Published online Dec 15, 2022. doi: 10.4239/wjd.v13.i12.1168
Peer-review started: July 20, 2022
First decision: September 4, 2022
Revised: September 20, 2022
Accepted: October 27, 2022
Article in press: October 27, 2022
Published online: December 15, 2022
Type 2 diabetes (T2D) patients are at increased cardiovascular and treatment-related hypoglycemia risk. Various guidelines recommend dipeptidyl peptidase-4 (DPP4) inhibitors as the first add-on therapy to metformin in T2D due to their confirmed cardiovascular benefits demonstrated through cardiovascular outcome trials. However, in resource limited countries like India, newer sulfonylureas, like gliclazide and glimepiride, are the most commonly used glucose-lowering drugs in T2D due to their low cost. Gliclazide and glimepiride have similar glycemic efficacy, but gliclazide has a 50% lower hypoglycemia risk.
A landmark cardiovascular outcome trial demonstrated the cardiovascular safety of glimepiride against linagliptin (a DPP4 inhibitor). However, the cardiovascular safety of gliclazide vs linagliptin has not been established through cardiovascular outcome trials. If the cardiovascular safety and lower hypoglycemia risk of gliclazide is established vs linagliptin, it will help physicians prescribe it with assurance of safety for their patients.
To assess the cardiovascular safety and hypoglycemia risk of gliclazide as compared to linagliptin (and other DPP4 inhibitors). The objective was to assess whether gliclazide was as safe as the guideline recommended DPP4 inhibitor (linagliptin) in providing cardiovascular safety and lowering hypoglycemia risk in T2D. This systematic review was likely to help provide assurance regarding cardiovascular and hypoglycemia safety of gliclazide in T2D as compared to costlier DPP4 inhibitors.
This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 through the present that compared the cardiovascular safety and hypoglycemia risk of the two drugs in patients with T2D with no cardiovascular disease. Using keywords such as “linagliptin”, “Gliclazide”, “hypoglycemia”, “myocardial infarction”, and “cardiovascular death”, we searched the databases MEDLINE and Google Scholar. Two independent reviewers assessed the trials included using the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews. We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of Evidence. The primary outcomes compared were major adverse cardiovascular events and hypoglycemia risk.
We could not find any trial comparing gliclazide with linagliptin, either as monotherapy or as add-on therapy to metformin. The cardiovascular safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) and CARdiovascular Outcome study of LINAgliptin vs glimepiride in patients with T2D (CAROLINA) trials were excluded from the comparative analysis as these trials demonstrated cardiovascular and hypoglycemia benefits in patients at high risk of cardiovascular disease. However, since these are landmark trials, their results are important and hence described in detail as a separate section. The final analysis included five gliclazide and three linagliptin trials (total eight studies) that individually studied the outcomes of interest in T2D patients with no established cardiovascular disease. Statistical comparisons of the results were not possible as the trials had different designs, different definitions of major adverse cardiovascular events and hypoglycemia and were conducted in different patient populations. Hence, no direct comparisons were possible. The trials were therefore described individually, and their results were compared through narrative synthesis. We assessed that both drugs were effective in achieving the desired glycemic control and had low major adverse cardiovascular events and hypoglycemia risk in adult patients with no cardiovascular disease.
Gliclazide can be considered as an effective and safe glucose-lowering drug in T2D patients with no established cardiovascular disease but at high risk of cardiovascular disease due to their T2D status.
Future randomized controlled trials comparing gliclazide with linagliptin or DPP4 inhibitors can add value to the findings of this systematic review.