Adding exenatide to usual care in T2D safe for the heart
The addition of once-weekly GLP-1* receptor agonist exenatide to usual care did not increase the risk of major cardiovascular events (MACE) compared with usual care alone in patients with type 2 diabetes (T2D) regardless of the presence of prior cardiovascular (CV) disease, according to the EXSCEL** study presented at EASD 2017 in Lisbon, Portugal.
“Exenatide was noninferior to placebo with respect to CV safety but was not superior to placebo with respect to [CV] efficacy,” said senior investigator Dr Adrian Hernandez of Duke University in Durham, North Carolina, US.
After a median follow-up of 3.2 years, the trial met its primary safety endpoint of noninferiority in terms of the composite 3-point MACE of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke (11.4 percent vs 12.2 percent for exenatide vs placebo, hazard ratio [HR], 0.91; p<0.001 for noninferiority). [EASD 2017, session S29; N Engl J Med 2017;doi:10.1056/NEJMoa1612917]
However, exenatide was not superior to placebo in terms of efficacy ─ the lower MACE was not statistically different from the placebo arm (HR, 0.91; p=0.061 for superiority).
“The study results show that exenatide had no adverse effects on CV health, meaning that the drug can be used safely in people with T2D who may have a wide range of existing CV conditions,” said lead author Dr Rury Holman, director of the University of Oxford Diabetes Trials Unit in Oxford, UK.
Noting that all-cause mortality was lower in the exenatide vs the placebo groups (6.9 percent vs 7.9 percent, HR, 0.86) although this was not associated with a lower CV mortality, Hernandez said, “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.”
“The reduction in all-cause mortality is unlikely to be explained by the glucose-lowering effect of exenatide long-acting release and suggests a pleiotropic action of the drug,” according to an independent commentator, Dr Francesco Giorgino of Università degli Studi di Bari Aldo Moro in Bari, Italy.
Similar rates of other key secondary outcomes were also observed between the two treatments, including rates of CV death (p=0.096), fatal/nonfatal MI (p=0.622), fatal/nonfatal stroke (p=0.095), hospitalization for heat failure (p=0.485), and hospitalization for acute coronary syndrome (ACS; p=0.402).
There were no clinically relevant differences in the rate of serious adverse events between the two groups (16.8 percent vs 16.6 percent).
“No specific safety issues were observed during the trial, particularly with respect to acute pancreatitis, pancreatic cancer or medullary thyroid cancer,” observed Holman, although there were more cases of thyroid papillary carcinomas with exenatide vs placebo (10 vs four).
“There was no adverse signal with respect to heart failure, despite the higher mean heart rate in the exenatide group than in the placebo group,” he added.
Putting EXSCEL into perspective: Comparison with other trials
The multinational, double-blind, phase IIIb/IV study randomized 14,752 patients with T2D, with or without previous CV disease (73.1 percent with history), in a 1:1 ratio to subcutaneous exenatide 2 mg once weekly or a matching placebo, in addition to usual care. Other open-label diabetes medications were allowed except for other GLP-1 receptor agonists.
Throughout the study period, lower overall mean values of glycated haemoglobin (least-squares mean difference [LSMD], -0.53 percent; p<0.001), body weight (LSMD, -1.27 kg; p<0.001), systolic blood pressure (LSMD, -1.57 mm Hg; p<0.001), and LDL cholesterol (LSMD, -0.04 mmol/L; p=0.004); but higher overall mean heart rate (2.51 beats/min; p<0.001) and diastolic blood pressure (0.25 mm Hg; p=0.02) were observed in the exenatide arm compared with the placebo arm.
“Comparing GLP-1 receptor agonist vs usual care, differences in HbA1c and other CV risk factors were smaller in EXSCEL than in SUSTAIN-6, but similar to those in LEADER; less hypoglycaemia was seen only in LEADER,” commented Giorgino. “It is unclear if these factors play a role in the observed results.”
He also added that the lack of CV benefit in EXSCEL could be due to multiple factors, noting that the EXSCEL trial has a shorter duration of follow-up (3.2 years vs 3.8 years) and exposure to study drug (2.4 years vs 3.5 years) compared with the LEADER trial.
“It is unclear which target T2D population is best to see the protective effects of GLP-1 receptor agonists on the CV system. Patients with ACS may be at too high risk, as in ELIXA. Evidence from lower-risk patients, as in EXSCEL, is important,” Giorgino added.
Nonetheless, lead author Holman noted that the drug class, taken as a whole, shows consistency in CV outcomes, saying, “The EXSCEL CV and mortality findings were consistent with those seen with other GLP-1 agonists in the ELIXA, LEADER, and SUSTAIN-6 trials, further supporting the use of these agents for the treatment of T2D.”
“Exendin-4-based and GLP-1-based agonists have the potential to differ in signalling and biological effects. However, as of today, they seem to not differ, at least from a qualitative point of view, in their direct positive effects on CV cells and tissues,” suggested Giorgino.
“Therefore, this trial is leading to more research needed to clarify these issues,” he concluded.