exenatide and Heart-Failure

Cardiovascular outcomes trials (CVOTs) have assessed the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on major adverse cardiovascular events (MACE) and mortality in high cardiovascular (CV) risk populations. Observational research can provide complementary evidence about these effects in unselected populations.. To systematically review retrospective observational cohort studies conducted in electronic healthcare databases (EHDs) assessing GLP-1 RAs´ effects on MACE and/or hospitalisation for heart failure (HHF) and/or all-cause mortality in Type 2 diabetes mellitus (T2DM) patients.. We systematically searched studies meeting inclusion criteria, compared design, methods and population characteristics, assessed risk for bias and did a meta-analysis (MA) using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals).. Sixteen studies included 285,436 T2DM patients exposed to GLP-1 RAs (exenatide bid, liraglutide, lixisenatide, long-acting exenatide), n ranged from 219 to 160,803 patients. Comparators included: no exposure, other antidiabetic medications (OADs), combined OADs, canagliflozin or multiple comparators. Ten studies estimated all-cause mortality, hazard ratios (HRs) ranged from 0.17 (95% CI 0.02-1.22) to 1.29 (95% CI 0.54-3.13). Thirteen studies assessed cardiovascular events and/or MACE; HRs ranged from 0.27 (95% CI 0.14-0.53) to 1.11 (95% CI 0.99-1.24). Eight studies assessed HHF, HRs ranged from 0.12 (95% CI 0.02-0.66) to 1.64 (95% CI 1.28-2.13). Excluding two studies because of temporal bias, we obtained pooled estimates for all-cause mortality: HR 0.63 (0.44-0.89), CV outcomes HR 0.84 (0.75-0.94) and HHF; HR 0.94 (0.78-1.14), (high between-study variability: I. Pooled results of EHDs' studies assessing GLP-1 RAs effects favoured GLP-1 RAs for all-cause mortality and MACE while were neutral for HHF. Results should be interpreted cautiously because of studies' substantial heterogeneity and limitations of observational research.

Topics: Cohort Studies; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Liraglutide; Retrospective Studies; Risk Factors

Studies designed to evaluate the short-term effects of incretin-related drugs in subjects with cardiac disease are still preliminary. In patients with heart failure, two of five studies showed that glucagon-like peptide-1 (GLP-1) infusion was associated with an absolute increase in left ventricular ejection fraction (LVEF) by 6-10 %, whereas no significant benefit was observed in the remaining three studies. In patients with coronary artery disease, single infusion of the GLP-1 receptor analog, exenatide, did not increase LVEF, but this drug may decrease infarct size in patients with myocardial infarction presenting with short duration of ischemic symptoms. Single dose of GLP-1 and the dipeptidyl-peptidase-IV (DPP-IV) inhibitor, sitagliptin, may improve left ventricular function, predominantly in ischemic segments, and attenuate post-ischemic stunning. Nausea, vomiting and hypoglycemia were the most common adverse effects associated with GLP-1 and exenatide administration. Increased heart rate was also observed with exenatide in patients with heart failure. Large randomized trials including diabetic patients with preexisting heart failure and myocardial infarction showed that chronic therapy with the DPP-IV inhibitors saxagliptin and alogliptin did not reduce cardiovascular events or mortality. Moreover, saxagliptin use was associated with significant increase in frequency of heart failure requiring hospitalization, hypoglycemia and angioedema. Overall, short-term preliminary data suggest potential cardioprotective effects of exenatide and sitagliptin in patients with heart failure and myocardial infarction. Meanwhile, long-term randomized trials suggest no benefit of alogliptin, and increased harm associated with the use of saxagliptin.

Topics: Animals; Cardiotonic Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Myocardial Infarction; Peptides; Venoms

Type 2 diabetes mellitus is acknowledged as a major risk factor for the development of cardiovascular disease (CVD). Advancing treatment options for person with diabetes beyond glucose control to prevent microvascular and macrovascular complications and ultimately have an impact on CVD development holds great significance for the growing number of persons with diabetes. Glucagonlike peptide-1 (GLP-1) is an incretin secreted in response to nutrient ingestion that inhibits glucagon secretion and gastric emptying, resulting in reduced postprandial glycemia. GLP-1 has insulinomimetic, insulinotropic, and antiapoptotic properties. GLP-1 agonists (exenatide and liraglutide) are a class of drugs approved for the treatment of diabetes that have significant cardiovascular (CV) effects. These CV effects potentially provide an opportunity for clinicians to address the multifactorial issues involved in the increased CV morbidity and mortality associated with diabetes. This article presents an overview of the CV effects of GLP-1 agonists, highlighting implications for the management of patients with diabetes and heart disease.

Topics: Animals; Blood Pressure; Cardiovascular System; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Ischemic Preconditioning, Myocardial; Liraglutide; Peptides; Venoms; Ventricular Function, Left

The aim of this study was to determine whether exenatide improves haemodynamic function in patients with type 2 diabetes with congestive heart failure (CHF).. The main eligibility criteria for inclusion were: male/female (18-80 years) with type 2 diabetes and CHF (ejection fraction ≤ 35%, and New York Heart Association functional class III or IV). Out of 237 patients screened, 20 male type 2 diabetic patients participated in this crossover trial design and were allocated (sequentially numbered) to i.v. infusions during two consecutive days with (1) exenatide (0.12 pmol/kg/min); and (2) placebo for 6 h followed by a washout period for 18 h, at Stockholm South Hospital, Sweden. Patients and researchers were blinded to the assignment. Cardiac haemodynamic variables were determined by right heart catheterisation. The primary endpoint was defined as an increase in cardiac index (CI) or a decrease in pulmonary capillary wedge pressure (PCWP) of ≥ 20%. Secondary endpoints were tolerability and safety of exenatide infusion.. CI increased at 3 and 6 h by 0.4 ± 0.1 (23%) and 0.33 ± 0.1 (17%) l min(-1) m(-2), during exenatide infusion vs -0.02 ± 0.1 (-1%) and -0.08 ± 0.1 (-5%) l min(-1) m(-2) during placebo (p = 0.003); and heart rate (HR) increased at 1, 3 and 6 h by 8 ± 3 (11%), 15 ± 4 (21%) and 21 ± 5 (29%) beats per min (bpm), during exenatide infusion vs -1 ± 2 (-2%), 1 ± 1 (2%) and 6 ± 2 (8%) bpm, during placebo (p = 0.006); and PCWP decreased at 1, 3 and 6 h by -1.3 ± 0.8 (-8%), -1.2 ± 1 (-8%) and -2.2 ± 0.9 (-15%) mmHg, during exenatide infusion vs 0.3 ± 0.5 (2%), 1 ± 0.6 (6%) and 1.4 ± 0.7 (8%) mmHg, during placebo (p = 0.001). No serious adverse event was observed. Adverse events were reported in nine patients (six, nausea; two, increased HR; one, increased systolic blood pressure).. Infusion of exenatide in male type 2 diabetic patients with CHF increased the CI as a result of chronotropy, with concomitant favourable effects on PCWP and reasonable tolerability of the drug. The clinical implications of using exenatide in patients with CHF are still not clear and further studies are warranted.. www.isrctn.org/ISRCTN47533126

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Heart Failure; Heart Rate; Hemodynamics; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Venoms

Polyvascular disease is an independent predictor of major adverse cardiovascular events (MACE). The relationship between the number of diseased arterial beds and MACE is unknown. How MACE risk changes in individuals with type 2 diabetes (T2D) is also understudied. Furthermore, it is unknown whether heart failure (HF) status and hemoglobin A1c (HbA1c) levels influence outcomes in polyvascular disease. This analysis from the Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL) aimed to examine the risk associated with increasing number of diseased arterial beds on MACE and all-cause mortality (ACM).. Cox models were used to test associations between the number of diseased arterial beds and MACE and ACM. Prespecified interaction testing between number of diseased arterial beds with baseline HF, HbA1c (≤8% vs. >8%), and treatment assignment was performed.. Overall, 14,751 participants were included; 26.5% were without atherosclerosis, 58.9% had 1-bed, 12.3% had 2-bed, and 2.3% had 3-bed disease. An increasing burden of atherosclerotic disease was associated with increasing risk of MACE (adjusted HR [aHR] 1.71 [95% CI 1.46-2.02]; 2.61 [2.17-3.15]; 3.46 [2.69-4.45] for 1, 2, and 3 beds, respectively, p < 0.001 for all) and ACM (1.94 [1.56-2.42]; 3.03 [2.33-3.95]; 3.66 [2.59-5.18] for 1, 2, and 3 beds, respectively, p < 0.001 for all). Prespecified interaction testing did not reveal any significant associations.. In patients with T2D, compared to those without atherosclerotic vascular disease, risk of MACE and ACM increases incrementally with each additional diseased arterial bed.

Topics: Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Exenatide; Heart Failure; Humans; Risk Factors

The aim of this study was to investigate the effect of exendin-4 (Ex-4) on ventricular arrhythmias and calcium sparks-mediated calcium leak in a myocardial infarction-heart failure model.We studied the influence of exendin-4 on ventricular arrhythmogenesis in a rat myocardial infarction-heart failure model. In vivo arrhythmia studies (electrocardiogram [ECG] telemetry studies), ex vivo arrhythmia studies calcium sparks tests, and analysis of total and phosphorylated ryanodine receptor (RyR) 2 and CaMK-II were carried out in sham group, myocardial infarction (MI) group, MI + Ex-4 and MI + Ex-4 + Exendin9-39 (Ex9-39) groups.ECG telemetry studies showed an antiarrhythmic effect of exendin-4 with reduction of spontaneous ventricular arrhythmias. Exendin-4 abbreviated the APD

Topics: Animals; Arrhythmias, Cardiac; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Electrocardiography; Exenatide; Heart Failure; Male; Rats; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum

Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW's effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events.. The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed.. In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF.. https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Topics: Aged; Cause of Death; Diabetes Mellitus, Type 2; Disease Progression; Drug Administration Schedule; Exenatide; Female; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Male; Middle Aged; Patient Admission; Risk Factors; Time Factors; Treatment Outcome

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

We aimed to assess the effect of exenatide treatment as an adjunct to primary percutaneous coronary intervention (PCI) on long-term clinical outcome.. We performed a post hoc analysis in 334 patients with a first STEMI included in a previous study randomised to exenatide (n=175) or placebo (n=159) as an adjunct to primary PCI. The primary endpoint was a composite of all-cause mortality and admission for heart failure during a median follow-up of 5.2 years (interquartile range: 5.0-5.5). Secondary endpoints were all-cause mortality and admission for heart failure, individually. The primary composite endpoint occurred in 24% in the exenatide group versus 27% in the placebo group, p=0.44 (HR 0.80, p=0.35). Admission for heart failure was lower in the exenatide (11%) compared to the placebo group (20%) (HR 0.53, p=0.042). All-cause mortality occurred in 14% in the exenatide group versus 9% in the placebo group (HR 1.45, p=0.20).. In this post hoc analysis of patients with a STEMI, treatment with exenatide at the time of primary PCI did not reduce the primary composite endpoint or the secondary endpoint of all-cause -mortality. However, exenatide treatment reduced the incidence of admission for heart failure.

Topics: Adult; Aged; Aged, 80 and over; Electrocardiography; Exenatide; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Peptides; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prognosis; Treatment Outcome; Venoms

Diacylglycerol acyltransferase 1 (DGAT1) catalyzes the final step in triglyceride synthesis, the conversion of diacylglycerol (DAG) to triglyceride. Dgat1(-/-) mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function, we created cardiomyocyte-specific DGAT1 knock-out (hDgat1(-/-)) mice. hDgat1(-/-) mouse hearts had 95% increased DAG and 85% increased ceramides compared with floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide increased 5-fold in hDgat1(-/-) hearts, and fractional shortening (FS) was reduced. This was associated with increased expression of peroxisome proliferator-activated receptor α and cluster of differentiation 36. We crossed hDgat1(-/-) mice with previously described enterocyte-specific Dgat1 knock-out mice (hiDgat1(-/-)). This corrected the early mortality, improved FS, and reduced cardiac ceramide and DAG content. Treatment of hDgat1(-/-) mice with the glucagon-like peptide 1 receptor agonist exenatide also improved FS and reduced heart DAG and ceramide content. Increased fatty acid uptake into hDgat1(-/-) hearts was normalized by exenatide. Reduced activation of protein kinase Cα (PKCα), which is increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

Topics: Aging; Animals; Blood Glucose; Cholesterol; Diacylglycerol O-Acyltransferase; Enzyme Inhibitors; Exenatide; Fatty Acids; Gene Deletion; Gene Expression Regulation; Heart Failure; Humans; Intestines; Lipids; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Myocytes, Cardiac; Organ Specificity; Peptides; Phenotype; Protein Kinase C; Triglycerides; Venoms

Topics: Amyloid; Analgesics; Anticonvulsants; Antiparkinson Agents; Diabetes Mellitus, Type 2; Diphtheria-Tetanus-Pertussis Vaccine; Drug Approval; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Exenatide; gamma-Aminobutyric Acid; Heart Failure; Humans; Hydralazine; Hypoglycemic Agents; Indenes; Indoles; Islet Amyloid Polypeptide; Isosorbide Dinitrate; Patient Education as Topic; Patient Selection; Peptides; Pregabalin; Sleep Wake Disorders; United States; United States Food and Drug Administration; Venoms