Over a month ago, the US Food and Drug Administration (FDA) rejected Merck's bid to add data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) to the prescribing information for the DPP-4 inhibitor sitagliptin (Januvia), which is licensed for the treatment of type 2 diabetes.
Merck declined an invitation from Medscape Medical News to provide further details about the "complete response letter" it received from the FDA in answer to its application for a supplemental new drug application (NDA).
"Merck is reviewing the letter and will discuss the next steps with the FDA," the company noted in a press release.
Of two experts quizzed by Medscape Medical News about the FDA decision, one expressed surprise that the request was rejected, while the other said the verdict may depend on what the company was actually asking for.
CV Safety Saga of Recent Diabetes Drugs
Trials such as TECOS were designed to demonstrate cardiovascular safety of type 2 diabetes drugs in the wake of the rosiglitazone (Avandia, GlaxoSmithKline) scandal.
Prior to TECOS, two other dipeptidyl peptidase-4 (DPP-4) inhibitors had shown a signal for heart failure in their respective cardiovascular outcomes trials — the SAVOR study with saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and the EXAMINE trial of alogliptin (Nesina, Takeda) and both of these agents now carry warnings about heart failure on their US labels.
In contrast, the TECOS trial, reported in June 2015, showed no signal for heart failure with sitagliptin, and overall the trial was neutral for cardiovascular outcomes — there was no CV benefit of sitagliptin, but no harm either.
This has led to sitagliptin being touted as the "safe" DPP-4 inhibitor.
However, just a few months later, another CV outcomes trial with a different diabetes drug class unexpectedly showed not just an absence of cardiovascular harm, but a reduction in deaths — reported in September 2015, the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) reduced cardiovascular mortality in patients with type 2 diabetes and established CV disease in the landmark EMPA-REG study.
Then, in June 2016, with a different drug class again, the glucagon peptide-1 (GLP-1) agonists, liraglutide (Victoza, Novo Nordisk) significantly reduced the rates of major adverse cardiovascular events in a similar patient population in the LEADER trial.
These two trials turned the type 2 diabetes world on its head. Endocrinologists had never before seen trials in which a glucose-lowering agent reduced cardiovascular events, and the results have led to a moving of the landscape in terms of type 2 diabetes drugs and their use.
Consequently, in December 2016, the FDA approved an additional indication for empagliflozin, for reducing risk of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease.
Speculations About the Rejected Request
Set against this background, Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California, said it's hard to speculate on why the FDA didn't grant the request to add the TECOS data to the sitagliptin label, because it's not really clear what the company asked for.
"Was is…to support cardiovascular safety, as assessed by the results of the primary end point," which showed no difference between sitagliptin or placebo in terms of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina? he wondered.
"Or [was it] the results of the secondary end point of hospitalization for heart failure, which showed no increased risk — unlike saxagliptin or alogliptin — [to differentiate sitagliptin from other DPP-4 inhibitors]?"
In rejecting the request, the FDA, Dr Kaul speculated, may have had some concerns about issues related to the conduct of the TECOS trial, since nearly 27% of the patients were enrolled from Eastern European countries.
But Darren McGuire, MD, of University of Texas Southwestern Medical Center, Dallas, a cardiologist who also treats diabetes and who was an investigator in TECOS, told Medscape Medical News he couldn't see any reason for the FDA to reject the request.
"The conduct of and results from TECOS met every measure for proof of cardiovascular safety as outlined by FDA. So, for the trial to meet all criteria and then the product label not able to be updated accordingly does not make sense to me," he told Medscape Medical News.
TECOS cannot claim any cardiovascular protection with sitagliptin, but the point is the trial illustrated a lack of harm, said Dr McGuire, and this was, after all, the main initial impetus for conducting all of these trials.
"While I have not seen the application for product-label modification [for sitagliptin], I have to assume that it was not for a claim or indication for CV effects/efficacy, but rather to include the data from the TECOS trial in the product label to support a claim of proven CV safety," he said.
Ultimately, this information would help clinicians who are making prescribing decisions, he concluded.
While Dr Kaul has few answers on the labeling query, he says he is mystified as to how sitagliptin came to be a blockbuster drug when it has "no desirable effects on any of the cardiometabolic factors such as cholesterol, blood pressure, or weight." And to boot, its glycemic efficacy "is quite modest," he observes.
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Medscape Medical News © 2017
Cite this: Why Did the FDA Refuse to Add TECOS Data to Sitagliptin Label? - Medscape - May 25, 2017.
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