Beyond Metformin: Initiating Combination Therapy in Patients with Type 2 Diabetes Mellitus

Abstract

The majority of patients with type 2 diabetes mellitus will eventually require combination therapy involving two or more agents to achieve their glycemic target as their disease progresses. This review contrasts current treatment guidelines and recommendations by the American Diabetes Association and the European Association for the Study of Diabetes (referred to as ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (referred to as AACE) for the initiation of combination therapy. Both treatment guidelines emphasize that treatment selection for patients with type 2 diabetes should be guided by the goal of lowering hemoglobin A(1c) (A1C) level and individualizing therapy to each patient based on clinical factors and comorbidities. In addition, combination therapy should include classes of drugs with complementary mechanisms of action that efficiently and effectively target the underlying type 2 diabetes pathophysiology. Both the ADA and AACE recommend metformin as a firstline oral agent; however, the ADA supports early use of sulfonylureas or insulin in patients who do not reach their target A1C goal, whereas the AACE recommends earlier and more frequent use of the newer incretin agents-glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Mechanisms of action, benefits, and risks of traditional and newer agents are discussed to better enable the pharmacist to recommend the best combinations of agents for individual patients.

Linagliptin plus metformin: a pharmacokinetic and pharmacodynamic evaluation

“…After failure of metformin monotherapy, several pharmacological options may be considered [3][4][5][6] , among which the addition of a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) occupies an increasing place in clinical practice [7][8][9] . Indeed, a progressive deterioration of the glycemic control is generally observed over years in patients with T2DM, which essentially results from an unavoidable decline of insulin secretion 10 and imposes a stepwise increasing use of combined therapies 2,3 .…”

Mini-Special Issue paper Management of diabetic patients with hypoglycemic agents Metformin and its clinical use: new insights for an old drug in clinical practice

“…It improves peripheral and liver sensitivity to insulin, reduces basal liver glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases appetite and causes weight reduction (Figure 1). Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists and American College of Endocrinology (referred to as AACE) recommend metformin as first-line therapy in T2DM [1]. In recent years, new indications for metformin use in clinical practice have emerged, besides diabetes.…”

Resistin, an adipokine, may affect the improvement of insulin sensitivity in the metabolic syndrome patient treated with metformin

“…Metformin is the first-line oral therapy for MS in recent guidelines of the American Diabetes Association (ADA) and European Association of the Study of Diabetes (EASD), which is superior to rosiglitazone in improvement of cardiovascular outcomes [3,5]. However, rosiglitazone is superior to metformin in enhancement of insulin sensitivity.…”

“…This hypothesis could explain why rosiglitazone is superior to metformin in enhancement of insulin sensitivity. Since resistin may decrease the insulin sensitivity, we recommend combination therapy in MS. For example, metformin combined with a GLP-1 receptor agonist, and then a sulfonylurea or pioglitazone.3 as the AACE recommended [28].…”

“…Insulin resistance could be reversed by insulin-sensitising drugs such as rosiglitazone and metformin [4,5]. Rosiglitazone is insulin-sensitizer, which improves insulin sensitivity by activating AMP-activated protein kinase (AMPK) [6].…”