GLP-1 Analogue Improves Renal Outcomes in Type 2 Diabetes

Pam Harrison

August 30, 2017

Liraglutide (Victoza, Novo Nordisk), a glucagonlike peptide 1 (GLP-1) analogue, significantly reduces the risk of adverse renal outcomes compared with placebo in patients with type 2 diabetes receiving usual care, results of a prespecified secondary analysis of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial suggest.

"New-onset persistent macroalbuminuria is an effect that is typically associated with subsequent progressive reductions in the [glomerular filtration rate (GFR)] in patients with type 2 diabetes," Johannes Mann, MD, KfH Kidney Center, Munich and Friedrich Alexander University of Erlangen, Germany, and colleagues report.

"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 study was published in the August 31 issue of the New England Journal of Medicine.

LEADER Trial

The LEADER trial randomized a total of 9340 patients with type 2 diabetes at high risk of cardiovascular disease to either active drug or placebo. Of those, 4668 patients were assigned to liraglutide and the remaining 4672 patients received placebo. Patients took the trial medication for a mean of 83% of the study interval. The mean age of patients in the study was 64 years; the mean blood pressure was 136/77 mm Hg, and the mean estimated glomerular filtration rate (eGFR) was 80 mL/min/1.73 m2.

As reported earlier by Medscape Medical News, liraglutide significantly reduced the rates of major adverse cardiovascular events, which was the primary end point, including a 22% relative reduction in the risk of cardiovascular death.

Now, Dr Mann and colleagues report a reduction with liraglutide in a composite renal end point of persistent macroalbuminuria (defined as a urinary albumin excretion rate >300 mg/day); persistent doubling of the serum creatinine level; end-stage renal disease (ESRD); or death from renal disease. At a median follow-up of 3.84 years, 22% fewer patients receiving liraglutide reached the primary composite renal end point compared those receiving placebo (5.7% vs 7.2%; hazard ratio [HR], 0.78; = .003).

Similarly, 26% fewer patients in the active-treatment group developed new-onset persistent macroalbuminuria compared with the placebo group (3.4% vs 4.6%; HR, 0.74, P = .004).

However, "the risks of doubling of the serum creatinine level and end-stage renal disease did not differ significantly between the liraglutide group and the placebo group, possibly owing to the moderate decline in the estimated GFR observed in this cohort and the few patients who had advanced kidney disease at randomization," Dr Mann and colleagues suggest.

Only a few patients in either group died of renal causes over the follow-up interval—eight in the liraglutide group and five in the placebo group.

Renal Risk at Baseline

When stratified according to baseline renal risks, the benefit of active therapy was seen across the different subgroups. For example, for patients with either microalbuminuria or macroalbuminuria at baseline, 13.7% of patients in the liraglutide group reached a renal end point over during follow-up compared with 16.3% of placebo patients (HR, 0.81, P = .02).

Similarly, among those with a baseline eGFR <60 mL/min/1.73 m2, composite renal end-point rates were seen in 13.1% of the liraglutide group compared with 15% for placebo controls (HR, 0.84, P = .13). And in patients who qualified for both subgroups, 22.5% of those in the study drug arm met the composite renal outcome compared with 25.8% of those in the placebo arm (HR, 0.81, P = .09).

"The estimated GFR declined continuously, but the decline was slightly slower in the liraglutide group than in the placebo group...corresponding to a 2% less decrease with liraglutide," Dr Mann and colleagues observe.

A similar trend was seen in the urinary albumin-to-creatinine ratio, which despite an overall increase in both arms, was 17% lower at 36 months in liraglutide arm compared with placebo (P < .001). As the study authors point out, the changes observed in albuminuria at 36 months in favor of liraglutide were independent of baseline eGFR levels as well as baseline levels of albuminuria.

The percentage of patients who developed an adverse renal event were also similar in both groups, at 15.1 events per 1000 patient years in the active-treatment arm and 16.5 events per 1000 patient-years in the placebo arm.

Investigators suggest that the effect that liraglutide had on renal outcomes might be the result of intensified glucose control, which itself has been associated with a lower incidence of new-onset macroalbuminuria compared with usual care alone.

Impressive Renal Benefits

In an accompanying editorial, Ian de Boer, MD, associate professor of medicine, nephrology, University of Washington, Seattle, points out that both the GLP-1 agonists and the sodium-glucose cotransporter 2 (SGLT2) inhibitors, including empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) and canagliflozin (Invokana, Janssen Pharmaceuticals), have demonstrated "impressive" renal benefits in patients with type 2 diabetes. These benefits include "markedly lower rates of decline in the estimated GFR in addition to lower rates of albuminuria," Dr de Boer writes.

The same two drug classes have also been shown to significantly lower the risk of cardiovascular end points in the same patient group independent of the presence or absence of diabetic kidney disease at baseline. "Taken together, these trial results suggest that the use of GLP-1 agonists and SGLT2 inhibitors may ultimately help to reduce the incidence of diabetic kidney disease.

"Overall, the new data on GLP-1 agonists, SGLT2 inhibitors, and kidney outcomes suggest a hopeful change in story line in which, over time, the incidence and progression of diabetic kidney disease may be reduced and its cardiovascular sequelae mitigated," Dr de Boer concludes.

As reported by Medscape Medical News, Dr Mann and colleagues presented preliminary results from the renal outcomes analysis last year at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting.

The study was funded by Novo Nordisk. Dr Mann reports receiving personal fees from Novo Nordisk, AstraZeneca, Amgen, Braun, ACI Clinical (a CRO), Fresenius, Gambro, MEDICE, Lanthio Pharma, Sanifit, Relypsa, and ZS Pharma. He has also received grants and personal fees from Celgene, AbbVie, Novo Nordisk, Roche, and Sandoz. Disclosures for the coauthors are listed on the journal website. Dr de Boer reports receiving personal fees from Boehringer Ingelheim, Janssen Global, and Ironwood.

N Engl J Med. 2017;377:839-848. Article, Editorial

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