Liraglutide was effective in reducing the risk for new-onset persistent macroalbuminuria, acute kidney injury and death due to renal disease in adults with type 2 diabetes and high cardiovascular risk, according to results from a secondary analysis of the LEADER trial.
Johannes F.E. Mann, MD, professor of medicine at Friedrich Alexander University of Erlangen-Nürnberg in Germany, and colleagues evaluated data from the LEADER trial on 9,340 adults (mean age, 64 years) with type 2 diabetes and high CV risk randomly assigned to liraglutide (Victoza, Novo Nordisk; n = 4,668) or placebo (n = 4,672) to determine the long-term effects of liraglutide on renal outcomes. The primary composite renal outcome included new-onset persistent macroalbuminuria, persistent doubling of serum creatinine level, renal-replacement therapy and death due to renal disease. Median follow-up was 3.84 years.
At randomization, microalbuminuria was present in 26.3% of participants and macroalbuminuria in 10.5%.
Fewer participants in the liraglutide group experienced the prespecified renal outcome compared with those in the placebo group (5.7% vs. 7.2%; HR = 0.78; 95% CI, 0.67-0.92). More participants in the placebo group experienced new-onset persistent macroalbuminuria compared with those in the liraglutide group (4.6% vs. 3.4%; HR = 0.74; 95% CI, 0.6-0.91). No significant differences in persistent doubling of the serum creatinine level or end-stage renal disease were observed between the two groups. Death was uncommon in the groups: eight in the liraglutide group vs. five in the placebo group.
Among the subgroup of participants with microalbuminuria or macroalbuminuria, participants in the liraglutide group were less likely to experience the composite renal outcome compared with those in the placebo group (13.7% vs. 16.3%; HR = 0.81; 95% CI, 0.68-0.96).
In the subgroup of participants with estimated glomerular filtration rate (eGFR) less than 60 mL per minute per 1.73 m2, participants in the liraglutide group were less likely to experience the composite renal outcome compared with the placebo group (13.1% vs. 15%; HR = 0.84; 95% CI, 0.67-1.05).
Similar rates of renal adverse events were observed between the two groups (liraglutide, 1.1 events per 1,000 patient-years vs. placebo, 16.5 events); the same was true for the rate of acute kidney injury (liraglutide, 7.1 events vs. placebo, 6.2 events).
“In this secondary analysis, among patients with type 2 diabetes at high risk for cardiovascular disease who were receiving usual care, liraglutide resulted in a lower risk of the composite renal outcome than placebo, primarily owing to a lower rate of new-onset persistent macroalbuminuria,” the researchers wrote
Both macrovascular and microvascular complications of diabetes are devastating. In patients with type 2 diabetes, physicians have often concentrated more on the cardiovascular effects of the disease. The microvascular complications have commonly been the emphasis in type 1 diabetes. However, it is clear that microvascular complications, including renal disease, retinopathy and neuropathy, are no less important in type 2 diabetes and should receive more emphasis. In their paper, Mann and colleagues describe the effects of liraglutide (a GLP-1 receptor agonist) on renal deterioration in a large placebo-controlled trial. Over about 3 to 5 years, there was significant reduction in macroalbuminuria. While these results are encouraging, it should be noted that these were prespecified secondary renal outcomes and were not associated with other improvements in measurements of renal function.
Furthermore, they were not associated with improvements in classically known factors, such as blood pressure improvements, that could explain the results, leading the authors to speculate direct effects of indirect, as yet unidentified, effects. Taken together, the short-term measurements are encouraging and portend long-term benefits by these and other anti-diabetic agents on renal complications of diabetes.
Derek LeRoith, MD, PhD
Endocrine Today Editorial Board Member
Professor of Medicine, Mount Sinai School of Medicine in New York
Disclosure: LeRoith reports no relevant financial disclosures.
Liraglutide and Renal Outcomes in Type 2 Diabetes
Johannes F.E. Mann, M.D., David D. Ørsted, M.D., Ph.D., Kirstine Brown-Frandsen, M.D., Steven P. Marso, M.D., Neil R. Poulter, F.Med.Sci., Søren Rasmussen, Ph.D., Karen Tornøe, M.D., Ph.D., Bernard Zinman, M.D., and John B. Buse, M.D., Ph.D., for the LEADER Steering Committee and Investigators*
N Engl J Med 2017; 377:839-848August 31, 2017DOI: 10.1056/NEJMoa1616011
In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown.
We report the prespecified secondary renal outcomes of that randomized, controlled trial in which patients were assigned to receive liraglutide or placebo. The secondary renal outcome was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The risk of renal outcomes was determined with the use of time-to-event analyses with an intention-to-treat approach. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed.
A total of 9340 patients underwent randomization, and the median follow-up of the patients was 3.84 years. The renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). This result was driven primarily by the new onset of persistent macroalbuminuria, which occurred in fewer participants in the liraglutide group than in the placebo group (161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). The rates of renal adverse events were similar in the liraglutide group and the placebo group (15.1 events and 16.5 events per 1000 patient-years), including the rate of acute kidney injury (7.1 and 6.2 events per 1000 patient-years, respectively).
This prespecified secondary analysis shows that, when added to usual care, liraglutide resulted in lower rates of the development and progression of diabetic kidney disease than placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.)
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