Meta-analysis examines risks, benefits of third-line antihyperglycemic drugs added to combination therapy

Antihyperglycemic drugs added to metformin/sulfonylurea combination therapy in adults with type 2 diabetes vary in efficacy and risks for adverse effects, according to a recent study.

Researchers performed a network meta-analysis of randomized trials published up to May 2014 that examined use of antihyperglycemic agents in adults with type 2 diabetes who had poor glycemic control on optimized combination therapy with metformin and a sulfonylurea. Optimized combination therapy was defined as at least 1,500 mg of metformin or the maximum tolerated dose, plus at least 50% of the maximum sulfonylurea dose for at least 3 weeks. Data were extracted on change in HbA1c, weight, systolic blood pressure, and relative risk for hypoglycemia, urinary tract infections, and genital tract infections. The study results were published online July 17 by Diabetic Medicine.

Overall, 20 trials of 13 antihyperglycemic agents were included in the study. The duration of the included trials ranged from 16 to 52 weeks; ranges of mean patient age and body mass index were 41 to 67 years and 24 to 35 kg/m², respectively. All of the third-line antihyperglycemic agents reduced HbA1c versus placebo or control, with the lowest reduction seen with acarbose and the highest reduction seen with liraglutide (0.6% and 1.20%, respectively). Statistically significant weight loss was seen only with sodium glucose contransporter-2 (SGLT2) inhibitors versus placebo or control, while significant weight gain was seen with thiazolidinediones, insulin glargine, and sitagliptin. Lower systolic blood pressure was seen with SGLT2 inhibitors, rosiglitazone, and liraglutide versus placebo or control, while pioglitazone, insulin glargine, and sitagliptin had a neutral effect.

Compared with placebo or control, insulin glargine, thiazolidinediones, liraglutide, sitagliptin, and canagliflozin had significant increased risk for confirmed hypoglycemia (relative risk, 1.92 to 7.47), while no such association was seen with empagliflozin, exenatide, and dipeptidyl peptidase 4 (DPP-4) inhibitors besides sitagliptin. In addition, insulin glargine and rosiglitazone increased confirmed hypoglycemia risk in active drug comparisons versus most of the other antihyperglycemic agents (relative risk, 2.81 to 7.47). Increased risk for urinary tract infection was not seen with any antihyperglycemic agent; however, available data for this outcome were limited. Data on genital tract infection were available only for 4 of 13 agents, but among these, greater risk was seen with canagliflozin versus placebo or control (relative risk, 3.9; 95% CI, 1.58 to 9.6) and versus sitagliptin (relative risk, 5.64; 95% CI, 2.68 to 11.88).

The researchers noted that there were more data available on some drugs than on others and that follow-up was only 24 weeks in most cases, among other limitations. However, they concluded that all of the antihyperglycemic agents studied significantly reduced HbA1c versus placebo or control when added to combination therapy with metformin and a sulfonylurea and that their results support current guideline recommendations on triple therapy.

“Understanding the comparative efficacy and safety of available agents is critical to individualizing therapy for patients with Type 2 diabetes,” the authors wrote. “When selecting an add-on agent to metformin and [a sulfonylurea], improving glycaemic control must be balanced with the risks of unwanted adverse effects (or the potential for other beneficial effects).” Their results may help clinicians choose among the available agents to find the right one for their patients, the authors said.