Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes

Abstract

Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin’s affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative that precedes the counterpoint narrative below, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative below, Dr. Inzucchi argues that based on the medical community’s extensive experience and the drug’s demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the “foundation therapy” for all patients with type 2 diabetes, barring contraindications. —William T. Cefalu Chief Scientific, Medical & Mission Officer, American Diabetes Association

Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose‐lowering therapy?

“…The fact that the CV benefits of empagliflozin are not attenuated without background metformin therapy may add to the debate regarding the historical preference for metformin as the initial glucose-lowering therapy of choice in patients with type 2 diabetes and CV disease. 26,27 Investigators were encouraged to adjust glucose-lowering therapy to achieve glycemic control according to local guidelines after week 12. Not surprisingly, additional glucose-lowering medications were introduced in a smaller proportion of patients treated with empagliflozin than placebo.…”

“…However, it should be noted that the EMPA-REG OUTCOME trial was designed to assess the effects of empagliflozin on CV outcomes in patients with type 2 diabetes and established CV disease and not 26 23 These glucoselowering agents have been proposed by some to have potential adverse CV effects, specifically weight gain and an increased risk of hypoglycaemia. 2 We did observe an overall greater risk of hypoglycaemia in patients taking insulin, but not in those taking SU.…”

Metformin Inhibits Mouse Islet Insulin Secretion and Alters Intracellular Calcium in a Concentration-Dependent and Duration-Dependent Manner near the Circulating Range

“…The first line of pharmacological treatment for patients with type 2 diabetes (T2D) is metformin [ 1 ]. Metformin is thought to reduce insulin resistance in diabetic patients primarily by inhibiting the mitochondrial respiratory-chain complex in hepatocytes to decrease hepatic glucose production, thus leading to a decrease in blood glucose concentrations [ 2 , 3 ].…”

Cardiovascular risk and the implications for clinical practice of cardiovascular outcome trials in type 2 diabetes

“…However, debate is ongoing on whether current treatment guidelines should be revised to consider other antidiabetic agents alongside metformin as first-line therapy options in T2D [53,54]. Moving towards this direction, the American…”