Similar CV outcomes with pioglitazone, sulfonylureas added to metformin

The incidence of cardiovascular events decreased among adults with type 2 diabetes who received pioglitazone or a sulfonylurea as an add-on to metformin monotherapy, according to findings from the TOSCA.IT study presented at the European Association for the Study of Diabetes Annual Meeting and published simultaneously in The Lancet Diabetes & Endocrinology.

Perspective from Alan J. Garber, MD, PhD, FACE

“The recommended first-line medication for patients with type 2 diabetes is metformin,” Gabriele Riccardi, MD, of the department of clinical medicine and surgery at the University of Naples Federico II in Italy, said in a press release. “However, there is considerable uncertainty as to the best therapeutic strategy when a patient is no longer well controlled with metformin alone. Adding a sulfonylurea to metformin is the most common option, although the impact of this drug combination on cardiovascular events is uncertain. Among others, the addition of pioglitazone to metformin could be a suitable alternative, given the evidence supporting the protective role of pioglitazone on ischemic cardiovascular diseases (myocardial infarction and stroke), despite concerns on possible clinically relevant side effects.”

and colleagues evaluated data on 3,028 adults with type 2 diabetes inadequately controlled with metformin monotherapy randomly assigned to pioglitazone (Actos, Takeda; n = 1,535) or a sulfonylurea (glibenclamide, 2%; glimepiride, 48%; or gliclazide, 50%). Researchers sought to compare the long-term effects of pioglitazone and sulfonylureas in addition to metformin on CV events in adults with type 2 diabetes. The study was stopped at a median 57.3 months based on futility analysis.

The primary composite outcome included first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke or urgent coronary revascularization. The key secondary outcome included the first occurrence of sudden death, fatal and nonfatal MI, fatal and nonfatal stroke, major leg amputation (above the ankle) and any revascularization of the coronary, carotid or leg arteries.

Researchers observed no significant difference in occurrence of the composite primary outcome between the two groups (1.5 events per 100 person-years occurred in each group). Further, the key secondary outcomes occurred in 5% of the pioglitazone group and 6% of the sulfonylurea group.

“However, when only ischemic events were considered and the evaluation was performed only in participants who were adhering to the prescribed treatment, the rate of events was 30% lower in the group on pioglitazone plus metformin,” Riccardi said.

The incidence of serious adverse events was similar in both groups, but the occurrence of severe hypoglycemic events, although rare, occurred more frequently in the sulfonylurea group than the pioglitazone group.

“Altogether, this study indicates that in patients with type 2 diabetes at low cardiovascular risk who are inadequately controlled with metformin, both treatment strategies tested as suitable; however, the combination of metformin and pioglitazone may be considered as a preferential therapeutic option over that of metformin plus a sulfonylur ea,” Riccardi said. “The information provided by TOSCA.IT is relevant not only for clinical practice, but also from the point of view of public health since the drug combinations tested are widely available and affordable.” – by Amber Cox

References:

Effects on the incidence of cardiovascular events of the add-on of pioglitazone as compared with a sulfonylurea in type 2 diabetic patients inadequately controlled with metformin: the TOSCA.IT study. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 11-15, 2017; Lisbon, Portugal.

Vaccaro O, et al. Lancet Diabetes Endocrinol. 2017;doi:10.1016/S2213-8587(17)30317-0.

Disclosure s : Vaccaro reports she receives speakers’ fees from Novartis and Sanofi Aventis, research grants from Guidotti and travel support from Sigma Tau. Please see the study for all other authors’ relevant financial disclosures.

Perspective

Alan J. Garber, MD, PhD, FACE

In TOSCA.IT, a randomized controlled trial of secondary therapy for patients failing metformin treatment for type 2 diabetes, 3,028 patients were randomized to either pioglitazone or sulfonylureas and followed for 57 months. There were 212 events occurring almost evenly split between the two groups over the entire time period. The authors concluded that either therapy was equally effective with regard to CV events. Unfortunately, this study was substantially underpowered compared with most CV outcome studies, which have as many as 15,000 to 20,000 subjects. As a result, there was a very low total event rate and a very low possibility of detecting a small to moderate effect size difference between the two comparator arms. In view of the studies and meta-analyses suggesting the possibility of increased CV risk with sulfonylureas, this underpowered study adds little to our understanding of the problems of secondary therapy selections for patients with type 2 diabetes.

Alan J. Garber, MD, PhD, FACE

Endocrine Today Chief Medical Editor

Disclosures: Garber reports he serves on the advisory boards for Janssen, Kowa, Lexicon, Merck, Novo Nordisk, Takeda, Viking Therapeutics and Vivus and serves as a consultant for Janssen, Kowa, Lexicon, Merck, Novo Nordisk, Takeda, Viking Therapeutics and Vivus.