Is It Time to Change the Type 2 Diabetes Treatment Paradigm? Yes! GLP-1 RAs Should Replace Metformin in the Type 2 Diabetes Algorithm

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 below that precedes the counterpoint narrative, 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 that follows Drs. Abdul-Ghani and DeFronzo’s contribution, 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. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association

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

“…By contrast, in EMPA‐REG OUTCOME, reductions in risk of CV outcomes and mortality in those not using metformin at baseline were numerically larger. 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 …”

“…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.…”

A review of phenformin, metformin, and imeglimin

“…In mouse islets metformin decreased insulin secretion in a concentration‐ and duration‐dependent manner (Gelin, Li, Corbin, Jahan, & Nunemaker, ). Metformin had no effect on muscle insulin sensitivity or β‐cell function in type 2 diabetes patients (Abdul‐Ghani & DeFronzo, ).…”

Enfoque terapéutico de la diabetes mellitus tipo 2 en adultos. Más allá de una meta glucémica

“…Es indiscutible que la evidencia avala el uso de GLP-1RA o iSLGT-2 sobre el de la metformina, incluso el raciocinio fisiopatológico es favorable a los nuevos medicamentos, un claro ejemplo de esto es que los agonistas del receptor de GLP-1 actúan en 6 componentes del octeto ominoso mientras que la metformina solo en 1 (inhibir la producción hepática de glucosa) 51 . Además, la metformina tiene un efecto neutro sobre el peso, mientras que los GLP-1RA e iSLGT-2 disminuyen el peso, condición que contribuye al riesgo cardiovascular.…”

“…Sin lugar a dudas los agonistas del receptor de GLP-1 y los inhibidores de SGLT-2 son más costosos que la metformina; sin embargo, un análisis de costos realizado por la Asociación Americana de Diabetes del año 2012 demostró que solo el 12% del costo de la diabetes mellitus tipo 2 parte de los medicamentos hipoglucemiantes, la gran mayoría del costo de la atención de la diabetes se relaciona con el desarrollo de complicaciones vasculares diabéticas, y la enfermedad cardiovascular contribuye con el 50% de ese costo; además, el costo del tratamiento de las complicaciones de diabetes excede en un 50% el de los medicamentos hipoglucemiantes 51,52 . La población de los estudios LEADER, SUSTAIN-6, EMPA-REG OUTCOME y CANVAS, es una población con alto riesgo cardiovascular o enfermedad cardiovascular establecido, por lo que quizás en esta población justifique, desde el punto de vista costo/beneficio, el uso de GLP-1RA o iSGLT2 sobre el uso de metformina; no obstante, queda la gran pregunta de si se tiene igual relación costo/beneficio en los pacientes sin riesgo cardiovascular que justifique el uso de estas moléculas o si la metformina continúa siendo la primera línea en ellos.…”