Combination Therapies for T2DM: Why Some May Work Better than Others

Pharmacological options for improving glucose control in patients with type 2 diabetes today include several classes of drugs that target one or more of the pathophysiological processes that contribute to this complex disease. Pharmacological management, accompanied by lifestyle changes, including diet modification, exercise, and weight loss, typically begins with monotherapy, most frequently with the biguanide metformin.¹ Over time, however, many patients with type 2 diabetes require insulin or a combination of oral antihyperglycemic agents to achieve targeted HbA1c and blood glucose levels.

Dual therapy may be indicated at the outset for patients who present with high HbA1c at diagnosis, since effective glucose control in patients with HbA1c greater than 8.5% to 9% is unlikely to be achieved with a single agent.³ Dual therapy may consist of two separate pills or one pill that combines two agents. Current guidelines suggest that when combination oral antihyperglycemic therapy is initiated, prescribers choose agents with complementary mechanisms of action.^2,3

The use of combination pills aims to enhance treatment effectiveness while minimizing side effects, especially hypogylcemia.³ Yet, as Mooradian and colleagues at the University of Florida College of Medicine, Jacksonville, noted in a recent article in the American Journal of Therapeutics, few clinical trials have addressed the efficacy of combination pills.³ The authors examined the “advantages and pitfalls of antihyperglycemic combination pills,” summarizing data from 14 clinical trials in which various combinations of glucose-lowering drugs were prescribed as first-line therapy for patients with type 2 diabetes. The combinations studied were: metformin with either glipizide, glyburide, nateglinide, repaglinide, sitagliptin, saxagliptin, rosiglitazone, miglitol, or dapagliflozin, administered as two individual medications or a combination pill; rosiglitazone/glimepiride; and nateglinide/troglitazone. Most of the trials combined an insulin provider with an insulin-sensitizing drug and compared the efficacy of the combination pill or regimen with the efficacy of each component drug given alone.³

Based on the data examined, the authors concluded that while the addition of a second antihyperglycemic agent to initial therapy improved glycemic control, the efficacy of combination pills for type 2 diabetes “is often less than the sum of the efficacy of its components.”³ That is, combining two agents—even two with different mechanisms of action—did not result in a demonstrable synergistic effect on the reduction of blood glucose levels. The authors attributed the less additive efficacy of certain combination therapies to the overlapping glucose-lowering mechanisms of the respective component drugs.³