Meta-analysis finds no significant difference in mortality risk between diabetes medications

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A random-effects network meta-analysis found that adults with type 2 diabetes had no significant difference in the risk of cardiovascular or all-cause mortality whether they took any of nine available classes of glucose-lowering medications.

Patients who received metformin had a lower or no significant difference in hemoglobin A1c (HbA1c) levels compared with patients who received other medications. The researchers mentioned the findings were consistent with the American Diabetes Association (ADA) guidelines recommending the use of metformin monotherapy as initial treatment for patients with type 2 diabetes.

Lead researcher Suetonia C. Palmer, PhD, of the University of Otago Christchurch in New Zealand, and colleagues published their results online in JAMA on July 19.

The researchers cited statistics that showed there were an estimated 1.5 million deaths attributable to diabetes in 2012 and that 47 million people with diabetes had a disability in 2010.

The FDA has approved several classes of medications to treat patients with type 2 diabetes, including metformin, insulins, sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose–linked cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, meglitinides and α-glucosidase inhibitors.

If patients do not achieve glycemic control with metformin, the ADA suggests adding a second drug. If patients still do not respond, the ADA recommends using a third drug.

For this analysis, the researchers examined several databases and searched for randomized trials that lasted for at least 24 weeks and compared two glucose-lowering drug classes for treating type 2 diabetes.

They identified 301 trials that met their criteria, including 177 studies of drugs given as monotherapy, 109 studies of drugs added to metformin and 29 studies of drugs added to metformin and sulfonylurea.

The mean HbA1 level was 8.2 percent in the montherapy trials, 8.2 percent in the dual therapy trials and 8.4 percent in the triple therapy trials. The mean body weight was 81.9 kg, 83.8 kg and 84.1 kg, respectively.

The median duration of diagnosed diabetes at randomization was 5.7 years in the trials, while the mean follow-up periods ranged from 24 weeks to 76.8 months.

“There was no evidence of differences in the associations between glucose-lowering drugs alone or in combination with odds of cardiovascular mortality, all-cause mortality, serious adverse events, myocardial infarction, or stroke,” the researchers wrote. “Considerable uncertainty about the association of drug treatment with cardiovascular mortality existed within trial evidence, largely because of few events in most available studies.”

The researchers said only a minority of the studies reported on cardiovascular mortality, which may have been a limitation. Other limitations included that the only triple therapy regimens they evaluated were adding drugs to metformin and sulfonylurea; they did not adjust for baseline kidney function; many of the studies were conducted in higher-income countries; and most of the studies were short-term.