After Metformin, Antihyperglycemic Choices a Judgment Call

A review of 140 trials and 26 observational studies supports metformin as the best first-line treatment for type 2 diabetes in adults, both stand-alone and in combination with other medications. But once metformin is in the mix, second-line treatments are still a judgment call, according to the authors of a Johns Hopkins–led study published in the May 3 edition of the Annals of Internal Medicine.¹

Eleven classes of medications are approved to treat hyperglycemia in type 2 diabetes. Most adults with the disease receive more than one medication to control blood sugar. The new study is an update and expansion of the Agency for Healthcare Research and Quality review of oral hypoglycemic medications for type 2 diabetes done in 2007.²

Most medications had similar effects on glycemic control, decreasing hemoglobin A1c level by about 1 percentage point, with most 2-drug combinations producing similar reductions.

Overall, combinations of 2 drugs had additive effects, in terms of not only improved glycemic control but also risk for adverse events and weight gain. Some combinations had lower relative risk for hypoglycemia, weight gain, congestive heart failure, and fractures, which could influence the choice of the metformin partner drug, the authors said. For example, metformin plus a sulfonylurea had efficacy similar to that of metformin plus a thiazolidinedione in reducing hemoglobin A1c level, and had a lower risk for heart failure-but the risk for hypoglycemia was increased 6-fold.

Other findings:

• Metformin was more effective than dipeptidyl peptidase-4 (DPP-4) inhibitors and led to an average of 2.5 kg less body weight than thiazolidinediones or sulfonylureas.

• Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors.

• Sulfonylureas had a 4-fold higher risk of mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones.

• Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk of for bone fractures compared with metformin.

• Diarrhea occurred more often with metformin than with thiazolidinediones.

• The researchers could not draw firm conclusions about the safety of DPP-4 and glucagon-like peptide-1 (GLP-1) antagonists because the studies reviewed were short-term and had few common comparators. More generally, evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) related to all therapies was lacking or of low strength.

1. Bennett WL et al. Comparative effectiveness and safety of medications for type 2
diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-613. http://www.annals.org/content/154/9/602.full.pdf+html.

2.  Bolen S, Wilson L, Vassy J, et al. Comparative effectiveness and safety of oral diabetes medications for adults with type 2 diabetes. Rockville, MD: Agency for Healthcare Research and Quality; 2007. AHRQ publication 07-EHC010-EF. See http://effectivehealthcare.ahrq.gov/ehc/products/6/39/OralFullReport.pdf; also Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007;147:386-399. [PMID: 17638715]