Spotlight on comparisons within diabetes drug classes

Two recent meta-analyses compared drugs within the glucagon-like peptide-1 (GLP-1) receptor agonist and sodium-glucose cotransporter-2 (SGLT-2) inhibitor classes.

The GLP-1 receptor agonist review, published by The BMJ on Jan. 29, included 76 trials with 39,246 participants that compared various GLP-1 receptor agonists with placebo. The review found that all 15 GLP-1 receptor agonists lowered HbA1c and fasting plasma glucose levels. Tirzepatide had the greatest effect on both outcomes (mean difference in HbA1c vs. placebo, −2.10% [95% CI, −2.47% to −1.74%] and in fasting glucose, −3.12 mmol/L [95% CI, −3.59 to −2.66]). Semaglutide with cagrilintide resulted in the greatest weight loss (mean difference, −14.03 kg [95% CI, −17.05 to −11.00]), followed by tirzepatide (mean difference, −8.47 kg [95% CI, −9.68 to −7.26]). Semaglutide was the only GLP-1 receptor agonist that significantly lowered low density lipoprotein cholesterol (−0.16 mmol/L [95% CI, −0.30 to −0.02]) and total cholesterol (−0.48 mmol/L [95% CI, −0.84 to −0.11]). The study also looked at adverse events, finding that the most commonly reported were GI-related and that several GLP-1 receptor agonists were significantly more likely to be discontinued due to adverse events than placebo (odds ratios: lixisenatide, 2.86 [95% CI, 1.48 to 5.51]; semaglutide, 2.61 [95% CI, 1.56 to 4.37]; exenatide, 2.39 [95% CI, 1.14 to 4.98]; tirzepatide, 2.30 [95% CI, 1.30 to 4.09]; and liraglutide, 2.15 [95% CI, 1.26 to 3.69]).

The study, which the authors called "the most comprehensive and up-to-date systematic review and network meta-analysis assessing a complete range of almost all available" GLP-1 receptor agonists validated the potency of these drugs and showed that tirzepatide performed best at lowering HbA1c and fasting glucose levels, they said. However, the authors also cautioned that the study highlighted how the drugs are associated with GI events, noting that "concern is especially warranted for high dose administration."

The SGLT-2 inhibitor review, published by the Journal of the American Heart Association on Jan. 31, included 21 trials with 96,196 participants that compared empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, or sotagliflozin to placebo. It found no significant differences among the drugs on the primary efficacy end point, a composite of cardiovascular death and hospitalizations for heart failure. Risk of acute kidney injury was significantly lower with empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53 to 0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56 to 0.96]) than sotagliflozin. The presence or absence of diabetes did not alter the results; however, in patients without chronic kidney disease (CKD), empagliflozin lowered risk of the primary outcome more than ertugliflozin (HR, 0.77 [95% CI, 0.60 to 0.98]). No significant differences were observed in rates of amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis.

The results show "that all SGLT2 inhibitors have generally equivalent efficacy profiles for cardiovascular and kidney outcomes, as well as safety profiles, although patients without CKD may benefit from empagliflozin," the study authors said. Clinicians may want to use these findings to help with selection of an SGLT-2 inhibitor for individual patients, but "further well-designed studies are warranted to clarify these findings," they wrote.