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In patients with type 2 diabetes and heart failure, the use of sitagliptin (Januvia) was associated with greater risk of hospitalization for heart failure, a study based on insurance claims showed.
Although patients exposed to the dipeptidyl peptidase-4 (DPP-4) inhibitor did not carry a greater risk of all-cause hospitalization or death, they were a relative 84% more likely to be admitted for heart failure (12.5% versus 9.0%; OR 1.84, 95% CI 1.16-2.92), , of the University of Alberta in Edmonton, and colleagues reported online in .
Action Points
- In patients with type 2 diabetes and pre-existing heart failure, the use of sitagliptin was not associated with an increased risk of all-cause hospitalizations or death, but was associated with an increased risk of HF-related hospitalizations.
- Note that studies evaluating the use of other dipeptidyl peptidase-4 inhibitors suggest that a small increase in the risk of heart failure in diabetics might be a class effect.
"The increase in heart failure events is likely clinically relevant (resulting in a number needed to harm of 29) and may have implications for choice of add-on therapy for patients with heart failure and diabetes poorly controlled with other agents," they wrote.
"Although our results are intriguing, it is clear that additional studies are required, specifically in patients with heart failure, to solidify the risk-benefit picture," they added, pointing to the inconsistent heart failure results in the recently reported SAVOR-TIMI 53 and EXAMINE trials, as well as the lack of a heart failure signal with DPP-4 inhibitors in large, population-based studies of diabetic patients.
"Thus, the ongoing is key to further assessing the safety of this drug (but is not set to report until 2015)," they wrote.
The SAVOR-TIMI 53 trial -- which evaluated the use of the DPP-4 inhibitor saxagliptin (Onglyza) in patients with type 2 diabetes -- indicated an increased risk of heart failure hospitalization with the drug versus placebo, whereas the EXAMINE trial -- which studied the use of the DPP-4 inhibitor alogliptin (Nesina) in patients with type 2 diabetes and a history of myocardial infarction or angina -- showed no significant differences in heart failure risk between the drug and placebo groups.
Earlier this year, the FDA announced that it was taking a deeper look at the heart failure finding in the SAVOR-TIMI 53 trial.
To further explore the potential heart failure risk of DPP-4 inhibitor therapy, Eurich and colleagues analyzed data from a large U.S. database that included claims from employed, commercially insured individuals from all 50 states. Their study included 7,620 patients with type 2 diabetes who were initially treated with metformin or a sulfonylurea and then developed heart failure. The researchers followed patients for a median of 1.4 years after they developed heart failure and compared outcomes between the 12% of patients who were exposed to sitagliptin and those who were not.
The rate of all-cause hospitalization or death -- the primary endpoint for the current analysis -- was 7.1% in patients who used sitagliptin and 9.2% in those who did not, a difference that was not statistically significant after multivariate adjustment (OR 0.84, 95% CI 0.69-1.03). Rates of the individual components did not differ either.
The rate of heart failure hospitalization, however, was higher in the sitagliptin group.
"These findings are particularly relevant given the results of the SAVOR-TIMI 53 ... trial," according to , and , of Brigham and Women's Hospital and Harvard Medical School.
But, they wrote in an accompanying editorial, certain limitations of the current analysis should be considered.
Residual confounding could be at play, they wrote, because of possible differences between the sitagliptin users and nonusers that remained even after adjustment and because of the use of claims data lacking information about certain clinical variables.
Also, the relationship between heart failure hospitalization and sitagliptin exposure was based on a small number of events, and the possibility of misclassification remained.
"This is of importance for this particular analysis given the impact that a change in only a few events could have on the overall association that was seen," Bhatt and Cavender wrote.
"With these considerations in mind, 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," they wrote. "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."
Eurich and colleagues acknowledged some limitations of their analysis, including the inability to establish causality in an observational study, possible confounding by indication, the inability to control for body weight or blood pressure, the lack of data on heart failure severity or ventricular function, the relatively small number of patients taking sitagliptin, and the short duration of follow-up.
From the American Association:
Disclosures
Eurich is a population health investigator with Alberta Innovates Health Solutions (AIHS) and a new investigator with the Canadian Institutes of Health Research (CIHR). One of the authors reported support from CIHR and AIHS. Another author is a Health Scholar with AIHS and holds the University of Alberta/Capital Health Chair in Cardiovascular Outcomes Research.
The study authors disclosed no relevant relationships with industry.
Bhatt disclosed relevant relationships with Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences, the Boston VA Research Institute, the Society of Cardiovascular Patient Care, the American Heart Association Get With The Guidelines Steering Committee, the Duke Clinical Research Institute, the Harvard Clinical Research Institute, Mayo Clinic, the Population Health Research Institute, the American College of Cardiology, Belvoir Publications, HMP Communications, Slack Publications, WebMD, Clinical Cardiology, the Journal of the American College of Cardiology, Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, sanofi aventis, The Medicines Company, FlowCo, PLx Pharma, and Takeda. Cavender disclosed relevant relationships with AstraZeneca and Bristol-Myers Squibb.
Primary Source
JACC: Heart Failure
Weir D, et al "Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study" JACC Heart Fail 2014; DOI: 10.1016/j.jchf.2014.04.005.
Secondary Source
JACC: Heart Failure
Bhatt D, Cavender M "Do dipeptidyl peptidase-4 inhibitors increase the risk of heart failure?" JACC Heart Fail 2014; DOI: 10.1016/j.jchf.2014.05.005.