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Heart Failure Warning Added to the DPP-4 Inhibitor Class of Drugs

Increased cardio risk of Saxagliptin found during trial prompts FDA decision.

Sitagliptin (Januvia) is a DPP-4 antidiabetic oral agent for treating type 2 diabetes. A new warning label regarding the risk of developing heart failure in patients with cardiovascular disease was issued to this drug by the FDA in September 2017. Other drugs within the same class, Nesina and Tradjenta, were also issued this warning, suggesting the associated risk to be a “class-effect” of the DPP-4 inhibitors. To date, no direct studies have linked this drug with increasing risk of cardiovascular events, including heart failure.

Saxagliptin (Onglyza), another DPP-4 inhibitor, was found to increase the risk of hospitalization for heart failure and the risk of hypoglycemic events. This study found that more patients in the Saxagliptin group than in the placebo group were hospitalized for heart failure.(1) This study happened to be the evidence and reason behind the FDA’s decision to correct Sitagliptin’s package insert. It appears that the FDA issued such warning in a conservative way without a solid controlled trial supporting the cardiovascular risk.

From 2008 until 2015, a major randomized, double-blind, placebo-controlled, event-driven trial was conducted by Duke Clinical Research Institute (DCRI) and the University of Oxford Diabetes Trials Unit (DTU). It evaluated a total of 14,735 patients with established cardiovascular disease. They compared the sitagliptin group vs placebo. The primary endpoint was the risk of developing major cardiovascular events such as nonfatal MI, nonfatal stroke, cardiovascular death, or unstable angina. Mean follow-up was 3 years and included patients from 38 different countries. Baseline characteristics were well balanced for both groups and all cardiovascular and noncardiovascular adverse events were recorded.

There was no significant difference in the primary composite cardiovascular outcome (hazard ratio 0.98 P<0.01). There was also no significant difference in the rate of hospitalization for heart failure, which was reported in 228 patients in the sitagliptin group (3.1%) and 229 in the placebo group (3.1%). The composite outcome of hospitalization for HF or cardiovascular death occurred in 538 patients in the sitagliptin group (7.3%) and 525 in the placebo group (7.2%) (hazard ratio in the ITT analysis, 1.02, P=0.74).

No significant increment in the rate of severe hypoglycemia was seen among patients in the sitagliptin group, as compared with the placebo group. Acute pancreatic events were found to be uncommon and not statistically significant between both groups.  There was also no significant difference between the sitagliptin group and the placebo group regarding the overall incidence of infections, cancer, or reported renal failures. Death from any cause occurred in 547 patients in the sitagliptin group (7.5%) and 537 in the placebo group (7.3%) (hazard ratio in the ITT analysis, 1.01, P=0.88).

This study suggested that sitagliptin may be used in diabetes patients with elevated risk of cardiovascular events. In a statistical perspective, this study had enough power to dismiss any association between sitagliptin use and cardiovascular events. On the other hand, these results cannot predict the risk of using sitagliptin when used for longer periods of time or in patients with more complicated diseases. Furthermore, this trial did not include patients with severe renal disease or patients with A1C levels above 8.0%, thus the risk was not determined for these populations. The publication of this article was 2 years prior to the FDA’s decision to issue the warning label to Sitagliptin, which was based on a trial that only included Saxagliptin; however, it is best evidence study of safety and direct cardiovascular effects related to Sitagliptin. Future trials should focus on comparing the risk of HF hospitalization between Sitagliptin, Saxagliptin, other DPP-4 Inhibitors versus placebo.

Practical Pearls:

  • The use of sitagliptin is not associated with increasing risk of heart failure hospitalization among patients with cardiovascular disease.
  • The use of sitagliptin is a reasonable treatment for patients with moderate diabetes without severe renal impairment.
  • All DPP-4 inhibitors have new warning for increasing risk of heart failure hospitalizations in high-risk populations.

References:

Benjamin M Scirica, MD, Deepak L. Bhatt, M.D. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. The New England of Journal Medicine. 2013; 369:1317-1326

Jennifer B. Green, M.D. Angelyn Bethel, M.D. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine. 2015; 373:232-242

 

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy