Risk of heart failure from saxagliptin and sitagliptin no higher than for other antidiabetics

Researchers find risk of heart failure with DPP-4 inhibitors is similar to or lower than other antidiabetic drugs.

An x-ray of congestive heart failure

New users of dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin and sitagliptin are not at increased risk of heart failure compared with users of other antidiabetic drugs, a study commissioned by the US Food and Drug Administration (FDA) has found.

The researchers, led by Sengwee Toh from Harvard Medical School, analysed data from 78,553 saxagliptin users and 298,124 sitagliptin users without recent history of acute myocardial infarction or heart failure to compare hospital admission rates for heart failure with other antidiabetic drugs.

The team found that the risk of being admitted to hospital with heart failure after saxagliptin and sitagliptin treatment was similar to or lower than with pioglitazone, second-generation sulfonylureas and long-acting insulin treatment. The associations did not seem to be affected by a prior history of cardiovascular disease.

The mean follow-up in Toh’s for each comparison was between seven and nine months, except for against insulin, where follow-up was around four months.

Elizabeth Robertson, director of research at Diabetes UK, who was not involved in the study, says the results are “very encouraging” but further trials focusing on heart failure in hospitalised patients were needed.

“Given the importance of gliptins as a treatment option for people with type 2 diabetes, and in light of the conflicting trial findings to date, it’s crucial that we fully understand any increased risk of heart failure associated with these drugs,” she says.

Overall, the rate of hospital admission for heart failure was around 2–4 per 1,000 person-years for saxagliptin users and 3–5 per 1,000 person-years for sitagliptin users. This compared with rates of about 4 per 1,000 person-years for pioglitazone users, 9 per 1,000 person-years for sulfonylurea users and 16 per 1,000 person-years for insulin users.

Concerns had been raised about the cardiovascular safety of DPP-4 inhibitors based on findings from several post-marketing trials. For example, a placebo-controlled post-marketing trial of saxagliptin showed an unexpectedly high rate of hospital admission for heart failure. However, two post-marketing trials of alogliptin and sitagliptin found no such association.

As a result, the researchers say it has been unclear whether the observed increased risk of heart failure among saxagliptin users was a true increased risk or a consequence of the study design.

Reporting their findings in the Annals of Internal Medicine
(online, 26 April 2016), the authors say: “By comparing DPP-4 inhibitor users and users of other antihyperglycaemic agents who received these treatments in routine clinical practice, our study provides information that complements recently completed post-marketing placebo-controlled trials.

“Our findings are clinically relevant because patients and physicians often choose among various treatment alternatives (including no treatment) for [type 2 diabetes] in practice.”

However, they agree that further studies, including randomised trials specifically looking at heart failure risk, are needed to clarify the relationship with heart failure.

The study used data from the FDA’s Mini-Sentinel programme, a trial project for a national pharmaco-surveillance system which is part of efforts by the FDA to conduct more rigorous assessments of antidiabetic drug safety.

In April 2016, the FDA issued a warning over the cardiovascular safety of saxagliptin and alogliptin, to make patients and physicians aware of a potential link with heart failure.

Other antidiabetic drugs, including pioglitazone, have also been associated with cardiovascular risks. In 2010, the European Medicines Agency suspended the marketing authorisation for rosiglitazone after deciding the cardiovascular risks did not outweigh the benefits of the drug. 


[1] Toh S, Hampp C, Reichman ME et al. Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs. Annals of Internal Medicine 2016. doi: 10.7326/M15-2568

Last updated
The Pharmaceutical Journal, Risk of heart failure from saxagliptin and sitagliptin no higher than for other antidiabetics;Online:DOI:10.1211/PJ.2016.20201101

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