Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus

Abstract

Background: Metformin is a first-line drug in type 2 diabetes mellitus (T2DM) treatment, yet whether metformin may increase all-cause or cardiovascular mortality of T2DM patients remains inconclusive.

Methods: We searched PubMed and Embase for data extracted from inception to July 14, 2020, with a registration in PROSPERO (CRD42020177283). This study included randomized controlled trials (RCT) assessing the cardiovascular effects of metformin for T2DM. This study is followed by PRISMA and Cochrane guideline. Risk ratio (RR) with 95% CI was pooled across trials by a random-effects model. Primary outcomes include all-cause mortality and cardiovascular mortality.

Results: We identified 29 studies that randomly assigned patients with 371 all-cause and 227 cardiovascular death events. Compared with untreated T2DM patients, metformin-treated patients was not associated with lower risk of all-cause mortality (RR: 0.98; 95%CI: 0.69-1.38; P = 0.90), cardiovascular mortality (RR: 1.13; 95% CI: 0.60, 2.15; P = 0.70), macrovascular events (RR: 0.87; 95%CI: 0.70-1.07; P = 0.19), heart failure (RR: 1.02; 95% CI:0.61-1.71; P = 0.95), and microvascular events (RR: 0.78; 95% CI:0.54-1.13; P = 0.19). Combination of metformin with another hypoglycemic drug was associated with higher risk of all-cause mortality (RR: 1.49; 95% CI: 1.02, 2.16) and cardiovascular mortality (RR: 2.21; 95% CI: 1.22, 4.00) compared with hypoglycemic drug regimens with no metformin.

Conclusion: The combination of metformin treatment may impose higher risk in all-cause and cardiovascular mortality. This finding, at least in part, shows no evidence for benefits of metformin in combination in terms of all-cause/cardiovascular mortality and cardiovascular events for T2DM. However, the conclusion shall be explained cautiously considering the limitations from UK Prospective Diabetes Study (UKPDS).

Keywords: Cardiovascular diseases; Metformin; Microvascular events; Mortality; Myocardial ischemia; Type 2 diabetes mellitus.

Fig. 1

Snapshot of trial design and roles of metformin in glycometabolism. In the left side of illustration, metformin promotes the uptake of bile acid and luminal bile acid, and increases the levels of GLP-1, which further inhibits the energy intake of brain, pancreatic levels of glucagon, and hepatic glucagon degradation. Metformin also increases the secretion of insulin. In the right side of illustration, clinical usage of metformin has diverse roles on mortality, myocardial ischemia, heart failure, hypertension, stroke, PVD microvascular events, nephropathy, and ocupathy

Fig. 2

All-cause mortality among patients with metformin vs. placebo; and combination vs. placebo. Metformin treatment has no meaningful impact on all-cause mortality versus control, with a moderate heterogeneity. When used in conjunction with another antidiabetic drug, it significantly increased the all-cause mortality risk, compared to the antidiabetic drug alone

Fig. 3

Choropleth map of all-cause mortality. The map reveals that regional difference of all-cause mortality in Denmark, Israel, Netherlands, UK, and USA. Metformin treatment has no meaningful impact on all-cause mortality versus control, in each country

Fig. 4

Choropleth map of cardiovascular mortality. The map reveals that regional difference of cardiovascular mortality in Israel, Netherlands, UK, and USA. Metformin treatment has no meaningful impact on cardiovascular mortality versus control, in each country

Fig. 5

Cardiovascular mortality among patients with metformin vs. placebo; and combination vs. placebo. Metformin treatment has no meaningful actions on cardiovascular mortality versus control, with a high heterogeneity. However, metformin in combination increases the cardiovascular mortality versus metformin alone