On cardiovascular complications in people with type 2 diabetes : Aspects of incretin-based therapy and glycemic control

Background: Hyperglycemia, insulin resistance, and the presence of advanced glycation end products are key features of type 2 diabetes (T2DM) and the leading mechanisms behind the increased cardiovascular risk observed in people with this condition. Percutaneous coronary revascularization has been associated with higher risk of stent failure in people with diabetes mellitus (DM), having greater risk of both in-stent restenosis (ISR) and stent thrombosis (ST). Moreover, the role of glycemic control in stent failure outcomes is uncertain. Glucagon-like pepetide-1 receptor (GLP-1R) agonists (GLP-1RA), a family of glucose-lowering agents, have demonstrated cardioprotective actions with reductions of relative risk of about 16% in subjects with T2DM compared with placebo. Preclinical data have indicated beneficial effects on the cardiac function and vascular healing associated with activation of GLP-1R. However, the specific mechanisms and actions of this class of drugs remain unexplored.

Methods: Studies I and II were randomized clinical trials including subjects with T2DM, both open label but assessor-blinded. Study I compared the effects of liraglutide with those of glimepiride on the subclinical systolic and diastolic cardiac function, represented by the longitudinal functional reserve index (LFRI). Study II studied the effects of exenatide over standard treatment on stent strut coverage and the extent of neointima hyperplasia in participants with coronary artery disease revascularized with a contemporary drug-eluting stent (DES). Studies III and IV were observational, retrospective studies with data derived from several Swedish national registers. Study III included all patients with DM revascularized percutaneously with DES in 2007-2017, whereas Study IV comprised only T2DM subjects in whom a DES was implanted in 2010-2020. The primary endpoint for Studies III and IV was stent failure, defined as the occurrence of ISR and ST. The exposure variable in Study III was incretin treatment, i.e., treatment with a GLP-1RA or dipeptidyl peptidase 4 inhibitor. In Study IV, the exposure variable was the level of glycemic control by stratified glycated hemoglobin A1c levels.

Results: No differences in LFRIsystolic or LFRIdiastolic were observed between the liraglutide and glimepiride groups in Study I. No significant effect on improved endothelialization of DES or neointima thickness was found for exenatide compared with standard treatment in Study II. A similar risk of stent failure was detected for those treated with incretins and the control group in Study III. An association was found between the risk of stent failure and glycemic control in persons with T2DM, the subgroups with worse glycemic control exhibiting the highest risk.

Conclusions: There is no compelling evidence for beneficial effects of GLP-1RA on cardiac function and/or improvement of heart failure (Study I). GLP-1RA treatment did not show any signs of improved endothelialization or reduced risk of stent failure in either Studies II or III. Poor glycemic control associated with the risk of stent failure, driven by ISR (Study IV).

List of scientific papers

I. Nyström T, Santos-Pardo I, Hedberg F, Wardell J, Witt N, Cao Y, Bojö L, Nilsson B, Jendle J. Effects on subclinical heart failure in type 2 diabetic subjects on liraglutide treatment vs. glimepiride both in combination with metformin: a randomized open parallel-group study. Front Endocrinol (Lausanne). 2017;8:325.
https://doi.org/10.3389/fendo.2017.00325

II. Santos-Pardo, I, Witt N, Angerås O, Nyström T. Effects of exenatide on coronary stent’s endothelialization in subjects with type 2 diabetes: a randomized controlled trial. The Rebuild study. Cardiovasc Diabetol. 2023;22(1):337.
https://doi.org/10.1186/s12933-023-02071-4

III. Santos-Pardo I, Lagerqvist B, Ritsinger V, Witt N, Norhammar A, Nyström T. Risk of stent failure in patients with diabetes treated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors: A nationwide observational study. Int J Cardiol. 2021;330:23-9.
https://doi.org/10.1016/j.ijcard.2021.02.011

IV. Santos-Pardo I, Andersson Franko M, Lagerqvist B, Ritsinger V, Eliasson B, Witt N, Norhammar A, Nyström T. Glycemic control and stent failure in subjects with type 2 diabetes: a nationwide observational study. [Submitted]