ESC 2023 Reaffirms CV Safety of Sulphonylureas Agents

The guidelines recommended applying tight glycemic control of glycated hemoglobin (HbA1c <7%) to reduce microvascular complications.

The 2023 ESC Guideline for the management of cardiovascular disease in patients with diabetes, was published online on 25 August 2023 in the latest issue of the European Heart Journal.

The new guideline is an update of the 2019 recommendations and reflects recent evidence from large cardiovascular outcome trials (CVOTs) of new classes of diabetes drugs and other new research developments in diabetes.

Tight Glycemic Targets in Patients with Diabetes

The new guideline strongly recommends (CoR 1, LoE A) applying tight glycemic control, that is HbA1c <7% to reduce microvascular complications. The guidelines suggest considering a multifactorial approach to managing T2DM with treatment targets (CoR I, LoE B), combining the knowledge and skills of different caregivers. (CoR I, LoE C)

Based on the results of multiple dedicated CVOTs of glucose-lowering medications in patients with diabetes, the new recommendations suggest prioritizing the use of glucose-lowering agents with proven CV benefits followed by agents with proven CV safety over agents without proven CV benefits or proven CV safety. (CoR I, LoE C)

Glucose-lowering with Proven CV Safety:

The glucose-lowering agents with proven CV safety include Sulfonylureas (SU) such as gliclazide and glimepiride, dipeptidyl peptidase 4 inhibitors (DPP4-i) including sitagliptin, alogliptin, linagliptin, insulin glargine or insulin degludec, ertugliflozin, and other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as lixisenatide, exenatide extended-release and oral semaglutide.

Evidence Substantiating CV Safety of Sulfonylureas (SUs)

The new guideline noted that the relative CV safety of SU agents (gliclazide and glimepiride) is supported by results of contemporary real-world data analyses. Multiple landmark trials including CAROLINA(Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, UKPDS (the United Kingdom Prospective Diabetes Study) assessed the CV safety and efficacy of SU agents (Gliclazide/glimepiride), and have reported the CV safety of SUs as a glucose-lowering treatment for patients with diabetes.

The ADVANCE trial evaluated diabetes patients comparing more intensive glucose control vs. usual glucose targets. The patients randomized to the more intensive study arm were treated with gliclazide-modified release and reported no major CV safety concerns.

Patients with diabetes are at higher risk of developing cardiovascular diseases (CVD), including coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), stroke, as well as peripheral artery diseases. Furthermore, diabetes is a major risk factor for developing chronic kidney disease (CKD), which may be an independent risk factor for developing CVD. Together, such cardio-renal comorbidities may raise the risk of cardiovascular (CV) events as well as CV and all-cause mortality.

LoE: Level of Evidence

Reference:

Adapted from:

Nikolaus Marx et al., 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes Developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC), European Heart Journal (2023) 00, 1–98 https://doi.org/10.1093/eurheartj/ehad192