Combination Therapy When Metformin Is Not an Option for Type 2 Diabetes

Objective: Consensus on combination options for patients with type 2 diabetes mellitus (T2DM) unable to use metformin is lacking. This review summarizes data describing–non-metformin based combination therapy. Data Sources: PubMed searches (January 1990 to August 2014) were conducted with terms for newer drug therapies alone and with the term combination; filters were applied for Clinical Trial, Meta Analysis, and English language. Study Selection and Data Extraction: Results were reviewed for multicenter, randomized controlled trials of non-metformin–based combination therapy conducted in the past 5 years and specific to the US or multinational populations. Data Synthesis: Although multiple injectable and oral agents have been studied in combination with metformin for management of T2DM, data are more limited for combinations without metformin. Combinations of incretins (injectable glucagon-like peptide-1 receptor agonists or oral dipeptidyl peptidase-4 [DPP-4] inhibitors) with a sulfonylurea, thiazolidinedione, or insulin are well studied and provide greater glucose-lowering efficacy than monotherapy. Incretins are associated with a low risk of hypoglycemia when used as monotherapy; the dosage of sulfonylurea or insulin should be reduced when used in combination. Newer studies are investigating the combined use of an oral sodium-glucose cotransporter 2 inhibitor and a DPP-4 inhibitor. In a recent study, reductions in glycated hemoglobin (A1C) of 1.1% to 1.2% and reduced weight with no additive risk of hypoglycemia were observed. Conclusions: Selecting the most appropriate combination therapy for patients with T2DM requires balancing clinical benefits with the risks, such as weight gain and hypoglycemia. Treatment approaches should be individualized for vulnerable patient populations for whom metformin is not appropriate.