Metformin and cardiorenal outcomes in diabetes: A reappraisal

Abstract

The guidance issued to the pharmaceutical industry by the US Food and Drug Administration in 2008 has led to the publication of a series of randomized, controlled cardiovascular outcomes trials with newer therapeutic classes of glucose-lowering medications. Several of these trials, which evaluated the newer therapeutic classes of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, have reported a reduced incidence of major adverse cardiovascular and/or renal outcomes, usually relative to placebo and standard of care. Metformin was the first glucose-lowering agent reported to improve cardiovascular outcomes in the UK Prospective Diabetes Study (UKPDS) and thus became the foundation of standard care. However, as this clinical trial reported more than 20 years ago, differences from current standards of trial design and evaluation complicate comparison of the cardiovascular profiles of older and newer agents. Our article revisits the evidence for cardiovascular protection with metformin and reviews its effects on the kidney.

Keywords: atherosclerotic cardiovascular disease; cardiovascular outcomes; chronic kidney disease; glucose-lowering therapy; metformin.

Figure 1

Summary of randomized allocation of patients to treatment in the UK Prospective diabetes study. SU, sulphonylurea; T2D, type 2 diabetes. ^aConventional treatment policy in the UKPDS. ^bThese patients were included in the main trial analysis (UKPDS 33). ^cUKPDS 34. ^dDefined as fasting plasma glucose 6.1–15 mmol/L (110–270 mg/dL) without symptoms of hyperglycaemia. Adapted from references7, 8 with permission from Elsevier

Figure 2

Relative risks of principal clinical outcomes from patients randomized to intensive glycaemic management with metformin or to conventional management policy in the UKPDS, and from patients previously in these randomized groups after 10 years of post‐trial follow‐up. ^aComposite of sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non‐fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation (≥1 digit), vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction. ^bDeath from myocardial infarction, stroke, peripheral vascular disease, renal disease, hypoglycaemia or hyperglycaemia, and sudden death. Drawn from data presented in references7, 10

Figure 3

Serum concentrations of metformin and lactate above and below 2.5 mg/L during 4 months of administration of metformin to people with type 2 diabetes and chronic kidney disease (CKD). Total daily metformin dosages differed between patients with CKD 3A (1500 mg), CKD 3B (1000 mg) and CKD 4 (500 mg); see text. Drawn from data presented in reference34

Figure 4

Proposed antiatherothrombotic mechanisms of metformin. Effects observed in humans are shown in black rectangles, while effects shown in experimental studies are shown in shaded rectangles. Adapted from reference65 with permission from Elsevier; see also references in this review