Diabetes drug classes associated with similar outcomes in low-risk patients

A systematic review and network meta-analysis found no differences between treatments for drug-naive patients with type 2 diabetes at low cardiovascular risk, leading the authors to conclude that metformin is justified as a first-line therapy.


Most available treatments for type 2 diabetes were associated with similar cardiovascular outcomes in patients at low baseline risk, according to a recent systematic review and network meta-analysis.

The analysis included 453 trials assessing 21 antidiabetic interventions from nine drug classes. There were 134 monotherapy trials, 296 testing an add-on to metformin, and 23 comparing monotherapy to metformin plus an add-on. All of the trials included at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality and on glycemic and vascular outcomes. The study was funded by The European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. Results were published by Annals of Internal Medicine on June 30.

The analysis found no differences between treatments among drug-naive patients at low cardiovascular risk. The greatest reductions in HbA1c levels were seen with insulin regimens and specific glucagon-like peptide-1 receptor agonists added to metformin. In the trials testing add-ons to metformin, patients at low cardiovascular risk showed no clinically meaningful differences for mortality and vascular outcomes with any treatment. In the 21 trials with patients at increased cardiovascular risk, adding oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, or dapagliflozin was associated with reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide were also associated with reduced risk of cardiovascular death. Odds of stroke were lower in patients receiving subcutaneous semaglutide or dulaglutide. Heart failure hospitalizations and end-stage renal disease were reduced with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Subcutaneous semaglutide increased diabetic retinopathy, and canagliflozin increased the risk of amputation.

The authors concluded that for diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes and thus “the use of metformin as first-line treatment of drug-naive patients at low cardiovascular risk seems justified.” For patients with low cardiovascular risk who are already on metformin, the choice of add-on should be based on nonvascular efficacy and safety outcomes because of lack of observed difference in vascular outcomes, the authors advised. For patients at increased cardiovascular risk, there aren't enough data to determine the optimal first-line treatment, and an add-on choice “between specific GLP-1 RAs [glucagon-like peptide-1 receptor agonists] and SGLT-2 inhibitors should be based on the cardiovascular profile of individual agents and guided by patients' personal preferences and therapeutic priorities,” the authors said. “Recently completed and ongoing trials are expected to strengthen the evidence base about the effects of GLP-1 RAs and SGLT-2 inhibitors on vascular end points.”

An accompanying editorial noted that the low confidence of the networks of drug trials “does not allow for answering whether any of the newer diabetes medications will be better initial monotherapy agents than metformin for lowering glycemia or reducing the risks for mortality and cardiovascular disease” and offered advice on how trials could provide better data.