Sitagliptin Shows No Increased Cardiovascular Risk In Merck’s TECOS Trial
This article was originally published in The Pink Sheet Daily
Executive Summary
Based on results of the TECOS study, Merck will seek approval to include additional safety information in the labeling for Januvia and Janumet.
Merck & Co. Inc.’s widely anticipated cardiovascular outcomes study on its DPP-4 anti-diabetic sitagliptin supports the long-term safety of the drug by demonstrating no association between treatment and an increased risk of cardiovascular events, according to researchers.
Sitagliptin is the active ingredient in Merck’s Januvia and is also used in combination with metformin in Janumet. FDA will review results of the new research as part of its ongoing assessment of the long-term cardiovascular safety of DPP-4 drugs (Also see "DPP-4 Class Labeling On Heart Failure May Hinge On Merck Study" - Pink Sheet, 20 Apr, 2015.).
In the multi-center Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS), Jennifer Green, Duke University, et al., compared treatment with the drug versus placebo for a median three years in 14,671 patients with type 2 diabetes and established cardiovascular disease.
Results were published in the New England Journal of Medicine June 8 and released at the American Diabetes Association annual scientific meeting the same day. A cardiovascular outcomes study on another diabetes drug, the GLP-1 agonist lixisenatide, also was presented at the ADA meeting June 8 (see related story, (Also see "Sanofi's Lixisenatide Gets Clean Bill Of Health On CV Safety, Heart Failure" - Pink Sheet, 8 Jun, 2015.)).
TECOS found “among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure or other adverse events,” Green and co-authors reported. Merck previewed the findings during its recent earnings call (Also see "Merck Asserts PD-1 inhibitor Keytruda’s Competitiveness In NSCLC" - Pink Sheet, 28 Apr, 2015.).
Sitagliptin was non-inferior to placebo for outcomes including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina, and rates of hospitalization for heart failure did not differ between the two groups. The study used a relative risk of 1.3 as the upper boundary to determine whether sitagliptin was non-inferior to placebo, in accordance with FDA’s policy on CV risk assessment for type 2 diabetes drugs.
The researchers also reported there were no significant between-group differences in rates of acute pancreatitis or pancreatic cancer. Earlier studies in other diabetes drugs raised concerns about a connection between the treatments and pancreatitis but FDA later concluded the data were insufficient to support a causal association (Also see "FDA, EMA Lay Out Incretin Mimetic Safety Analysis In NEJM" - Pink Sheet, 26 Feb, 2014.).
Next Steps For Merck
Merck said it will seek to include additional safety information in the labeling for Januvia and Janumet. “We believe the results of TECOS provide important clinical information about the cardiovascular safety profile of sitagliptin. Merck anticipates submitting an application to the U.S. Food and Drug Administration and other regulatory agencies later this year to have the findings from TECOS reviewed for potential additional labeling for sitagliptin,” the company said in an email.
The findings represent especially good news for Januvia and Janumet in light of concerns over the safety of other DPP-4 inhibitors that have emerged from outcomes studies.
In an outcomes trial known as SAVOR, AstraZeneca PLC’s Onglyza (saxagliptin) was associated with a 27% increased risk of hospitalization for heart failure, a statistically significant finding.
A separate study of Takeda Pharmaceutical Co. Ltd.’s Nesina (alogliptin), called EXAMINE, found an unfavorable imbalance in heart failure hospitalization in the alogliptin-treated group, although this did not reach the level of statistical significance.
FDA is investigating whether a link to increased risk of heart failure in patients taking the two other DPP-4 inhibitors is real and whether it extends across the class. An agency advisory committee recently recommended that new warnings be added to the labels of the drugs based on the studies (Also see "Diabetes Drug Labels Should Reflect Heart Failure Risk, FDA Panel Says" - Pink Sheet, 14 Apr, 2015.).
Why TECOS Results Differed From Other Outcomes Trials
The TECOS researchers suggested a number of explanations for the difference in the TECOS results versus cardiovascular outcomes studies for Onglyza and Nesina.
“The reason for the lack of heart-failure safety signal in our trial as compared with previous trials of DPP-4 agents may relate to differences in patients who were enrolled, in the background care that was provided, or in the recording and definition of health failure events, or to intrinsic pharmacologic differences among DPP-4 inhibitors or it may simply represent the play of chance in previous findings.”
The NEJM article also notes TECOS “was adequately powered, with greater-than-anticipated event rates for the primary composite cardiovascular outcome, and had a longer follow-up than previous outcome studies for DPP-4 inhibitors.”
However, limitations include the fact that enrolled patients had moderate hyperglycemia and the study excluded those with severe renal insufficiency, the researchers pointed out. There also may have been a confounding effect on cardiovascular outcomes brought about by a “small residual between-group difference” in glycated hemoglobin levels and a greater use of anti-hyperglycemic agents in the placebo group, they added.