Cardiovascular Safety of DPP-4 Inhibitors

A large observational study using real-world data has found no increased risk for hospitalized heart (hHF) failure among patients who initiated use of dipeptidyl peptidase-4 (DPP-4) inhibitors, compared to other antihyperglycemics. Results were published online in the Annals of Internal Medicine.¹

“In this large population-based cohort study, we did not observe an increased risk for hHF among new users of saxagliptin or sitagliptin compared with new users of pioglitazone, second-generation sulfonylureas, or longacting insulin products,” wrote first author Senwee Toh, ScD, of Harvard Medical School, and colleagues.

The study was motivated in part by several large postmarketing trials, which have reported conflicting results about the cardiovascular safety of DPP-4 inhibitors. The SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) trial reported 27% increased incidence of hospitalized heart failure for saxagliptin users compared to placebo.² The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial found slightly higher numbers of hospitalizations for heart failure among alogliptin users compared to placebo, though the results were not statistically significant.³ And the TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) found no significant difference in hospitalized heart failure for alogliptin or sitagliptin users, compared to placebo.⁴

In the population-based retrospective cohort study, researchers used data from the US Food and Drug (FDA) Administration’s Mini-Sentinel program, a pilot program being developed to help monitor the safety of FDA-regulated medical products. Researchers included adults with T2DM who initiated treatment with the two most commonly prescribed DPP-4 inhibitors, saxaglitpin and sitagliptin, between 2006 and 2009, and compared these to pioglitazone, second generation sulfonylureas, or long-acting insulin.

The analysis included 78,553 saxaglitpin users and 298,124 sitagliptin users, with an average follow-up of 7-9 months. Researchers used two sophisticated statistical techniques (disease risk score [DRS] stratification and 1:1 propensity score matching) to adjust for the following confounders: patient demographics, medical history, medication use, risk factors for hospitalized heart failure and other cardiovascular events, other antihyperglycemics, and health services utilization.

Key Results:

• Risk of hospitalized heart failure using DRS stratification: No higher for DPP-4 inhibitors compared to other study drugs:

♦ Saxagliptin vs sitagliptin: HR 0.83 (95% CI, 0.70 to 0.99)

♦ Saxagliptin vs pioglitazone: HR 0.63 (CI, 0.47 to 0.85)

♦ Saxagliptin vs sulfonylureas: HR 0.69 (CI, 0.54 to 0.87)

♦ Saxagliptin vs insulin: HR 0.61 (CI, 0.50 to 0.73)

♦ Sitagliptin vs pioglitazone: HR 0.74 (CI, 0.64 to 0.85)

♦ Sitagliptin vs sulfonylureas: HR 0.86 (CI, 0.77 to 0.95)

♦ Sitagliptin vs insulin: HR 0.71 (CI, 0.64 to 0.78)

• Similar results for propensity score–matched analyses

• Similar results in patients with and without past cardiovascular disease

The authors discussed several reasons for the varying results between this study and SAVOR-TIMI. This the study used data from patients in routine ambulatory setting, who were generally healthier than patients in the SAVOR-TIMI study. They were younger, less likely to have a past history of heart failure or myocardial infarction, and had lower baseline insulin use at baseline. 

The authors also noted the short average follow-up (less than one year), which may not have captured hospitalized heart failure associated with saxagliptin that took longer to develop. The median follow-up in SAVOR-TIMI was 2.1 years.

Nevertheless, conflicting results between these postmarketing trials, at least two meta-analyses and past observational studies, lead the authors to conclude, “Additional investigations are needed to better understand the relation between DPP-4 inhibitors and hHF risk. Well-designed randomized trials with hHF as the main end point or observational studies that address the limitations of our study will help provide more definitive evidence on the topic.”

In a linked editorial, Joseph Selby, MD, MPH, of the Patient-Centered Outcomes Research Institute (PCOR, Washington, DC),⁵ stressed that data from electronic health records (EHRs) could have been useful in adjusting for baseline differences in this study, including body mass index, blood pressure, glucose and creatinine levels, and ejection fractions. He also emphasized PCORnet, a research EHR network, as a way to standardize EHR data.

“In a country with a health care system as partitioned as that of the United States, sharing complementary data resources could go a long way toward answering safety and effectiveness questions quickly and more definitively, linking clinical trial investigation with real-world experience, eliminating waste and redundancy in research data collection, and incorporating the voices of patients and other stakeholders,” he concluded.

Take-home Points

• Large postmarketing trials, metanalyses, and obersvational studies conflict about whether DPP-4 inhibitors increase the risk of hospitalized heart failure.

• A large, observational study using real-world data suggests that new users of saxagliptin and sitagliptin do not have an increased risk of hospitalized heart failure, compared to pioglitazone, second-generation sulfonylureas, or long-acting insulin users.

• Further studies are needed to confirm these results, and shared electronic health records could help facilitate research in this area.  

References:

1. Toh S, et al. Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: a retrospective cohort study. Ann Intern Med. 2016 Apr 26

2. Scirica BM, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.

3. Zannad F, et al; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076.

4. Green JB, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242.

5. Selby JV. Complementary efforts make for efficient research. Ann Intern Med. 2016 Apr 26.