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.

Figure 1

GLP-1 RAs correct six components of the Ominous Octet, whereas metformin corrects only one component.

Figure 2

Not all antidiabetes agents are equal in their ability to reduce cardiovascular risk.

Figure 3

Effect of metformin on glycemic control, insulin secretion, and insulin sensitivity in T2D. A: Metformin does not improve muscle insulin sensitivity (measured with euglycemic insulin clamp) in T2D individuals (n = 20) in the absence of weight loss (72). B: Metformin has no effect on β-cell function in T2D individuals (n = 14) (measured with an oral glucose tolerance test [OGTT] and hyperglycemic clamp) (73). C: The primary effect via which metformin reduces the HbA_1c in T2D is related to the suppression of hepatic glucose production (HGP) via inhibition of gluconeogenesis (72). FPG, fasting plasma glucose. D: Effect of metformin on HbA_1c. Because metformin does not affect muscle insulin sensitivity or β-cell function, following an initial decline after metformin administration, the HbA_1c rises progressively in T2D patients (5,6,74). KPNW, Kaiser Permanente Northwest.