitagliptin and liraglutide inhibited endothelial-mesenchymal transition (EndMT) via downregulating transforming growth factor-

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Glomerular Mesangium; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Microcirculation; Monocrotaline; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sitagliptin Phosphate

Glucagon‑like peptide‑1 (GLP‑1) is a gut incretin hormone that is considered to be a promising target for the treatment of patients with type 2 diabetes. However, the mechanisms underlying the protective effects of GLP‑1 on diabetic nephropathy are yet to be fully elucidated. Sirtuin (SIRT)1 encodes a member of the SIRT family of proteins that serves an important role in mitochondrial function and is reported to be associated with the pathogenesis of chronic kidney disease. The present study treated mouse podocytes with various concentrations of D‑glucose to establish a high glucose (HG)‑induced model of renal injury. The results of a 2',7'‑dichlorodihydrofluorescein diacetate assay, Annexin V/propidium iodide staining and ELISA demonstrated that treatment of podocytes with HG significantly enhanced the production of reactive oxygen species (ROS), promoted cell apoptosis and increased the secretion of proinflammatory cytokines, respectively. The cytokines increased following HG treatment included tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. Notably, treatment with GLP‑1 attenuated HG‑induced increases in ROS production and podocyte apoptosis, which may occur via downregulation of the expression of caspase‑3 and caspase‑9, and increased expression of nephrin, podocin and SIRT1, as determined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Treatment with GLP‑1 led to protective effects in podocytes that were similar to those of resveratrol. Furthermore, SIRT1 knockdown using short hairpin RNA significantly enhanced the expression of caspase‑3 and caspase‑9 in mouse podocytes, compared with normal mouse podocytes. SIRT1 knockdown with or without GLP‑1 administration significantly decreased the expression of caspase‑3 and caspase‑9 in mouse podocytes, compared with SIRT1 knockdown mouse podocytes. In conclusion, the results of the present study indicated that GLP‑1 may be a promising target for the development of novel therapeutic strategies for HG‑induced nephropathy, and may function through the activation of SIRT1.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cytokines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Gene Knockdown Techniques; Glucagon-Like Peptide 1; Glucose; Humans; Mice; Podocytes; Reactive Oxygen Species; Renal Insufficiency, Chronic; Sirtuin 1

Accumulating evidence shows that a gut-released hormone, the glucagon-like peptide-1 (GLP-1), has not only a glucose-lowering effect but also a renoprotective effect against kidney injury. In this study, we investigated whether a dipeptidyl peptidase (DPP) IV inhibitor has a protective effect against tacrolimus-induced renal injury. Rats were treated with tacrolimus (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. MK0626 treatment attenuated tacrolimus-induced renal dysfunction, tubulointerstitial fibrosis, and arteriolopathy. Moreover, these improvements were accompanied by a reduction in oxidative stress and apoptosis. MK0626 treatment increased the blood level of GLP-1 and the level of its receptor in tissue sections but did not alter the levels of other DPP IV substrates, such as neuropeptide Y and the stromal cell-derived factor-1. These data suggest that DPP IV inhibition has an important role in the renoprotection against tacrolimus-induced nephrotoxicity via antioxidative and antiapoptotic effects and preservation of the GLP-1 system.

Topics: Animals; Antioxidants; Apoptosis; Biomarkers; Calcineurin Inhibitors; Diet, Sodium-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Fibrosis; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Immunosuppressive Agents; Kidney; Male; Oxidative Stress; Random Allocation; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tacrolimus; Triazoles

Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular disease, and a strategy to counteract CKD must be established. CKD caused by immunological abnormalities is treated by steroids, frequently resulting in steroid diabetes. Although insulin is the most effective drug against steroid diabetes, administering it to patients can be difficult. Dipeptidyl peptidase-4 (DPP-4) inhibitors were developed for diabetes mellitus with a new mechanism of action. However, their efficacies and mechanisms of action for steroid diabetes are unclear.. We studied 11 CKD patients treated with steroids admitted to our hospital (3 men and 8 women; age, 66.0 ± 15.9 years). DPP-4 inhibitor alogliptin was administered for steroid diabetes. Levels of markers related to glucose metabolism were measured before alogliptin treatment and after alogliptin treatment, before the prednisolone dose was reduced.. Alogliptin treatment significantly increased plasma glucagon-like peptide-1 (GLP-1) levels from 1.16 ± 1.71 pmol/L to 4.48 ± 1.53 pmol/L and significantly reduced levels of plasma glucose recorded 2 h after lunch and hemoglobin A1c (HbA1c). No significant differences were seen in insulin secretory ability of homeostasis model assessment (HOMA) (HOMA-β) and insulin resistance index of HOMA (HOMA-R) before and after alogliptin treatment. In contrast, alogliptin treatment significantly decreased plasma glucagon levels, from 116.1 ± 38.7 pg/mL to 89.6 ± 17.3 pg/mL. Moreover, there were significant correlations among HbA1c, GLP-1, and glucagon levels.. Alogliptin improves steroid-induced hyperglycemia by decrease of glucagon levels through an increase in plasma GLP-1 levels.

Topics: Aged; Asian People; Body Mass Index; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Japan; Kidney Function Tests; Male; Piperidines; Regression Analysis; Renal Insufficiency, Chronic; Steroids; Uracil; Vital Signs