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So Many Oral Antidiabetic Drugs; What Combinations Work?

Researchers have identified several combinations of drugs that outperform metformin monotherapy in patients with type 2 diabetes mellitus.

Every endocrinologist knows that diabetes is epidemic, and the number of Americans with type 2 diabetes (T2DM)—almost 26 million—is not surprising. The cost of diabetes is measured in billions of dollars, and the most recent figures concerning costs in the United States (2008-2009) indicate that this diagnosis consumed $174 billion. About 10% of this total was used to purchase drugs. Metformin remains the corner- stone of pharmacologic treatment. A large proportion of patients—more than 30%—remain uncontrolled despite treatment with drugs, biologics, and other interventions. Half of T2DM patients will require at least two drugs within 3 years of diagnosis, and three-quarters will need additional medication at 9 years post-diagnosis. These facts leave many clinicians wondering what oral combinations work best.

Researchers from Tufts University in Boston and Brown University in Providence set out to discover which drug combinations lead to the best glycemic control, and to determine if hypoglycemia plays a role in adherence. Because so few studies are available to address this specific concern, they used a network meta-analysis of available randomized clinical trials that employed drugs to treat T2DM. Their data covered more than 100,000 patients over 30 years. Using metformin as their reference drug, they compared monotherapy and combination regimens. This study appears in the August 2014 issue of Clinical Therapeutics.

They identified 8 treatment regimens that outperformed metformin monotherapy: glucagon-likepeptide-1 [GLP-1] agonists plus metformin, sulfonylureas plus metformin, dipeptidylpeptidase-4[DPP-4]inhibitors] plus metformin, colesevelan plus metformin, thiazolidinediones plus metformin, metiglinides plus metformin, α-glucosidase inhibitor plus metformin, and rosiglitazone monotherapy. The authors note that, although most guidelines consider α-glucosidase inhibitors and colesevelan drugs of modest activity, they did prompt an improved response as add-on to metformin.

Using triple combinations (GLP-1, thiazolidinedione, insulin, metiglinide, or sulfonylureas added to a metformin backbone) also improved glycemic control.

Combinations including GLP-1, thiazolidinedione, insulin, metiglinide, and/or sulfonylureas with metformin were the most potent.

Patients who took sulfonylureas, α-glucosidases, and metiglinides in addition to metformin were at elevated risk for hypoglycemia.

The authors note that their results only identify good combinations of drugs. Actual clinical decisions must consider patient comorbidities and potential drug interactions. The authors also point out that combining metformin with older (and less expensive) drugs like sulfonylureas was deemed highly effective. Patients who have concerns about cost are candidates for these combinations.