Evidence Mounts Showing No Increased Risk of Heart Failure With Incretin-Based Antidiabetic Drugs

A new observational study suggests the incretin-based drugs for the treatment of diabetes mellitus do not increase the risk of heart failure when compared with commonly used combinations of antidiabetic drugs. The absence of harm was evident when investigators separately analyzed the risks of heart failure with the dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, as well as when they stratified use of the agents in patients with and without heart failure.

The results provide some measure of reassurance about the two drug classes, particularly the DPP-4 inhibitors, given concerns about heart failure that first emerged in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes-Thrombolysis in Myocardial Infarction 53), a large cardiovascular outcomes study.

“It’s important to remember that all drugs have benefits, risk, and some uncertainty,” lead investigator Kristian Filion, PhD (Jewish General Hospital, Montreal, Canada), told TCTMD. “As the evidence accumulates, we’re providing some reassurance and decreasing the uncertainty with respect to heart failure.”

Published March 23, 2016, in the New England Journal of Medicine, the retrospective, observational study includes nearly 1.5 million individuals from six large cohorts of patients from Canada, the United States, and the United Kingdom. Of these individuals, 29,741 were hospitalized for heart failure, amounting to an incidence rate of 9.2 events per 1,000 persons per year.

Among patients without a history of heart failure, use of the incretin-based drugs was not associated with an increased risk of heart failure when compared with patients taking two or more oral antidiabetic drug combinations. Similarly, when the researchers stratified the results by drug class, there was no signal of heart-failure risk among patients taking the DPP-4 inhibitors or GLP-1 receptor agonists.

When the researchers analyzed only patients with a history of heart failure, the results also failed to show an association between the use of the incretin-based therapies and hospitalizations for heart failure. Again, these results were similar when stratified by drug class.

The incretin-based therapies are typically prescribed as second- or third-line therapy in patients with type 2 diabetes, but use has increased “exponentially” in the last several years, according to Filion. During the study, approximately 12% of patients with type 2 diabetes were prescribed an incretin-based agent, with the large majority being the DPP-4 inhibitors. To TCTMD, Filion said the signal of risk with respect to hospitalizations for heart failure was unexpected in SAVOR-TIMI 53, pushing safety to the forefront among clinicians and researchers.

Bit of Backstory

In SAVOR-TIMI 53, which included more than 16,000 patients with type 2 diabetes and cardiovascular disease (or at high risk for cardiovascular disease), the use of the DPP-4 inhibitor saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) was associated with a 27% increased risk heart failure hospitalization.

Benjamin Scirica, MD (Brigham and Women’s Hospital, Boston, MA), who led the SAVOR-TIMI 53 study, also told TCTMD the heart-failure finding was unexpected, since investigators had anticipated, based on early clinical and preclinical data, that the drug class might provide protection from cardiovascular events. In the end, the trial showed saxagliptin did not increase or decrease the risk of ischemic cardiovascular events, but the heart-failure risk, a predefined secondary endpoint, led them on a 2-year expedition to determine if the finding was real, what the potential mechanism might be, and if there was a patient population particularly at risk.

“The short answer to a lot of that work is that we could not identify a mechanism, nor could we identify a patient population in whom saxagliptin was either more or less likely to lead to heart failure,” he said. “And I think we’ve still been left with the question about whether it was a chance finding or a real finding. You just can’t prove chance.”

In contrast to SAVOR-TIMI 53, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) study did not show a risk of heart failure, although heart-failure hospitalizations were numerically higher among patients treated with alogliptin (Nesina, Takeda Pharmaceuticals). In the TECOS study with sitagliptin (Januvia, Merck), there was no sign of an increased risk of heart failure or cardiovascular events with treatment.

Scirica said the SAVOR-TIMI 53 study sparked concerns about the drug class, and while the three major cardiovascular outcomes studies testing different DPP-4 inhibitors all go in different directions, he suspects the magnitude of risk—if it is real—is likely very small. Moreover, the concern about heart failure is lessened as the drugs are being used in lower-risk patients than those randomized in TECOS, SAVOR, and EXAMINE, all trials that included ACS or high-risk patients who had diabetes for at least 10 years.

“These are people pretty late in their diabetes so it really doesn’t speak to the patient who is younger without cardiovascular disease or risk factors, who maybe has only had diabetes for a year or two,” said Scirica. “In that population, these are a very well-tolerated class of drugs. There are very few side effects. It’s a modest glucose-lowering drug. People seem to be using it appropriately in that setting without a whole lot of hesitation.”

How the Agents Are Used Outside of Randomized Trials

Other researchers have also attempted to study the safety issue. Alison Goldfine, MD (Joslin Diabetes Center, Boston, MA), and others published data last year from a US commercial insurance claims database looking at cardiovascular outcomes among patients treated with DPP-4 inhibitors. Goldfine told TCTMD their work also was focused on patients with established cardiovascular disease and found similar results as the NEJM paper: the use of a DPP-4 inhibitor did not increase the risk of cardiovascular events, including heart failure. 

To TCTMD, Scirica said there are important caveats with observational studies, including the potential for residual confounding where younger, healthier patients at a low risk for heart failure might be treated with the DPP-4 inhibitors. While observational analyses can provide some reassurance, they do not trump the evidence from randomized controlled trials. 

“Say we did this the other way, where this was published first, and everybody said, ‘Great, these drugs seem to lower the risk of heart failure,’” said Scirica. “And then three large randomized trials came out and showed there was no difference whatsoever and maybe one of them went the wrong way; everybody would say this was another example of hormone replacement therapy. The randomized trials have to trump that.

A large outcomes trial testing the GLP-1 receptor agonist lixisenatide (Lyxumia, Sanofi) was published last year, and investigators showed the drug had a neutral effect on cardiovascular events, including heart failure. Just a few weeks ago, Novo Nordisk released the topline results of the LEADER trial, a large cardiovascular outcomes study in patients treated with liraglutide (Victoza). In that trial, the use of the GLP-1 receptor agonist significantly reduced the risk of cardiovascular events—a composite of cardiovascular death, nonfatal MI, and nonfatal stroke—in patients with type 2 diabetes. Full results of LEADER will be presented in June at the American Diabetes Association Scientific Sessions. 

Scirica said that while DPP-4 inhibitors and GLP-1 analogues are considered incretin-based drugs, they have different mechanisms of action. The early data from the GLP-1 analogue studies, particularly the positive results from LEADER, suggest there is something different about these agents.

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