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Meta-analysis Aims to Compare Antidiabetic Medications in T2D Population


Metformin-based therapy may be an optimal first-line treatment for patients with type 2 diabetes (T2D) and low cardiovascular risk, according to a systematic review and network meta-analysis published in Annals of Internal Medicine.

Metformin-based therapy may be an optimal first-line treatment for patients with type 2 diabetes (T2D) and low cardiovascular risk, according to a systematic review and network meta-analysis published in Annals of Internal Medicine.

The review also revealed there is not enough evidence to determine the best initial treatment for drug-naïve patients with T2D and increased cardiovascular risk. Because of this, safety and efficacy of medications prescribed to this cohort should be considered above cardiovascular outcomes.

Evidence has shown that antidiabetic drug classes and individual agents differ when it comes to glycemic efficacy, effects on mortality, and vascular end points.

“Pharmacologic management has shifted its focus from glycemic control to prevention of cardiovascular outcomes,” the authors write. Because of this, therapeutic decision-making is now based in part “on patients' history of atherosclerotic disease, heart failure, or chronic renal disease.”

To investigate the outcomes of antidiabetic medications in patients with T2D and varying cardiovascular risks, the researchers compiled 453 English-language randomized trials in a systematic review. Twenty-one antidiabetic interventions from 9 drug classes were included.

Studies were pulled from online databases such as Medline, Embase, and the Chocrane Central Register of Controlled trials. All trials had an intervention period of at least 24 weeks and assessed glucose-lowering medications approved or pending approval from European or US regulators.

Single interventions evaluated included metformin, sulfonylureas, pioglitazone, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium—glucose cotransporter-2 (SGLT-2) inhibitors, among others. Overall, 134 trials included monotherapies, 296 included add-ons to metformin-based therapies, and 23 trials compared add-on to metformin therapies with monotherapies.

Primary outcomes were changes in hemoglobin A1C (A1C) from baseline and all-cause mortality, and the secondary outcomes were severe hypoglycemia, cardiovascular death, stroke, myocardial infarction, hospitalization for heart failure, diabetic retinopathy, and amputation.

The median trial duration was 26 weeks, and the majority of studies (300) were double-blind. “For all-cause mortality, overall risk of bias was low in 80 trials (20%), whereas 292 trials (74%) had high risk of bias,” the authors said.

The study yielded the following results:

  • In drug-naïve patients, all treatments reduced A1C level compared with placebo, with mean differences (MDs) ranging from —1.48% (95% CI, –2.15% to –0.81%) for subcutaneous semaglutide to –0.60% (95% CI, –0.75% to –0.46%) for DPP-4 inhibitors
  • All treatments reduced A1C level to a similar extent with metformin, except for DPP-4 inhibitors (MD, 0.32%; 95% CI, 0.17%-0.46%), which were also inferior to liraglutide, subcutaneous semaglutide, pioglitazone, and sulfonylureas in drug-naïve patients
  • For patients on metformin-based background therapy, the greatest placebo-subtracted reductions in A1C level were seen with GLP-1 RAs, premixed insulin, and basal—bolus insulin regimens
  • Subcutaneous semaglutide was more efficacious in lowering A1C level than all other treatments (MD vs placebo, —1.33%; 95% CI, –1.50% to –1.16%) in patients with metformin-based background therapy, while sulfonylureas, premixed insulin, and basal–bolus insulin were associated with an increase in the incidence of severe hypoglycemia

Notably, no differences between treatments in drug-naïve patients at low cardiovascular risk were reported.

For patients at increased cardiovascular risk receiving metformin-based background therapy, the results showed “oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality.” Administration of oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death in this cohort, while lower odds of stroke were associated with subcutaneous semaglutide and dulaglutide.

Furthermore, SGLT-2 inhibitors were shown to reduce heart failure hospitalization and end-stage renal disease in this population. However, subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively.

Based on the results, the authors concluded, “The use of metformin as first-line treatment of drug-naive patients at low cardiovascular risk seems justified.”

They point out the analysis incorporates a considerably large number of randomized controlled trials compared with previous reviews, although inconsistent definitions of cardiovascular risk in different studies serve as a limitation.

In addition, an editorial published in response to the findings raises concerns about the indirect comparisons of T2D treatments. “In the network meta-analysis of drug-naive patients with T2D, problems with network consistency and low confidence in estimates do not allow conclusions to be made for the head-to-head comparison of diabetes medications used for initial monotherapy in lowering glycemia.”

Overall the analysis’ estimates were limited, they argue. “Low confidence in estimates from networks of trials of initial drug therapy 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,” the authors conclude.


Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes. Ann Intern Med. Published online June 29, 2020. doi:10.7326/M20-0864

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