Abstract
Metformin is the most commonly used glucose-lowering therapy (GLT) worldwide and remains the first-line therapy for newly diagnosed individuals with type 2 diabetes (T2D) in management algorithms and guidelines after the UK Prospective Diabetes Study (UKPDS) showed cardiovascular mortality benefits in the overweight population using metformin. However, the improved Major Adverse Cardiovascular Events (MACE) realised in some of the recent large cardiovascular outcomes trials (CVOTs) using sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have challenged metformin’s position as a first-line agent in the management of T2D. Many experts now advocate revising the existing treatment algorithms to target atherosclerotic cardiovascular disease (ASCVD) and improving glycaemic control as a secondary aim. In this review article, we will revisit the major cardiovascular outcome data for metformin and include a critique of the UKPDS data. We then review additional factors that might be pertinent to metformin’s status as a first-line agent and finally answer key questions when considering metformin’s role in the modern-day management of T2D.
Highlights
Almost 60 years after it was first introduced for the treatment of type 2 diabetes (T2D), metformin (1,1-dimethylbiguanide hydrochloride) remains the most widely prescribed oral glucose-lowering therapy (GLT) for the management of T2D worldwide [1]
Metformin is endorsed by most clinical guidelines after the UK Prospective Diabetes Study (UKPDS) first demonstrated long-term metabolic benefits and reduced cardiovascular risk with metformin therapy in addition to less weight gain and fewer hypoglycaemic episodes compared to therapy with insulin and sulfonylurea (SU) [2]
Rachmani et al reported no cases of lactic acidosis in individuals with congestive heart failure (CHF) (New York Heart Association (NYHA) III-IV), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) [69], which are regarded as traditional contraindications to use of metformin due to potentially increased risk of lactic acidosis
Summary
Almost 60 years after it was first introduced for the treatment of type 2 diabetes (T2D), metformin (1,1-dimethylbiguanide hydrochloride) remains the most widely prescribed oral glucose-lowering therapy (GLT) for the management of T2D worldwide [1]. A 10-year post-trial monitoring of the UKPDS cohort showed that in the metformin group, significant RR persisted for any diabetes-related end-point (RR 0.79, 95% CI 0.66, 09.5; p = 0.01), MI (RR 0.67, 95%CI 0.51, 0.89; p = 0.005), and death from any cause (RR 0.73, 95% CI 0.59, 0.89; p = 0.002) even though between-group differences in glycated haemoglobin (HbA1c) were lost 1-year after completion of the main trial [20] This lead to the concept of “legacy effect” or “glycaemic memory” suggesting that putative long-term benefits of intensive early glycaemic control in newly diagnosed individuals with T2D persist even if followed by a return to “usual” less intense care [21]
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