TECOS: Reassurance on Sitagliptin's Safety With Heart-Failure Deep Dive

September 01, 2015

LONDON, UK — In an analysis of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin, researchers confirm the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) is not associated with any risk of developing heart failure in diabetic patients who received the drug[1].

The absence of a heart-failure signal in TECOS is not unknown, but investigators confirmed the safety of sitagliptin as part of a prespecified secondary analysis that examined heart-failure end points and multiple patient subgroups.

Dr Frans van de Werf

Presenting the results today at the European Society of Cardiology (ESC) 2015 Congress, Dr Paul Armstrong (University of Alberta, Edmonton) and Dr Frans Van de Werf (University of Leuven, Belgium) report no increased risk of hospitalization for heart failure even among diabetic patients with prior heart failure who received sitagliptin.

"I think, with over 14,000 patients, we've definitively shown that it's safe, and that's great news," Armstrong told heartwire from Medscape. "As a cardiologist, along with the endocrinologists, we're very satisfied that the data are clean—it's prespecified. It's good news for people who want to use this drug."

The bottom line, said Armstrong, is that sitagliptin should be the preferred DPP-4 inhibitor in diabetic patients, given the 27% increased risk of heart failure observed with saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) in SAVOR TIMI 53. In April, a US Food and Drug Administration (FDA) advisory committee recommended an update to the label for saxagliptin to indicate there is an increased risk of heart failure and a trend toward higher all-cause mortality.

Alogliptin (Nesina, Takeda Pharmaceuticals), another of the DPP-4 inhibitors, was tested in the large cardiovascular safety study EXAMINE and was not associated with any increased risk of heart failure. However, there was a numerically greater number of heart-failure events with alogliptin (hazard ratio 1.19; 95% CI 0.89–1.59). Although the excess in events was not statistically significant, FDA reviewers and committee members noted that EXAMINE was not designed primarily to evaluate heart failure and recommended the alogliptin label also carry a warning about the potential risk of heart failure.

Just three days ago, the FDA warned the DPP-4 inhibitors can also cause severe joint pain, reporting 33 cases of severe arthralgia in patients receiving the drugs in the past 7 years. The agency said the pain will go away, often within a month, if patients discontinue the medication. Sitagliptin was associated with 28 of the 33 reported events.

Deeper Dive Into Heart-Failure Events

Dr Paul Armstrong

In TECOS, which was first presented at the American Diabetes Association (ADA) Scientific Sessions last June, investigators enrolled 14,671 patients with type 2 diabetes and established cardiovascular disease to sitagliptin or placebo on top of their existing therapy. Designed as a safety study, there was no significant difference among those treated with sitagliptin and those treated with placebo in terms of the primary end point, a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina.

At the ESC meeting, Armstrong and Van de Werf presented data from a prespecified secondary analysis looking at heart failure and related outcomes. In this analysis, there was no difference in heart failure, heart failure/cardiovascular mortality, or heart failure/all-cause mortality among the sitagliptin- and placebo-treated patients after adjustment for baseline heart failure and other variables.

In a subgroup analysis of more than 2600 patients with prior heart failure, there was no increased risk of heart failure among those treated with sitagliptin. Overall, the group observed no difference in total heart-failure events (first and recurrent events) or mortality among patients with at least one hospitalization for heart failure in the sitagliptin-treated patients.

TECOS: Clinical Outcomes in Patients With Prior Heart Failure

Outcome Sitagliptin, n=1303 (%) Placebo, n=1340 (%) P
Hospitalization for heart failure 7.4 7.0 0.86
Cardiovascular death 9.2 9.9 0.46
Hospitalization for heart failure/CV death 14.0 14.3 0.71
All-cause death 12.7 13.6 0.46

"I think we can conclude that sitagliptin can be safely used in patients with type 2 diabetes without the concerns that have been raised about worsening heart failure," said Armstrong.

Addressing why one study showed a clear signal of heart-failure risk, one suggested only a trend, and the other found no signal at all, Armstrong said there might be differences in the patients enrolled, their background care, or even differences in how heart-failure events were defined and documented in the trials. However, he also noted there could be intrinsic pharmacological differences among the DPP-4 inhibitors, and these might explain the different outcomes. All of these reasons, however, are just speculation, said Armstrong.

Interestingly, another diabetes drug gained some traction in the media last week when Eli Lilly and Boehringer Ingelheim announced the top-line results of their cardiovascular safety trial with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance). Instead of simply showing safety in the 7000-patient trial of patients with diabetes, the company said the drug, given on top of standard care, reduced the primary composite end point of cardiovascular mortality, nonfatal MI, or nonfatal stroke compared with patients receiving placebo.

The results will be presented September 17, 2015 at the European Association for the Study of Diabetes in Stockholm, Sweden.

"All of us look forward to seeing whether the data, which have been suggested in the press release, are validated in a proper scientific, peer-reviewed forum," said Armstrong. If the results hold up, such a drug and its advantage in terms of reducing clinical cardiovascular outcomes would have the potential to alter existing guidelines, he added.

TECOS was funded by Merck. Armstrong reports research grants from Boehringer Ingelheim, Merck, Bayer, and CSL; educational grants from Bayer, AstraZeneca, Merck, Servier, and Novartis; and consulting for Boehringer Ingelheim, Merck, AstraZeneca, and Eli Lilly.

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