medwireNews: A wide-ranging network meta-analysis published in the Annals of Internal Medicine reveals critical knowledge gaps in the use of glucose-lowering medications in people with type 2 diabetes.
Apostolos Tsapas (Aristotle University of Thessaloniki, Greece) and colleagues analyzed 453 trials of 21 antidiabetic medications from nine drug classes.
In an accompanying editorial, Christine Lee and William Cefalu (National Institutes of Health, Bethesda, Maryland, USA) observe that this makes it the largest network meta-analysis of glucose-lowering drugs to date, and stress that the authors attempted “to evaluate outcomes beyond glycemia, mortality, and cardiovascular outcomes.”
First, the researchers concluded that “the use of metformin as first-line treatment of drug-naive patients at low cardiovascular risk seems justified.” This was because glucose-lowering efficacy was similar among the medication classes for drug-naïve people (although it was poorest for dipeptidyl peptidase-4 inhibitors), and vascular and mortality outcomes also did not significantly differ.
“In patients at low cardiovascular risk receiving metformin-based background therapy, choice among available agents should be based on their effect on other efficacy and safety outcomes because of lack of difference in vascular outcomes,” Tsapas and team therefore advise.
But they stress: “We did not identify any trials exclusively recruiting drug-naive patients at increased cardiovascular risk” and therefore “could not reach a conclusion about the optimal initial treatment” for this subgroup.
Lee and Cefalu highlight the issue of which first-line medication to use in people at high vascular risk as being one of several “pressing clinical questions” the analysis was unable to address.
Despite the researchers’ intention to evaluate “patient-important outcomes like amputation, diabetic eye disease, and sexual dysfunction […] the limited number of events and trials collecting such outcomes has made conclusive comparisons of diabetes medications through [network meta-analysis] for these outcomes impossible,” say the editorialists.
The researchers did find that among people at high vascular risk already taking metformin, no medication significantly affected the likelihood for diabetic retinopathy with the exception of injectable semaglutide, which significantly increased the likelihood (odds ratio [OR]=1.75). The odds for amputation were significantly increased with canagliflozin (OR=1.61) and reduced with liraglutide (OR=0.65).
Direct comparisons confirmed mortality benefits for various glucagon-like peptide (GLP)-1 receptor agonists and sodium-glucose cotransporter (SGLT)2 inhibitors versus placebo, and indirect comparisons suggested benefits of oral semaglutide and empagliflozin on all-cause mortality risk and empagliflozin on cardiovascular mortality risk when compared with a range of other medications and classes.
GLP-1 receptor agonists significantly reduced stroke risk, and SGLT2 inhibitors reduced the risk for heart failure hospitalization. No medication outperformed any other in reducing the risk for myocardial infarction.
“For patients at increased cardiovascular risk receiving metformin-based background therapy, the optimal choice between specific GLP-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,” Tsapas and team therefore conclude.
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Ann Intern Med 2020; doi:10.7326/M20-0864
Ann Intern Med 2020; doi:10.7326/M20-4266