Trials of Incretin Drugs Examine Cardiovascular Risk: Investigators for TECOS and ELIXA Report Results at ADA
Outcomes from 2 major cardiovascular trials evaluating the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin and the glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide were presented at the American Diabetes Association’s 75th Scientific Sessions held in Boston this past June. Results from Trial to Evaluate Cardiovascular Outcomes After Treatment with Sitagliptin (TECOS) of sitagliptin in patients with type 2 diabetes and cardiovascular disease showed no increase risk of cardiovascular events.1 Findings from Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) of patients with type 2 diabetes who experienced an acute coronary syndrome (ACS) event showed that lixisenatide was noninferior, although not superior, to placebo for cardiovascular safety.
In 2008, the FDA mandated more stringent clinical trials for all new diabetes drugs. The FDA now requires that all new drugs approved for diabetes to lower glucose rule out cardiovascular toxicity. The agency requires that these glucose-lowering agents have an upper limit of harm no more than 1.3.
The study investigators said the TECOS trial should reassure clinicians about the cardiovascular safety of sitagliptin for this high-risk patient population.
“In this study, we specifically looked at the rates of heart failure events and found there were no differences,” said Eric Peterson, MD, Duke Clinical Research Institute, co-chair of the TECOS executive committee, “There was no hint of heart failure seen in the sitagliptin-treated patients relative to placebo. Given the size of our study, the longer duration of follow-up, as well as the higher risk of our population, we feel that this very adequately addresses the question and puts to bed the question that there is any risk for heart failure with this drug. We feel quite confident this drug can be used very safely in patients with cardiovascular disease.”
TECOS is the third major cardiovascular trial of DPP-4 inhibitors. Two previous cardiovascular outcome trials of other DDP-4 inhibitors— Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 (SAVOR-TIMI 53) and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE)—did not show an increase or decrease in the number of major adverse cardiovascular events but did raise safety concerns regarding a possible elevated risk of hospitalization for heart failure. TECOS enrolled its first patients in 2008, around the same time the FDA required that new antihyperglycemic agents not only show glucose-lowering effects but are also not associated with clinically meaningful increases in rates of major adverse cardiovascular events.
TECOS was a randomized, double-blind, placebo-controlled, large-scale, cardiovascular outcome study that included 14,671 patients with type 2 diabetes and established cardiovascular disease in the intent-to-treat analysis. The study was conducted at 673 sites in 38 countries. Patients were at least 50 years old with a hemoglobin A1c (HbA1c) of 6.5% to 8.0% and treated with stable doses of 1 or 2 oral antihyperglycemic agents (metformin, pioglitazone, sulfonylurea, or insulin). Patients were randomized 1:1 to sitagliptin 100 mg daily (n=7332) or placebo (n=7339), in addition to usual care. The primary composite cardiovascular end point was defined as the first confirmed event of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina (UA). The secondary composite cardiovascular end point was the same as the first with exclusion of hospitalization for UA. Other secondary end points included death from any cause and hospitalization from heart failure.
During a median follow-up of 3.1 years, there was a small difference in HbA1c (least-squares mean difference for sitagliptin vs placebo,−0.29%; 95% confidence interval [CI], −0.32-−0.27). Speaking at the press conference, study co-chair Rury Holman, FRCP, director of the University of Oxford Diabetes Trial Unit and co-chair of TECOS executive committee, emphasized that the study was designed to achieve “glycemic equipoise” between the 2 treatment arms. “This is a glucose-lowering drug being tested for cardiovascular benefit or harm,” he said. “The idea was not to see a glucose difference. That’s important because we don’t want a glucose difference that might have influenced the cardiovascular outcomes one way or another.”
The Table highlights the key primary and secondary outcomes. In terms of safety, there was no significant difference in the overall incidence of infections, cancer, renal failure, or severe hypoglycemia between the sitagliptin group and the placebo group. Confirmed acute pancreatitis events were uncommon overall but numerically more frequent in the sitagliptin group than in the placebo group (23 vs 12 events; respectively), but the difference was not statistically significant. Confirmed pancreatic cancers were also uncommon overall but numerically less frequent in the sitagliptin group than the placebo group (9 vs 14 events; respectively).
When asked how clinicians can take the data from the 3 cardiovascular trials of DDP-4 inhibitors and put into clinical practice, Peterson said, “As cardiologists, we’re driven by the evidence. We can look at only the evidence we have from studies. These are not cross-comparative studies, so the degree to which we extrapolate from one drug to another is done with caution. That said, if you look at sitagliptin specifically, it is remarkably clean with just about every signal looked at, every subgroup looked at, and in every way we can look at the data. We teased this data backward and forward. Everything comes up looking like the drug does not have a cardiovascular safety signal.”
Although lixisenatide did not show a benefit on cardiovascular outcomes in high-risk diabetes patients, the GLP-1 agonist did not cause any harm, according to investigators, who noted that ELIXA is the first clinical trial to examine cardiovascular safety in a GLP-1 receptor agonist.
Lead investigator and cardiologist Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital, explained that although EXLIXA was configured as a superiority trial, the trial met the FDA requirement for cardiovascular safety for diabetes drugs. “We are well within that safety range but on the other hand we cannot say randomization to lixisenatide improved the prognosis of these high-risk patients,” he said. “This should provide physicians and patients with reassurance for this adjunctive therapy to better control their glucose status.”
ELIXA was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase 3 trial conducted in 49 countries that enrolled 6068 patients with type 2 diabetes who had an ACS event within 180 days following hospital admission for the ACS. The mean age of the patients was 60 years with an HbA1c >7% and an average duration of diabetes of 9 years. A majority of the patients had an MI as their qualifying ACS event for participation in the trial rather UA, which accounted for only 17% in both groups. Patients were randomized 1:1 to lixisenatide 10 µg a day (n=3034) or placebo (n=3034). The dose of lixisenatide could be down- or up-titrated to a maximum of 20 µg a day in the absence of symptoms such as hypoglycemia and GI distress.
During a follow-up period of more than 2 years, the researchers found little difference between the lixisenatide and placebo arms in terms of the primary composite end point—cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for UA (13.4% vs 13.2%, respectively; hazard ratio [HR], 1.02; 95% CI, 0.89-1.17). When adding heart failure hospitalizations to the primary end point, the results were also neutral between the 2 groups (HR, 0.97; 95% CI, 0.85-1.10)
The study also showed that those who took lixisenatide were not more likely to experience problems with hypoglycemia compared with those who took placebo, despite slightly better HbA1c control (mean post-baseline difference −0.27%; 95% CI, −0.32-−0.22). In addition, there was no increase in pancreatitis, pancreatic cancer, or drug-related systemic allergy and a modest benefit in terms of weight gain with lixisenatide. However, adverse events, particularly nausea and vomiting were increased.
“There is no reason from our result not to use lixisenatide as a GLP-1 receptor agonist as another tool in the toolbox to maintain good glucose control even in high-risk patients,” said ELIXA investigator Matthew Riddle, MD, professor of medicine in the division of endocrinology, diabetes, and clinical nutrition at Oregon Health & Science University.
The drugmaker Sanofi plans to resubmit a New Drug Application for lixisenatide for FDA later this year.
1.Green J, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242.