Among patients receiving metformin for type 2 diabetes, adding insulin rather than a sulfonylurea is associated with an increased risk of cardiovascular events and all-cause mortality, according to a report published online June 11 in JAMA.
This finding calls into question the recommendation that insulin is equivalent to sulfonylureas as an add-on agent when metformin alone fails to reduce hemoglobin A1c, said Dr. Christianne L. Roumie of the Veterans Health Administration–Tennessee Valley Heathcare System Geriatric Research Education Clinical Center, Nashville, and her associates.
Dr. Christianne L. Roumie
At present, there is no consensus as to which add-on medication is preferred: insulin (long acting, premixed, or fast acting), sulfonylureas (glyburide, glipizide, or glimepiride), thiazolidinediones, glucagon-like peptide-1 receptor agonists, or dipeptidyl peptidase 4 inhibitors. The investigators performed this comparative study expecting that intensifying therapy with insulin rather than sulfonylureas would improve cardiovascular outcomes because of insulin’s superiority in achieving glycemic control.
They assessed 42,938 patients who began taking metformin alone during 2001-2008 and were followed for a median of 50 months. A total of 2,948 added on insulin therapy and 39,990 added on a sulfonylurea. The rate of the primary composite outcome – acute MI or stroke hospitalization or death from any cause – was 42.7 events per 1,000 person-years with insulin, compared with 32.8 events per 1,000 person-years with sulfonylureas. The adjusted hazard ratio was 1.30, Dr. Roumie and her colleagues reported (JAMA 2014;311:2288-96).
These findings remained robust in a sensitivity analysis and in subgroup analyses that stratified patients by CVD history and age. They are consistent with the results of two recent large clinical trials and several observational studies, all of which found no advantage of add-on insulin over add-on sulfonylureas and some of which reported increased cardiovascular risks with insulin, the investigators said.
This study was funded by the Agency for Healthcare Research and Quality, a Veterans Affairs Clinical Science Research and Development grant, and the Center for Diabetes Translation Research. Dr. Roumie and her associates reported no potential financial conflicts of interest.