Type 2 patients who used saxagliptin or sitagliptin had similar risks for heart failure as those who received other anti-hyperglycemic agents, according to a retrospective cohort study.
Recent post-marketing trials produced conflicting results about the risk for hospitalized heart failure associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these anti-hyperglycemic agents.
To examine the associations of heart failure with saxagliptin and sitagliptin, a population-based, retrospective, new-user cohort study was performed. Patients age 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2014 were observed.
The results from 78,553 saxagliptin users and 298,124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for heart failure was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)–stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin.
The researchers noted that post marketing trials have found conflicting results about the cardiovascular safety of DPP-4 inhibitors. For instance, the SAVOR-TIMI 53 study found patients who received saxagliptin had a 27 percent higher relative incidence of hospitalized heart failure compared with a placebo group. However, two other trials did not find significant differences in the risk of hospitalized heart failure among patients who received alogliptin or sitagliptin versus placebo.
This analysis was part of an ongoing active surveillance project to complement SAVOR-TIMI 53 and was conducted within Mini-Sentinel, a pilot program that assists the FDA in developing a national active surveillance system of FDA-regulated products.
The FDA funded the study and was actively involved. The researchers evaluated patients who were at least 18 years old with type 2 diabetes who initiated treatment with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas or long-acting insulin products from 2006 to 2015.
The researchers said they chose the comparators because they were common alternatives to saxagliptin in clinical practice. They defined type 2 diabetes as patients who had at least one prescription for an oral anti-hyperglycemic medication other than metformin or at least one diagnosis of diabetes plus at least one prescription for metformin.
The mean age of patients was approximately 60 years old, and approximately 55 percent were males. The age and sex distributions were similar between the new users of the study medications. The proportion of patients with a prior heart failure diagnosis was 5 percent for saxagliptin users, 7 percent for sitagliptin users, 7 percent for sulfonylurea users and 11 percent for insulin users.
The researchers said the risk for hospitalized heart failure was not higher with DPP-4 inhibitors compared with the other medications. They said the hazard ratios from the disease risk score-stratified analyses were 0.83 for saxagliptin versus sitagliptin, 0.63 for saxagliptin versus pioglitazone, 0.69 for saxagliptin versus sulfonylureas, 0.61 for saxagliptin versus insulin, 0.74 for sitagliptin versus pioglitazone, 0.86 for sitagliptin versus sulfonylureas and 0.71 for sitagliptin versus insulin.
They added that results were similar from 1:1 propensity score-matched analyses and subgroup analyses of patients with and without prior cardiovascular disease.
“By comparing DPP-4 inhibitor users and users of other anti-hyperglycemic agents who received these treatments in routine clinical practice, our study provides information that complements recently completed post marketing placebo-controlled trials,” the researchers wrote. “Our findings are clinically relevant because patients and physicians often choose among various treatment alternatives (including no treatment) for [type 2 diabetes] in practice.”
The researchers provided a few explanations for why their results differed from the SAVOR-TIMI 53 trial, including population differences and limitations of an observational study design. They also obtained data from patients who received anti-hyperglycemic treatments in routine ambulatory clinical settings, which may differ from participants in other studies.
In this analysis, patients who received saxagliptin were younger, less likely to have a prior history of heart failure or MI, and had less concurrent insulin use at baseline compared with saxagliptin users from the SAVOR-TIMI 53 study. Further, the mean follow-up in this analysis was less than one year compared with 2.1 years in the SAVOR-TIMI 53 trial.
So from the results in this large cohort study, a higher risk for heart failure was not observed in users of saxagliptin or sitagliptin compared with other selected anti-hyperglycemic agents.
- The results came from 78,553 saxagliptin users and 298,124 sitagliptin users for an average of 7 to 9 months of follow-up
- Findings are clinically relevant because patients and physicians often choose among various treatment alternatives (including no treatment) for [type 2 diabetes] in practice.
- The risk for hospitalized heart failure was not higher with DPP-4 inhibitors compared with the other medications.
Sengwee Toh, ScD, Annals of Internal Medicine on April 25.