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Trials of Incretin Drugs Examine Cardiovascular Risk

Eileen Koutnik-Fotopoulos
August 2015

Boston, MA—Outcomes from 2 major cardiovascular (CV) trials of the DPP-4 inhibitor sitagliptin and the glucagon- GLP-1 receptor agonist lixisenatide were presented at the ADA meeting.

Results from TECOS of sitagliptin in patients with type 2 diabetes and CV disease showed no increased risk of CV events [N Engl J Med. 2015;doi:10.1056/ NEJMoa1501352]. Findings from ELIXA of patients with type 2 diabetes who experienced an acute ACS event showed that lixisenatide was noninferior to placebo for CV safety.

Sitagliptin Demonstrates CV Safety

Investigators said that the trial should reassure clinicians about the CV safety of sitagliptin for high-risk patients.

“We specifically looked at the rates of heart failure (HF) 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 HF seen in the sitagliptin-treated patients. 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 puts to bed the question that there is any risk for HF with this drug.”

TECOS is the third major CV trial of DPP-4 inhibitors. Two previous outcome trials of other DDP-4 inhibitors did not show an increase or decrease in the number of major adverse CV events, but did raise concerns about a possible elevated risk of hospitalization for HF. TECOS enrolled its first patients in 2008, around the same time the FDA required that new antihyperglycemic agents show both glucose-lowering effects and that they are not associated with clinically meaningful increases in rates of major adverse CV events.

TECOS was a randomized, double- blind, placebo-controlled, large-scale, CV outcome study that included 14,671 patients with type 2 diabetes and established CV disease. The study was conducted at 673 sites in 38 countries. Patients were at least 50 years of age with an HbA1c of 6.5% to 8.0% and treated with stable doses of 1 or 2 oral antihyperglycemic agents. Patients were randomized 1:1 to sitagliptin 100 mg daily (n=7332) or placebo (n=7339), in addition to usual care. The primary composite CV endpoint was defined as the first confirmed event of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina (UA).

During a median follow-up of 3.1 years, there was a small difference in HbA1c. Study co-chair Rury Holman, FRCP, director, University of Oxford Dia- betes 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 CV 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 CV 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. Confirmed pancreatic cancers were also uncommon.

When asked how clinicians can put the data from the 3 CV trials of DDP-4 inhibitors into clinical practice, Dr Peterson said, “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. We teased this data backward and forward. Everything comes up looking like the drug does not have a CV safety signal.”

Lixisenatide: Another Tool For Glucose Control

In the ELIXA trial, although lixisenatide did not show a benefit on CV outcomes in high-risk diabetes patients, the GLP-1 agonist did not cause any harm, according to investigators. This is the first clinical trial to examine CV safety in a GLP-1 receptor agonist.

Lead investigator and cardiologist Marc Pfeffer, MD, PhD, Brigham and Women’s Hospital, explained that although ELIXA was configured as a superiority trial, the trial met the FDA requirement for CV 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 event. 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. UA 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 titrated up to a maximum of 20 μg a day in the absence of symptoms such as hypoglycemia and gastrointestinal distress, or down if not tolerated.

During a follow-up period of more than 2 years, the researchers found little difference between the lixisenatide and placebo arms in terms of composite CV death, nonfatal MI, nonfatal stroke, or hospitalization for UA (13.4% versus 13.2%, respectively). When adding HF hospitalizations to the primary endpoint, the results were also neutral between the 2 groups.

The study also showed that those who took lixisenatide were not more likely to experience problems with hy- poglycemia compared with those who took placebo, despite slightly better HbA1c control. In addition, there was no increase in pancreatitis, pancreatic cancer, or drug-related systemic allergy. There was a modest benefit in terms of weight gain with lixisenatide. However, adverse events were increased.

“There is no reason from our results not to use lixisenatide as a GLP-1 receptor agonist as another tool to maintain good glucose control even in high-risk patients,” said ELIXA investigator Mat- thew Riddle, MD, professor of medicine, division of endocrinology, diabetes & clinical nutrition, Oregon Health & Science University.

The drugmaker, Sanofi, plans to resubmit a New Drug Application for lixisenatide for FDA approval later this year.—Eileen Koutnik-Fotopoulos