Glucose-Lowering Drugs, Diabetes, & CV Mortality

No significant differences exist in the associations between any of 9 available classes of glucose-lowering drugs alone or in combination for type 2 diabetes mellitus (DM) and the risk of cardiovascular or all-cause mortality, according to a new study.

Patients receiving metformin monotherapy had lower or similar hemoglobin A1C (HbA1C) levels as those receiving sulfonylurea, thiazolidinedione, or α-glucosidase inhibitor monotherapy.

“Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations,” state the researchers, led by Suetonia C. Palmer, PhD of the Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.

The results suggest that metformin is as good as basal insulin, but does not answer the question about whether some patients should receive insulin as a first-line treatment, they note.

The researchers conducted a systematic review with network meta-analysis to estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. The researchers identified 301 clinical trials that met criteria for inclusion in the study, which included randomized clinical trials of 24 weeks or longer duration.

The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, HbA1C level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight.

Of the trials included in the study, 177 trials including 56,598 patients were of drugs given as monotherapy; 109 trials including 53,030 patients of drugs added to metformin as dual therapy; and 29 trials of 10,598 patients of drugs added to metformin and sulfonylurea as triple therapy. The researchers found no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular, all-cause mortality, serious adverse events, heart attack, or stroke.

Compared with metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, and α-glucosidase inhibitor monotherapy were associated with higher HbA1C levels. Sulfonylurea and basal insulin were associated with the greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while sodium-glucose co-transporter 2 inhibitors offered the lowest odds of hypoglycemia. When added to metformin and sulfonylurea, glucagon-like peptide-1 receptor agonists were associated with the lowest odds of hypoglycemia.

Considerable uncertainty about the association of drug treatment with cardiovascular mortality existed within the trial evidence, largely because of few events in most available studies, they state.

“A central finding in this meta-analysis was that despite more than 300 available clinical trials involving nearly 120,000 adults and 1.4 million patients-months of treatment, there was limited evidence that any glucose-lowering drug stratified by coexisting treatment prolonged life expectance or prevented cardiovascular disease,” they state.

Reference: Palmer SC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016 Jul 19;316(3):313-324.