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Exenatide, placebo comparable for major adverse CV events in type 2 diabetes
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The incidence of major adverse cardiovascular events was similar among adults with type 2 diabetes with or without previous cardiovascular disease treated with subcutaneous injections of extended-release exenatide and placebo, according to findings from EXSCEL that were presented at the European Association for the Study of Diabetes Annual Meeting and published simultaneously in The New England Journal of Medicine.
“The study results show that exenatide had no adverse effects on cardiovascular health, meaning that the drug can be used safely in people with type 2 diabetes who may have a wide range of existing cardiovascular conditions,” Rury R. Holman, MD, FRCP, of the diabetes trials unit at Churchill Hospital in Oxford, United Kingdom, said in a press release. “There did not seem to be any increase in the risk of hypoglycemia, acute pancreatitis, pancreatic cancer or medullary thyroid carcinoma.”
Holman and colleagues evaluated data from EXSCEL on 14,752 adults with type 2 diabetes (73.1% with previous CVD) randomly assigned to exenatide (Bydureon, AstraZeneca; n = 7,356) or placebo (n = 7,396) once per week between June 18, 2010, and Sept. 16, 2015, to examine the CV effects of exenatide.
The primary outcome included first occurrence of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. Secondary outcomes included death from any cause, death from CV causes, and the first occurrence of nonfatal or fatal MI, nonfatal or fatal stroke, hospitalization for acute coronary syndrome and hospitalization for heart failure. Follow-up was a median of 3.2 years and the trial was completed in April.
Mean HbA1c, body weight, systolic blood pressure, LDL cholesterol and triglycerides were lower and diastolic BP and heart rate were higher in the exenatide group than the placebo group.
In the intention-to-treat analysis, exenatide was noninferior to placebo with respect to safety (P for noninferiority < .001) and not superior to placebo with respect to efficacy (P for superiority = .06).
The risk for death from any cause was lower in the exenatide group than the placebo group (6.9% vs. 7.9%; HR = 0.86; 95% CI, 0.77-0.97). However, no significant differences were observed between the groups for rates of first fatal or nonfatal MI, fatal or nonfatal stroke and other secondary outcomes.
Both groups had similar rates of CV or peripheral revascularization procedures. The risks for receiving an additional cointerventional glucose-lowering agent (HR = 0.67; 95% CI, 0.63-0.71) and initiating long-term insulin therapy (HR = 0.61; 95% CI, 0.54-0.68) were lower, and use of open-label SGLT2 inhibitors and GLP-1 receptor agonists were lower in the exenatide group than the placebo group.
No significant differences were observed between the groups for incidence of serious adverse events, events of clinical interest or rates of severe hypoglycemia. Rates of confirmed events of acute pancreatitis, cancer overall, pancreatic cancer and medullary thyroid carcinoma were also similar between the groups.
“It’s encouraging for the field of diabetes to see these results in patients similar to what we see in clinical practice can have a potentially lower risk of death from all causes with the convenience of once-weekly dosing,” Adrian F. Hernandez, MD, MHS, of Duke Clinical Research Institute at Duke University School of Medicine, said in the release. “This confirms the importance of carrying out large studies to evaluate impacts on cardiovascular outcomes. EXSCEL largely mirrored what we’ve learned from other studies of this class of medications — that they are safe and may have outcomes benefits.” – by Amber Cox
References:
Holman RR, et al. Exenatide study of cardiovascular event lowering (EXSCEL): Primary results. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 11-15, 2017; Lisbon, Portugal.
Holman RR, et al. N Engl J. Med. 2017;doi:10.1056/NEJMoa1612917.
Disclosures: Hernandez reports he receives grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Luitpold, Merck and Novartis, personal fees from Amgen, Bayer, Boehringer Ingelheim, Boston Scientific and Pfizer, and grants from GlaxoSmithKline. Holman reports he receives grants from AstraZeneca, Bayer AG, personal fees from Amgen, Bayer AG and Servier, grants and personal fees from Boehringer Ingelheim and Merck Sharp & Dohme, and chairs or participates in independent data monitoring committees for Elcelyx, GlaxoSmithKline, Janssen and Takeda. Please see the study for all other authors’ relevant financial disclosures.
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Alan J. Garber, MD, PhD, FACE
EXSCEL is a randomized, placebo-controlled, multicenter trial of once-weekly exenatide vs. placebo in patients with type 2 diabetes. In this study, 14,752 patients were randomized to once-weekly exenatide or to placebo and followed for 5 years. Using a MACE endpoint, 839 patients treated with exenatide had an endpoint whereas 905 patients on placebo experienced a MACE event. This difference was not significantly superior, but was non-inferior, compared to placebo. This finding is in contrast to the findings of LEADER in which daily liraglutide was shown to be superior to placebo with regard to an expanded MACE endpoint reduction. One possible explanation for the difference is that exenatide has much less homology with human GLP-1 than does liraglutide. Another untested possibility is that once-daily administration yields different CV benefits than does once-weekly administration. The difference remains to be seen, although semaglutide, a once-weekly GLP-1 receptor agonist, which is highly similar to liraglutide in structure, has shown a striking reduction in CV events in a smaller CV safety trial.
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