Sitagliptin Use in Patients With Diabetes and Heart Failure: A Population-Based Retrospective Cohort Study

Weir DL, McAlister FA, Senthilselvan A, et al., 
JACC Heart Fail. 2014 Jun 25. doi: 10.1016/j.jchf.2014.04.005. [Epub ahead of print]

Background

There is considerable controversy on how to best control blood glucose in patients with diabetes and heart failure (HF), which is a frequent complication of type 2 diabetes (T2D)[1]. Metformin is currently considered first-line treatment in this patient population [2,3]. Use of alternative treatment options sulfonylureas and insulin may be limited in these patients due to undesirable side effects such as fluid retention, weight gain and hypoglycaemia [2,3]. Thiazolidinediones (TZDs) are contraindicated in case of HF due to fluid retention.
Incretin therapies such as DPP4-inhibitors have received attention for the treatment of this patient group, since they may improve cardiorenal function, in addition to having antihyperglycaemic effects [4]. However, recent safety analyses have yielded conflicting results [5-9]. This population-based, retrospective cohort study aimed to evaluate the effects of sitagliptin in patients with T2D and HF. Primary outcome of interest was a composite endpoint of all-cause hospital admission or death. 7620 diabetic patients with incident HF were included, with median follow-up of 1.4 years (12.704 years at risk).

Main results

• The primary composite endpoint occurred in 4137 patients (54.3%).
• Sitagliptin users showed a similar risk of all-cause hospital admission or death as compared with patients not using sitagliptin (7.1% vs. 9.2%, adjusted odds ratio: 0.84, 95%CI: 0.69-1.03).
• Metformin users showed a lower risk of all-cause death alone or all-cause hospitalisation alone (aOR: 0.8, 95%CI: 0.71-0.85), while users of insulin (aOR: 1.16, 95%CI: 1.05-1.28) or sulfonylureas (aOR: 1.10, 95%CI: 1.00-1.23) had a higher risk.
• Sitagliptin use was not associated with an increased risk of HF-related hospital admission or death (9.0% vs. 9.1%, aOR: 1.34, 95%CI: 0.93-1.92). However, sitagliptin use was associated with an increased risk of HF-related hospital admission alone (aOR: 1.84, 95%CI: 1.16-2.92).

Conclusion

This population-based study shows that although sitagliptin is not associated with an increased risk of all-cause death or hospital admission in patients with T2D and HF, use of sitagliptin was associated with an increase in HF-related hospital admissions. The increase in HF events (yielding a number needed to harm of 29), thus may have implications for the choice of add-on therapy for patients with established HF and poorly controlled diabetes with other agents. Other studies should confirm these observations. Benefits and potential risks of sitagliptin should be carefully weighed in this patient group.  

Editorial comment [10]

“The present findings are important and do add to a small but growing body of evidence that suggests DPP-4 inhibitors as a class of drugs, and possibly diabetes drugs in general, may increase the risk of heart failure. This increase in absolute risk, if present at all, appears to be small. Thus far, this association does not seem to increase significantly the risk of mortality given the neutral effects on mortality seen in the present analysis and the randomized clinical trials.The findings of this analysis, as well as other recent studies, highlight the need for well-designed trials that rigorously assess for heart failure in patients with diabetes.In the meantime, diabetic patients at risk for heart failure hospitalization (e.g., those with pre-existing heart failure) who are started on DPP-4 inhibitors, and perhaps diabetes medications in general, should be followed closely as outpatients for symptoms and signs of heart failure.”

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