LIRA-RENAL: Liraglutide Safe in Diabetes With Renal Failure

December 24, 2015

Data from the LIRA-RENAL study, examining the use of the injectable glucagonlike peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) in patients with type 2 diabetes and moderate renal impairment, have been published online December 7 in Diabetes Care.

Lead investigator Dr Melanie J Davies, University of Leicester, United Kingdom, told Medscape Medical News: "People with diabetes are more likely to have renal problems, whether due to the diabetes or other comorbidities, but there is a limited choice of glucose-lowering agents that can be used in these patients."

Liraglutide therefore represents one of the few glucose-lowering agents officially sanctioned for use in this difficult-to-treat patient population — it is approved for use in adults with type 2 diabetes and moderate renal impairment in the European Union.

Dr Davies first presented the findings of LIRA-RENAL at the American Diabetes Association (ADA) 2014 Scientific Sessions and also at the European Association for the Study of Diabetes 2014 Meeting.

LIRA-RENAL Results

In LIRA-RENAL, patients with type 2 diabetes and moderate renal impairment (estimated glomerular filtration rate [eGFR], 30–59 mL/min/1.73 m2) received liraglutide injected at a dose of 1.8 mg once daily (n=140) or placebo (n=139) added to current therapies, either oral glucose-lowering agents or insulin, for a period of 26 weeks. The patients were, on average, 67 years old, and the mean duration of diabetes was 15 years.

The primary end point was change in HbA1c from baseline, and liraglutide showed superior glycemic control relative to placebo: the mean change in HbA1c from baseline to week 26 for liraglutide was -1.05% vs -0.38% for placebo.

Those taking liraglutide also lost weight, a known advantage of GLP-1 agonists, and there was a low risk for hypoglycemia.

But gastrointestinal side effects, mostly nausea and vomiting, were higher among those taking liraglutide, at 35.7%, vs 17.5% with placebo, and there was a higher withdrawal due to adverse events in the liraglutide vs placebo group (13.6% vs 2.9%).

Importantly, there was no worsening of renal function in subjects over the 6 months of the study. In addition, the effect of liraglutide on blood glucose was consistent across glomerular-filtration subgroups.

Most Glucose-Lowering Agents Need Adjustment in Renal Impairment

Another new agent that already has clinical-trial data demonstrating safety in a diabetic kidney disease population is the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (Tradjenta/Trajenta, Boehringer Ingelheim), which has the distinguishing feature that it can be used in patients with renal failure without any dose adjustment.

Most newer agent for diabetes will require dose adjustment in diabetic kidney disease because the majority are renally excreted; this includes DPP-4 inhibitors other than linagliptin, most GLP-1 agonists with the exception of liraglutide, and another new class, the sodium-glucose cotransporter 2 (SGLT-2) inhibitors.

The current licenses for most SGLT-2 inhibitors precludes their use in patients with renal failure (eGFRs < 60 mL/min/1.73 m2 in some cases or < 45 mL/min/1.73 m2 in others).

But despite SGLT-2 inhibitors being metabolized by the kidney, there is excitement about their potential to provide a renoprotective effect. One of these agents, canagliflozin (Invokana, Janssen), is being tested in a diabetic kidney disease population in the large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial.

This will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.

In addition, the data on renal outcomes from the landmark EMPA-REG OUTCOME trial, so far only presented in abstract form, with the SGLT2 inhibitor empagliflozin (Jardiance, Lilly/Boehringer Ingelheim) "are encouraging," said Dr Davies.

EMPA-REG demonstrated that empagliflozin was the first-ever agent for type 2 diabetes to reduce mortality in a cardiovascular outcomes study.

LIR-RENAL was sponsored by Novo Nordisk. Dr Davies has attended advisory panels for Novo Nordisk, Novartis, Sanofi, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Omnia-Med, Janssen, and Merck Sharp & Dohme; has attended speaker's bureaus for Novo Nordisk, Sanofi, Eli Lilly, Merck Sharp & Dohme, AstraZeneca, Mitsubishi Tanabe Pharma, and Boehringer Ingelheim; has acted as consultant for Novo Nordisk, Sanofi, Eli Lilly, and Merck Sharp & Dohme; and has received research support from Novo Nordisk, Novartis, Eli Lilly., and Merck Sharp & Dohme. Disclosures for the coauthors are listed in the article.

Diabetes Care. Published online December 7, 2015. Abstract

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