Novel antidiabetic drugs and risk of cardiovascular events in patients without baseline metformin use: a meta-analysis

Abstract

Aims To evaluate the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major cardiovascular events (MACE) in metformin-naïve patients with type 2 diabetes (T2D). Methods and results A meta-analysis was performed of randomized controlled clinical trials of GLP-1RAs and SGLT-2 inhibitors on T2D populations, after searching the PubMed/MEDLINE, Embase, and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoint, explored in the subgroup of SGLT-2 inhibitors studies, was cardiovascular death or hospitalization for heart failure. A random-effects meta-analysis model was applied. Six eligible trials (three studies of SGLT-2 inhibitors and three trials of GLP-1RAs), including 11 235 patients, were identified and considered eligible for the analyses. The new antidiabetic drugs were associated with a significant reduction in MACE [odds ratio (OR): 0.82, 95% confidence interval: 0.70–0.95; I2: 48%]. The subgroup analysis showed the following findings: GLP-1RAs group, OR: 0.79 (95% confidence interval 0.68–0.93); SGLT-2 inhibitors, OR: 0.85 (95% confidence interval 0.63–1.15). SGLT-2 inhibitors were associated with a significant reduction in hospitalization for heart failure or cardiovascular mortality incidence (OR: 0.67, 95% confidence interval: 0.47–0.95; I2: 78%). Conclusion In this meta-analysis, new antidiabetic drugs reduced the incidence of MACE in metformin-naïve T2D patients. The beneficial effect was especially observed in the GLP-1RAs subgroup. The use of SGLT-2 inhibitors was associated with a reduction in cardiovascular death or hospitalization for heart failure. These results support the fact that metformin would not be indispensable to obtain positive cardiovascular effects when new antidiabetic drugs are administered.

Comparison of the clinical effect of empagliflozin on glycemic and non-glycemic parameters in Japanese patients with type 2 diabetes and cardiovascular disease treated with or without baseline metformin

“…A meta-analysis on SGLT2 inhibitors also showed a consistent reduction in the risk of cardiovascular, renal, and mortality outcomes, irrespective of baseline use of metformin [ 16 ]. The finding that SGLT2 inhibitors are associated with a reduced risk of cardiovascular death or hospitalization for HF even in metformin-naïve patients with T2D at high cardiovascular risk or with CVD [ 17 ] supports the updated guidelines that recommend SGLT2 inhibitors as first-line therapy in this patient population [ 1 , 2 ]. However, in such clinical settings, it remains uncertain whether SGLT2 inhibitors affect clinical parameters similarly or differently according to the use of background metformin therapy.…”

“…To date, several secondary observations and meta-analyses using data obtained from CVOTs on newer glucose-lowering agents have been conducted to assess the influence of baseline metformin therapy on the effect of these agents on cardiovascular outcomes [ 13 – 17 ]. A secondary analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) trial showed that the cardiovascular benefits of empagliflozin treatment in patients with T2D and CVD were unaffected by the use of baseline glucose-lowering agents, including metformin [ 15 ].…”

“…This raised the clinical question as to whether or not the cardiovascular benefits of the agents would be expected even in patients with T2D at high cardiovascular risk or those with CVD, independent of the effects of baseline metformin. However, subsequent analyses demonstrated that treatment with these agents consistently improved cardiovascular outcomes regardless of the baseline use of metformin [ 13 – 17 ]. These findings also support recent updated treatment guidelines for better outcomes especially in patients with T2D either at high cardiovascular risk or with CVD.…”

Dysfunctional High-Density Lipoproteins in Type 2 Diabetes Mellitus: Molecular Mechanisms and Therapeutic Implications

“…A number of trials have shown significant reductions in major CV events after treatment with GLP-1 receptor agonists [ 152 , 153 , 154 , 155 ]. These results were further supported by a recent meta-analysis, in which GLP-1 receptor agonist treatment reduced major adverse CV events (MACE) by 12% [ 156 ].…”

Glucagon-like Peptide-1 Receptor Agonists and Cardioprotective Benefit in Patients With Type 2 Diabetes Without Baseline Metformin: An Update Meta-analysis

“…This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews [21].…”