Renal complications were lower in patients randomized to liraglutide rather than placebo, according to a secondary analysis of an industry-funded trial with 9,340 adults who had type 2 diabetes (T2DM) and were either 50 years of age or older with at least one cardiovascular (CV) condition or 60 years of age or older with a CV risk factor. The study's primary outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of serum creatinine level, end-stage renal disease, or death due to renal disease, and it occurred in 15% of patients on liraglutide and 19% of those on placebo.
The study was published in the Aug. 31, 2017, New England Journal of Medicine and summarized in the September 2017 ACP Diabetes Monthly. The following commentary by Lorraine L. Lipscombe, MD, MSc, was published in the ACP Journal Club section of the Dec. 19, 2017, Annals of Internal Medicine.
Given that most pharmacologic agents for T2DM have comparable glucose-lowering effects, the second-line choice after metformin has been mainly guided by such factors as adverse effects, convenience, and cost. Until recently, effects of different drugs on complication rates were unclear. The primary analysis of the LEADER trial showed that liraglutide reduced risk for major CV events compared with placebo when added to existing therapy in T2DM patients at high CV risk. The secondary analysis of LEADER by Mann and colleagues also shows a benefit of liraglutide on renal outcomes.
The mechanism by which liraglutide improves renal outcomes is uncertain. The renal benefit in LEADER was driven by a decrease in the surrogate outcome of macroalbuminuria—measures of renal impairment were unchanged. These results may be explained by greater reductions in HbA1c and blood pressure with liraglutide compared with placebo, both of which have been shown to reduce albuminuria rates. We cannot exclude the possibility that other agents with equivalent glucose- and blood pressure-lowering effects have similar benefits.
The LEADER results support liraglutide as a second-line agent for T2DM patients with high CV risk. Liraglutide may be favored by patients as it is associated with more weight loss and less hypoglycemia than other agents. Disadvantages include the need for injection and high cost. The sodium-glucose co-transporter-2 inhibitor empagliflozin also reduces CV and renal outcomes compared with placebo in patients at high CV risk, making it another second-line option. Until we have data on the comparative effectiveness of liraglutide over empagliflozin or other agents, the choice of second-line therapy still needs to be individualized.