In patients who have type 2 diabetes (T2D) and low cardiovascular risk, receiving metformin as first-line therapy appears justified based on existing trial data, according to study results published in the Annals of Internal Medicine.

The aim of this systematic review and network meta-analysis of randomized controlled trials was to assess long-term effects of antidiabetic drugs and inform pharmacologic management of T2D. Because evidence shows that antidiabetic drug classes differ in their effects on mortality and vascular end points along with glycemic efficacy, focus in pharmacologic selection and management has shifted from glycemic control to prevention of adverse cardiovascular outcomes.

Randomized controlled trials that included adults with T2D who received ≥24 weeks of intervention, had ≥1 reported outcome of interest, and assessed glucose-lowering drugs were included. Trials that compared medications of the same drug class were excluded, except for those with intraclass comparisons of glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors. These were also analyzed as individual agents.

Of the 52,374 records pulled, 453 trials that assessed 21 antidiabetic interventions from 9 drug classes were eligible for the meta-analysis. Treatment interventions were used as monotherapy in 134 of the trials (101 in drug-naive patients). In 296 trials, treatment interventions were used as add-ons to metformin-based therapy. In the remaining 23 trials, both groups that evaluated treatment as monotherapy and add-on therapy were included.


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In the drug-naive patients, all treatments reduced hemoglobin A1c levels similarly to metformin except for dipeptidyl peptidase-4 inhibitors, which were slightly inferior (mean difference, 0.32%; 95% CI, 0.17- 0.46). With regard to the incidence of severe hypoglycemia, there was no difference between each drug class and placebo or metformin. Because there were no trials that exclusively recruited drug-naive patients at increased cardiovascular risk, trials were analyzed in a single network, but the researchers did not reach any clear consensus on the optimal initial treatment in these patients.

Subcutaneous semaglutide was more effective than all other treatments in lowering hemoglobin A1c levels in patients on metformin-based background therapy (mean difference vs placebo, -1.33%; 95% CI, -1.50 to -1.16). The greatest incidence of severe hypoglycemia was associated with sulfonylureas, premixed insulin, and basal-bolus insulin.

In patients at increased cardiovascular risk who were receiving metformin, all-cause mortality and cardiovascular death risk were reduced with addition of oral semaglutide, empagliflozin, and liraglutide, whereas addition of extended-release exenatide or dapagliflozin only reduced all-cause mortality. Odds of stroke were lowered with dulaglutide (odds ratio [OR], 0.76; 95% CI, 0.62-0.94) and subcutaneous semaglutide (OR, 0.61; 95% CI, 0.37-0.99). Canagliflozin (OR, 0.72; 95% CI, 0.60-0.87), dapagliflozin (OR, 0.75; 95% CI, 0.64-0.86), and empagliflozin (OR, 0.65; 95% CI, 0.50-0.85) had a positive effect on heart failure, as well as end-stage renal disease (for all SGLT2 inhibitors: OR, 0.63; 95% CI, 0.50-0.79). Odds of diabetic retinopathy were increased with subcutaneous semaglutide (OR, 1.75; 95% CI, 1.10-2.78), and incidence of amputation was increased with canagliflozin (OR, 1.61; 95% CI, 1.27-2.05) and decreased with liraglutide (OR, 0.65; 95% CI, 0.45-0.96).

“[T]he use of metformin as first-line treatment of drug-naïve patients at low cardiovascular risk seems justified. [But] given the lack of pertinent evidence, we could not reach a conclusion about the optimal initial treatment of drug-naïve patients at increased cardiovascular risk,” the study authors concluded.

“For patients at increased cardiovascular risk receiving metformin-based background therapy, the optimal choice between specific [newer pharmacologic options] should be based on the cardiovascular profile of individual agents and guided by patients’ personal preferences and therapeutic priorities,” they suggested.

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Reference

Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes [published online June 30, 2020]. Ann Intern Med. doi:10.7326/M20-0864