Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel

Abstract

Aim The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). Background The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. Review results The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. Conclusion Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.

Maximizing treatment benefits in type 2 diabetes by affordable oral anti diabetes agents in India

“…24 Modern SUs (glimepiride and gliclazide MR) are associated with a lower risk of all-cause and CV-related mortality compared to conventional SUs in T2DM patients. 25 The results of the recent CAROLINA demonstrated no difference in the composite of time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke between the linagliptin and glimepiride groups. 24,26 In a study of gliclazide MR, of 4.3 years follow-up with people with diabetes co-treated with perindopril-indapamide combination, was associated with 15% reduction in major macro-and micro-vascular events , 28% reduction in risk of all renal events and 18% reduction in all-cause death.…”

Position of Sulfonylureas in the Current ERA: Review of National and International Guidelines

“…The CV safety of second-generation SUs was established by 3 cardiovascular outcome trials (CVOTs): Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA), and Thiazolidinediones or SUs Cardiovascular Accidents Intervention Trial (TOSCA.IT). 27-29…”

“…The incidence of total CV events with SUs (mostly gliclazide and glimepiride) in the TOSCA.IT trial following its addition in people with T2DM inadequately controlled with metformin was similar to that with pioglitazone. 29…”

“…IT). [27][28][29] CAROLINA was the first and only active-comparator CVOT that demonstrated noninferior CV safety of glimepiride compared with linagliptin as a second-line glucose-lowering treatment option. Since the participants in the CAROLINA trial mirrored real-world population in clinical practice, the results unequivocally established the robust safety of a secondgeneration SU.…”

Utility and benefits of sulfonylureas beyond glycemic control

“…Several recent cardiovascular outcome trials show that glimepiride is safe in major adverse cardiovascular events, heart failure, and hospitalization for heart failure. 15 Conventional SUs such as glibenclamide are associated with adverse effects on the cardiovascular system. Glibenclamide may lead to the closure of mitochondrial KATP channels, which are essential in ischemic preconditioning (IP) protection.…”