Thessaloniki, Greece—Newer isn’t always better, at least when it comes to first-line therapy for patients newly diagnosed with type 2 (T2D) diabetes who are at low cardiovascular risk.

That was the conclusion of a comparison of glucose-lowering drugs, which found that metformin-based therapy might be a preferred first-line treatment for drug-naive patients with T2D who are at low cardiovascular risk. The report in Annals of Internal Medicine points out that not enough evidence exists to reach a conclusion about the optimal initial treatment of drug-naive patients at increased cardiovascular risk.

The systematic review and network meta-analysis were conducted by Greek researchers from Aristotle University of Thessaloniki and colleagues.

The article notes that increasing evidence is indicating that antidiabetic drug classes and individual agents differ not only in glycemic efficacy but also in their effect on mortality and vascular end points.

The study team searched several databases from inception through December 18, 2019, and on April 10, 2020, in an effort to compare benefits and harms of glucose-lowering drugs in adults with T2D.

Included were English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes. Data was extracted by pairs of reviewers who also appraised risk of bias.

Ultimately, the focus was on 453 trials assessing 21 antidiabetic interventions from nine drug classes. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials).

No differences were detected between treatments in drug-naive patients at low cardiovascular risk. The authors point out that insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level.

In addition, they note, “In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death.”

The review determined that odds of stroke were lower with subcutaneous semaglutide and dulaglutide, while sodium–glucose cotransporter-2 (SGLT-2) inhibitors reduced heart-failure hospitalization and end-stage renal disease. Subcutaneous semaglutide was found to increase diabetic retinopathy and treatment with canagliflozin was linked to higher amputation risks.

“In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes,” the study concludes. “In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes.”

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