Effective, safe glycemic control is a global priority because uncontrolled diabetes contributes to a substantial burden of morbidity and mortality related to chronic kidney disease (CKD), ESKD, and cardiovascular disease (CVD) (1, 2). However, achieving this goal in patients with advanced kidney disease is complicated by evolving safety recommendations and contraindications to several existing antihyperglycemic medications when kidney function is substantially impaired (2). Amid robust evidence for inhibition of the renin-angiotensin system as the mainstay of managing diabetic kidney disease and growing attention to the significant cardiovascular, kidney, and survival benefits of sodium glucose cotransporter 2 inhibitors, the important role of metformin should not be forgotten (1, 3, 4).
The therapeutic efficacy of metformin, its 60-plus-years history of use, and its relatively strong safety profile, low cost, and weight neutrality render it a first-line antiglycemic agent by European and U.S. guidelines (Figure 1) (5, 6). Metformin is a biguanide recognized for its important role in improving glycemic control through mechanisms distinctly different from those of insulin, sulfonylureas, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose co-transporter 2 inhibitors. Our understanding of the mechanisms of action of metformin remains incomplete, although its antiglycemic effects occur primarily through enhanced insulin sensitivity and decreased gluconeogenesis by mitochondrial inhibition and increased activation of AMP-kinase (7, 8).
Bolstered by evidence regarding the long-term cardiovascular, diabetes-related, and survival benefits of metformin therapy, the American Diabetes Association (ADA) 2019 guidelines recommend consideration of metformin for the prevention of type 2 diabetes in individuals with prediabetes, especially in those older than 60 years, those with body mass index >35, and women with a history of gestational diabetes (9). Moreover, metformin continues to be the ADA’s preferred initial agent for the treatment of type 2 diabetes as long as it is well tolerated and not contraindicated.
When metformin is used as a single agent, the average hemoglobin A1c reduction associated with it ranges from 1% to 1.5%. In addition, important longer-term benefits of metformin in reducing cardiovascular risk date back to compelling data from the UK Prospective Diabetes Study (UKPDS) (8). Metformin significantly reduced the risk for any diabetes-related endpoint, diabetes-related mortality, and all-cause mortality in obese individuals with newly diagnosed type 2 diabetes when it was compared with conventional therapy (with dietary control) alone (8). Although additional studies are needed to 1) understand the effects of metformin in combination with sulfonylureas and 2) better understand the impact of metformin in non-U.S. and European populations, the long-term effects of metformin are robust. For example, the 10-year follow-up of the metformin group in UKPDS showed that significant reductions persisted for diabetes-related endpoints, death of any cause, and myocardial infarction (10). Finally, metformin continues to be studied for its potential pleiotropic benefits, including antineoplastic effects mediated by AMP-kinase–dependent and independent inhibition of mTOR, treatment of polycystic ovary syndrome, attenuated atherosclerosis and vascular senescence as demonstrated in mouse models, and lipid-lowering and anti-inflammatory effects (2, 11).
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Chowdhury TA, et al.. Could metformin be used in patients with diabetes and advanced chronic kidney disease? Diabetes Obes Metab 2017; 19:156–161.
Hung SC, et al.. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3:605–614.
An H, He L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol 2016; 228:R97–R106.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–853.
Holman RR, et al.. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577–1589.
Inzucchi SE, et al.. Metformin in patients with type 2 diabetes and kidney disease: A systematic review. JAMA 2014; 312:2668–2675.
Eurich DT, et al.. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure. Circ Heart Fail 2013; 6:395–402.