Sitagliptin is 'Safest' DPP-4 Inhibitor for Type 2 Diabetes

A deeper dive into data from the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) with the type 2 diabetes drug sitagliptin (Januvia, Merck), confirming that the dipeptidyl peptidase-4 (DPP-4) is not associated with any risk of developing heart failure in diabetic patients at high cardiovascular risk, has been published in JAMA Cardiology.

"Overall, this is very reassuring data for sitagliptin," says cardiologist Benjamin M Scirica, MD, MPH, of Harvard Medical School, Boston, Massachusetts, writing in an accompanying editorial.

These results from TECOS were first reported at the European Society of Cardiology meeting last September in London and represent a prespecified secondary analysis of the overall TECOS study, the findings of which were presented at the American Diabetes Association conference in June 2015.

These newly published data, by cardiologist Darren McGuire, MD, of the University of Texas Southwestern Medical Center, Dallas, and colleagues, come on the heels of the FDA requiring safety warnings with regard to the potential for increased risk for heart failure to be added to the labels of two other dipeptidyl peptidase-4 inhibitors: saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda) — and combination products containing these agents.

"Of the three DPP-4 inhibitors, sitagliptin appears to have the safest cardiovascular profile," states Dr Scirica.

Why the Discrepancy? Likely DPP-4 Inhibitors Differ

Dr Scirica says that, in this new paper, Dr McGuire and colleagues provide "a very detailed assessment of the hospitalization for heart failure end point in TECOS. Regardless of how it was analyzed…there was no signal of any increased risk of hospitalization for heart failure…by time or in different subgroups."

Dr McGuire and colleagues concur: "The TECOS findings do not confirm the signals for increased risk of hospitalization of heart failure observed in two previous large DPP-4 inhibitor trials [SAVOR-TIMI 53 with saxagliptin and EXAMINE with alogliptin]," they write.

So, Dr Scirica wonders, what is the explanation for these discordant findings from three cardiovascular-outcomes trials with agents from the same drug class?

"The patient populations in the three trials were more similar than different," he observes. And "although there were some distinctions…[these] subtle differences…are unlikely to explain the differences in outcomes.

"Moreover, all three studies used a similar well-defined heart-failure end point adjudicated by a blinded committee."

One possible explanation is "chance," or "another possibility is that the different DPP-4 inhibitors have different pharmacologic properties."

He comes down in support of the latter: "One would have to hypothesize that there is a differential selectivity between DPP-4 inhibitors for non-[glucagonlike peptide 1] GLP-1 substrates that somehow tips the balance and worsens the risk for hospitalization for heart failure.

"No class of diabetes drugs has now been as thoroughly evaluated as the DPP-4 inhibitors," he adds. "Overall, they are safe without any increase in cardiovascular death, myocardial infarction, or stroke."

Nevertheless, he reiterates, sitagliptin appears to have the "safest" cardiovascular profile.

EMPA-REG Has Raised the Bar: Watch This Space

Despite the reassuring findings of TECOS with regard to cardiovascular safety, the trial did not show any cardiovascular benefit of sitagliptin and, prior to September last year, nor had any other cardiovascular outcomes trial of any type 2 diabetes drug.

But the EMPA-REG OUTCOME findings, reported at the European Association for the Study of Diabetes in Stockholm, changed all of that.

Empagliflozin (Jardiance, Boehringer Ingelheim) — from another class of agent for type 2 diabetes, the sodium-glucose cotransporter-2 (SGLT-2) inhibitors — was associated, for the first time, with a reduction in cardiovascular death and overall mortality in a population similar to TECOS; EMPA-REG was thus hailed as a "landmark" trial.

Empagliflozin was also associated with a reduction in hospitalization for heart failure in EMPA-REG, thought to be the main mechanism by which the drug lowered cardiovascular deaths, since it didn't affect myocardial infarction or stroke — a point that has been the subject of much discussion.

These EMPA-REG data, "which require confirmation from the other ongoing SGLT-2 inhibitor cardiovascular-outcomes trials," are "the first definitive demonstration that a diabetes drug can improve cardiovascular outcomes," notes Dr Scirica, and the SGLT-2 inhibitors "have now 'raised the bar' on expectations of new diabetes therapies," he adds.

He also mentions the recent report of improved cardiovascular outcomes with the older type 2 diabetes drug pioglitazone in the IRIS study in patients with insulin resistance but not diabetes. [However, pioglitazone is also well-known for its associations with higher rates of edema, weight gain, and heart failure.]

"Good Luck to the Guideline Writers"

But Dr Scirica doesn't discuss the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial with the GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) — which, according to the company, significantly reduces the risk of major adverse cardiovascular events.

This is possibly because only top-line results for LEADER have so far been released; the full data are to be presented at the American Diabetes Association meeting in New Orleans in June.

LEADER followed 9340 high-risk adults with type 2 diabetes for 5 years, and it's fair to say the findings are eagerly awaited by the diabetes community.

After years of nothing, diabetologists now have the tantalizing possibility of three drugs for type 2 diabetes that show proven cardiovascular benefit — empagliflozin, liraglutide, and pioglitazone.

Asked by Medscape Medical News how this would all pan out, Dr McGuire commented: "Quite a nice conundrum to have…good luck to the guideline writers!"

Dr McGuire reported receiving personal fees from Boehringer Ingelheim, Janssen, Sanofi, Genentech, Merck Sharp & Dohme, Daiichi Sankyo, Lilly, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, AstraZeneca, Orexigen, Lexicon, Eisai, Regeneron, Merck, Pfizer, and Genfit. Disclosures for the coauthors are listed in the article. Dr Scirica reports research grants via the TIMI Study and Brigham and Women's Hospital from AstraZeneca, Daiichi-Sankyo, Gilead, Eisai, Merck, and Poxel, as well as consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Boston Clinical Research Institute, Covance, Dr Reddy's Laboratory, Eisai, Elsevier Practice Update Cardiology, Forest Laboratory, GE Healthcare, Gilead, GlaxoSmithKline, Lexicon, Merck, St Jude's Medical, and the University of Calgary.


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Sitagliptin is 'Safest' DPP-4 Inhibitor for Type 2 Diabetes. Medscape. Apr 14, 2016.

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