“In the U.S., eleven unique classes of medication are approved to treat hyperglycemia in type 2 diabetes mellitus, and, remarkably, 9 of these classes became available since 1995,” write Dr. Wendy L. Bennett, at Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues.
To summarize the benefits and harms of these medications as monotherapy and in combination, the investigators extracted and synthesized data from 140 randomized clinical trial and 26 observational studies. The review covered metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists.
The team notes at the outset that most studies were of short duration, so the evidence was insufficient of draw conclusions about the comparative effectiveness of different medications on long-term outcomes.
For intermediate outcomes, the researchers found that most diabetes medications used as monotherapy lowered HbA1c on average by 1 absolute percentage point. “One exception was metformin which reduced HbA1c more than the DPP-4 inhibitors as monotherapy.”
Combination therapy reduced HbA1c by about another percentage point, according to the report. “Overall, combinations of two drugs when compared with monotherapy had additive effects, both in terms of improved glycemic control, but also risk for adverse events and weight gain,” the authors observe.
In terms of the effect on body weight, the review showed that metformin decreased weight relative to thiazolidinediones and sulfonylureas. “Sulfonylureas and meglitinides increased weight similarly, sulfonylureas increased weight less than thiazolidinediones, and GLP-1 agonists decreased weight relative to sulfonylureas.” The paper outlines the varying effect of different combinations on body weight.
In general, metformin had a favorable effect on lipid levels by decreasing LDL and triglycerides and slightly increasing HDL. Rosiglitazone and pioglitazone increased both LDL and HDL. “Compared to metformin monotherapy, metformin plus rosiglitazone increased HDL while metformin plus DPP-4 inhibitors affected HDL similarly,” the investigators note.
As for safety, “No monotherapy or combination therapy convincingly demonstrated more occurrences of severe hypoglycemia than another,” the team found. However, sulfonylureas consistently increased the risk of hypoglycemia more than metformin, thiazolidinediones, DPP-4 inhibitors and liraglutide monotherapy.
Other possible adverse effects include an increased risk of congestive heart failure and bone fractures with thiazolidinediones and greater GI side effects with metformin.
Dr. Bennett and colleagues conclude that their review confirms support for metformin, “both as monotherapy and in combination with other medications, as having the highest benefit to risk profile in most comparisons.”
Furthermore, they add, “Because of the comprehensiveness of this review, we identified deficiencies in the published literature, most importantly the need for future research to evaluate long-term clinical outcomes in higher risk sub-populations, such as different ethnic groups, older adults, and patients with underlying co-morbid conditions, who may also have higher event rates.”
Ann Intern Med 2011.