Effects of intravenous exenatide in type 2 diabetic patients with congestive heart failure: a double-blind, randomised controlled clinical trial of efficacy and safety

Nathanson, David; Ullman, Bengt; Löfström, Ulrika; Hedman, Anders; Frick, Mats; Sjöholm, Åke

doi:10.1007/s00125-011-2440-x

Cited by 87 publications

(59 citation statements)

References 41 publications

(51 reference statements)

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“…Similar mitigating results were reported with an infusion of exenatide (0.12 pmol/kg/min for 6 h) in 20 T2D patients with HF and LVEF ≤ 35% vs saline infusion in a crossover trial [30]. A significant increase in cardiac output was observed, mainly due to a significant increase in heart rate, but stroke volume remained almost unchanged with exenatide vs saline [30].…”

Section: Glp-1 and Cardiac Functionsupporting

confidence: 78%

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GLP-1 receptor agonists and heart failure in diabetes

Scheen

2017

Diabetes & Metabolism

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The prevalence of heart failure (HF) is increasing in patients with type 2 diabetes (T2D), and glucose-lowering agents have distinctive effects on the risk of developing HF that requires hospitalization. Such an increased risk has been consistently reported with thiazolidinediones (glitazones) and perhaps also with the dipeptidyl peptidase (DPP)-4 inhibitor saxagliptin (at least in SAVOR -TIMI 53), whereas a markedly decreased risk was highlighted with the sodium -glucose cotransporter type 2 (SGLT2) inhibitor empagliflozin in EMPA-REG OUTCOME. Yet, the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on myocardial function remain controversial. Whereas some promising observations have been reported in various animal models, the effects of GLP-1RAs on myocardial function in humans are more heterogeneous, while the positive effect on left ventricular ejection fraction (LVEF), if any, appears to be inconsistent and rather modest in most patients with HF. However, no increased risk of hospitalization for HF has been reported with GLP-1RAs in meta-analyses of phase-II/III trials (exenatide, albiglutide, dulaglutide, liraglutide), demonstrating the safety of this pharmacological class, and such findings have been confirmed by three large prospective cardiovascular outcome trials (ELIXA with lixisenatide, LEADER with liraglutide and SUSTAIN-6 with semaglutide). In particular, LEADER reported a trend towards a reduction in HF hospitalization (-13%, P = 0.14), together with a significant reduction in cardiovascular and all-cause mortality in patients with T2D at risk of cardiovascular disease. These results are reassuring in the face of the somewhat negative results of the FIGHT trial, which evaluated the effects of liraglutide in patients with advanced HF and low LVEF, such that further studies and caution are now required when using this agent to treat such patients in clinical practice.

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Section: Glp-1 and Cardiac Functionsupporting

confidence: 78%

“…A significant increase in cardiac output was observed, mainly due to a significant increase in heart rate, but stroke volume remained almost unchanged with exenatide vs saline [30].…”

Section: Glp-1 and Cardiac Functionmentioning

confidence: 88%

GLP-1 receptor agonists and heart failure in diabetes

Scheen

2017

Diabetes & Metabolism

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“…These drugs lower glucose levels by inhibiting the secretion of glucagon, promoting the release of insulin in response to hyperglycemia, slowing gastric emptying, and augmenting satiety. 14 On the basis of some evidence of cardioprotection in preliminary studies in animal models 15,16 and in pilot studies of myocardial ischemia 17,18 and heart failure in humans, 19 it was postulated 20,21 that in addition to improving glycemic control and promoting weight loss, GLP-1-receptor agonists may improve cardiovascular outcomes.…”

mentioning

confidence: 99%

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

Pfeffer¹,

Claggett²,

Dı́az³

et al. 2015

N Engl J Med

197

360

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BACKGROUND: Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS: We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.). Jean-Claude (2015). Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.

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“…Exenatide and liraglutide lowered BP, reduced myocardial infarct size, and improved systolic and diastolic cardiac function in various animal models of ischemia-reperfusion injury and congestive heart failure (HF) (16,21,22). Infusion of exenatide during two consecutive days in men with T2DM and HF led to significantly increased cardiac index and decreased pulmonary capillary wedge pressure compared to placebo (23) (Figure 1).…”

Section: Glp-1 Receptor Agonists (Ras)mentioning

confidence: 99%