Becky McCall

September 20, 2016

MUNICH – The glucagonlike-peptide 2 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) delays progression of renal events — in particular, new-onset persistent macroalbuminuria — in patients with type 2 diabetes, according to the latest data from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial.

Johannes Mann, MD, from the University of Erlangen, Germany, presented the microvascular outcomes from LEADER, which were key secondary outcomes, at a session here at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting.

Dr Mann reported, "On top of standard therapy, this GLP-1 agonist [liraglutide] reduced microvascular outcomes, particularly renal ones."

He emphasized that the main driver for the microvascular outcomes was new and persistent macroalbuminuria, with a risk reduction of 26% seen with liraglutide compared with placebo (both on top of standard therapy).

EMPA-REG Renal Findings "Stronger" Than LEADER

Asked to put the findings into context, nephrologists told Medscape Medical News that these findings do not appear to be as strong as the renal data from the EMPA-REG OUTCOME trial with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim), reported at the annual meeting of the American Diabetes Association in June this year and simultaneously published in the New England Journal of Medicine.

That drug significantly reduced the incidence of new or worsening nephropathy by 39% in the population of type 2 diabetes patients studied, who were at high cardiovascular risk — again, this was primarily driven by a reduction in new-onset macroalbuminuria of 38% with empagliflozin compared with placebo.

Per-Henrik Groop, MD, professor of nephrology, the University of Helsinki, Finland, said that although these latest LEADER results "are reassuring…they will not be sufficient to give liraglutide an indication to reduce risk of renal events. For that they need a dedicated renal study."

And although EMPA-REG is also a cardiovascular-outcomes trial mandated by the Food and Drug Administration (FDA) to show that empagliflozin is safe and does not cause cardiovascular disease, Dr Groop observed that the renal data from that trial appear more encouraging.

"It must be said that empagliflozin had a profound effect on the preservation of renal function, which was not seen with liraglutide. Furthermore, the renal effects of empagliflozin were seen rather early, in contrast to liraglutide, probably due to their totally different mechanisms of action."

Christoph Wanner, MD, head of nephrology, University Hospital of Würzburg, Germany, who was the lead author on the renal-outcomes paper from EMPA-REG, told Medscape Medical News: "EMPA-REG and LEADER cannot be compared because of the different mechanism of action. Whereas empagliflozin spills out glucose, salt, and water, and all subsequent outcome reductions are based on these things, GLP-1 agonists work totally differently."

In outcome trials of patients with diabetic nephropathy, he said that retrospective analyses demonstrate a robust relationship between magnitude of albuminuria reduction and slowing of chronic kidney disease progression.

"So although authorities, such as the FDA, have not yet accepted albuminuria as an outcome marker in phase 3 clinical trials, clinicians believe that it is a good surrogate parameter for kidney outcomes," and they believe about a 30% reduction in albuminuria is clinically meaningful, he said.

"So it's nice to have these signals in LEADER…but the magnitude of the effect in EMPA-REG OUTCOME was much larger."

Microvascular Findings Driven by Renal Events in LEADER

The microvascular outcomes from LEADER follow on from the cardiovascular-outcome data that were reported earlier this year at the ADA meeting, which indicated that liraglutide significantly reduced the rates of major adverse cardiovascular events in type 2 diabetes.

The 9340 study participants in LEADER all had type 2 diabetes and were at high cardiovascular risk but represented a population at moderate risk of microvascular events, according to Dr Mann. Patients received either a subcutaneous injection of liraglutide 1.8 mg once daily (or the maximum tolerated dose) or placebo along with standard treatment. They were followed over the long term (3.5–5 years).

For microvascular events overall (renal and eye), 7.6% of the liraglutide group experienced these vs 8.9% in the placebo group (hazard ratio [HR], 0.84; P = .02).

"These curves separated very early on and represent a risk reduction of 16% for patients on liraglutide," explained Dr Mann.

"The microvascular findings were driven by the renal events," he highlighted. An overall risk reduction of 22% was found for time to first renal event (HR, 0.78; P = .003) of new-onset or worsening renal disease in patients on liraglutide vs placebo.

The renal microvascular end point of new or worsening kidney disease comprised new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, continuous renal-replacement therapy, or death due to kidney disease.

The renal finding was primarily driven by new onset of persistent macroalbuminuria, which occurred significantly less (HR, 0.74) in patients treated with liraglutide than in those treated with placebo.

Eye events occurred in 2.3% of patients on liraglutide compared with 2.0% of patients on placebo (P = .33).

Death due to renal disease occurred in eight patients on liraglutide and five patients on placebo (HR, 1.59; 95% CI, 0.52–4.87), "but this had a very large confidence interval," highlighted Dr Mann.

A more detailed analysis of the renal data for LEADER will be presented at the upcoming American Society of Nephrology (ASN) meeting, he concluded.

Dr Mann declares receiving fees for serving on committees from AstraZeneca, Braun, ACI Clinical, Fresenius, Celgene, AbbVie, Novo Nordisk, Roche, Sandoz, Lanthio Pharma, Sanifit, Relypsa, and ZS Pharma; lecture fees from AstraZeneca, Amgen, Braun, Fresenius, Celgene, Gambro, AbbVie, Medice, Novo Nordisk, Roche, Sandoz, Relypsa, and ZS Pharma; and grant support from Celgene, AbbVie, Novo Nordisk, Roche, and Sandoz. Dr Wanner reports grant support from the Foundation for the Study of Diabetes (EFSD) and personal fees from Boehringer Ingelheim, Janssen, and Novo Nordisk. Dr Groop has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genzyme, MSD, Novo Nordisk, and Sanofi and is an advisory board member for Abbot, Abbvie, AstraZeneca, Boehringer Ingelheim, Cebic, Eli Lilly, Janssen, Medscape, MSD, Novartis, and Sanofi. He has received grants from Roche and Lilly.

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European Association for the Study of Diabetes 2016 Annual Meeting. September 15, 2016; Munich, Germany.

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