Cardiovascular and Renal Outcomes of Insulin-Sensitizing and Glucose-Lowering Agents in Type 2 Diabetes with Established Cardiovascular Disease: A Systematic Review and Meta-Analysis

Abstract

Background: Adults with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) experience a substantially increased risk of both cardiovascular complications and chronic kidney disease (CKD), reflecting shared underlying pathophysiological mechanisms. Although insulin sensitizing and glucose lowering therapies such as metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors) have each been shown to influence cardiorenal outcomes, a comprehensive synthesis of their combined effects in this population remains limited.

Objectives: To systematically evaluate and quantitatively synthesize the cardiovascular and renal outcomes associated with metformin, GLP-1 receptor agonists, and SGLT2 inhibitors in adults with T2DM and established CVD, and to provide pooled effect estimates for clinically relevant endpoints.

Data Sources: PubMed/MEDLINE, Scopus, and EMBASE were systematically searched from database inception through January 31, 2025, without language restrictions. The review followed PRISMA 2020 guidelines.

Study Selection: Randomized controlled trials (RCTs) and pre-specified meta-analyses of cardiovascular or renal outcome trials enrolling adults (≥18 years) with T2DM and established CVD, reporting at least one primary cardiovascular endpoint (MACE, cardiovascular death, HHF, stroke, MI) or renal endpoint (CKD progression, ESKD, eGFR decline ≥40%, new onset macroalbuminuria, or renal death) were included. Studies in populations without established CVD or reporting only surrogate glycaemic endpoints were excluded.

Data Extraction and Synthesis: Two reviewers independently extracted data using standardized forms, with disagreements resolved by a third reviewer. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool for randomized trials (CIs) and AMSTAR-2 for meta-analyses. Pooled hazard ratios or risk ratios with 95 % confidence intervals were calculated using a DerSimonian-Laird random effects model. Heterogeneity was assessed using the I² statistic and Cochran’s Q test.

Results: A total of 49 studies were included, comprising 22 major cardiovascular outcome trials or their pre-specified subgroup analyses, 16 pooled meta-analyses, and 11 observational or real-world studies. These studies represented more than 250,000 patients with T2DM and over 900,000 patient-years of follow-up. For cardiovascular outcomes, SGLT2 inhibitors were associated with significant reductions in hospitalization for heart failure (HR 0.69, 95 % CI 0.61 to 0.78; I² = 6 %), cardiovascular death (HR 0.82, 95 % CI 0.74 to 0.90), and three-point MACE (HR 0.89, 95 % CI 0.83 to 0.96) in patients with established CVD. GLP-1 receptor agonists were associated with reductions in three-point MACE (HR 0.86, 95 % CI 0.80 to 0.93), all-cause mortality (HR 0.88, 95 % CI 0.82 to 0.94), and ischaemic stroke (HR 0.84, 95 % CI 0.76 to 0.93). For renal outcomes, SGLT2 inhibitors reduced the risk of CKD progression by approximately 38 to 40 % (RR 0.60, 95 % CI 0.53 to 0.69 in diabetic kidney disease trials) and acute kidney injury by 25 % (RR 0.75, 95 % CI 0.66 to 0.85). GLP-1 receptor agonists reduced albuminuria by 24 % compared with placebo and improved composite kidney outcomes (HR 0.79, 95 % CI 0.73 to 0.87). The FLOW trial showed that semaglutide reduced the primary kidney endpoint by 24 % (HR 0.76) and major adverse cardiovascular events by 18 % in patients with established CKD. Metformin demonstrated possible cardiovascular benefit in randomized studies, although this remains inconclusive, and no dedicated renal outcomes trial has been conducted.

Conclusions: SGLT2 inhibitors and GLP-1 RAs bth provide substantial and complementary cardiorenal protection in patients with T2DM and established CVD, with partially distinct patterns of benefit. SGLT2 inhibitors show greater effects on heart failure and progression of CKD, whereas GLP-1 receptor agonists have a stronger impact on atherosclerotic cardiovascular outcomes, particularly stroke. Their combined use may offer additive benefits. These findings support current guideline recommendations that position these agents as therapies for cardiovascular and renal risk reduction, rather than solely for glycaemic control.