EU Green Light for Liraglutide in Diabetes With Renal Disease

December 04, 2014

The injectable glucagonlike peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) has received a positive opinion in the European Union for an additional indication: use in adults with type 2 diabetes and moderate renal impairment.

Formal approval normally follows a Committee for Medicinal Products for Human Use (CHMP) recommendation within a couple of months, and if this label extension is endorsed in the European Union, liraglutide will become one of a few glucose-lowering agents officially sanctioned for use in this difficult-to-treat patient population, as Dr Melanie J Davies (University of Leicester, United Kingdom) explained. Dr Davies is the principal investigator of LIRA-RENAL, the study that looked at this issue,

"People with diabetes are more likely to have renal problems, whether due to the diabetes or other comorbidities," she said. "But there is a limited choice of glucose-lowering agents that can be used in these patients."

Nephrologist Dr David Scott (Clinical Research Development Associates, Rosedale, New York) agrees. "There are challenges in managing patients with diabetes and chronic kidney disease. There are limited treatment options — many antidiabetic agents are not well tolerated in these patients and have safety issues and many are contraindicated," he explained to Medscape Medical News.

Dr Davies presented the findings of LIRA-RENAL at the American Diabetes Association (AHA) 2014 Scientific Sessions and European Association for the Study of Diabetes 2014 Meeting, and she says they have now submitted the manuscript for publication. Dr Scott reported the same results recently at Kidney Week 2014 in Philadelphia.

Patients with moderate or severe renal failure are often excluded from clinical trials of new glucose-lowering agents, so liraglutide — if approved for this use — will be a useful addition to the therapeutic armamentarium for these patients, said both physicians.

As Dr Davies noted, "It just gives you a bit more choice as a clinician."

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," Dr Davies observed.

Can Older Agents Be Used in Renal Failure?

One reason there is great interest in testing newer agents in type 2 diabetic patients with renal failure is that many of the older antidiabetic medications cannot be used in this patient population — they are contraindicated or require dose reduction, restricting their use.

Metformin, for example, is traditionally not used in patients with any significant amount of renal failure, because of the risk of lactic acidosis.

But Dr Scott said he believes that a lot of the clinical decision making with regard to metformin and renal impairment is based "on really old data." More recently, as well as early-stage renal failure, "it's been suggested you can use metformin…[in] patients who have stable stage 3a or 3b chronic kidney disease," he said. Stage 3a is defined as an estimated glomerular filtration rate (eGFR) of 45 to 59 mL/min/1.73m2 and stage 3b as an eGFR of 30 to 44 mL/min/1.73m2.

"And there are not a lot of great data evaluating metformin in [chronic kidney disease] CKD, but there is one scholarly report that I’m aware of published several years that pooled data from hundreds of trials, which revealed no cases of fatal lactic acidosis in patients with normal and impaired kidney function," he added.

Dr Davies says she will generally use metformin down to an eGFR of 45, but not below, which reflects National Institute for Health and Care Excellence (NICE) guidance in the United Kingdom.

With regard to sulfonylureas, both said they try to avoid this drug class in patients with kidney impairment, who are generally older, because of the side effects associated with these agents, such as weight gain and the risk of hypoglycemia. The thiazolidinedione pioglitazone has issues that often preclude its use in these populations, such as the risk of edema and heart failure, notes Dr Davies.

As CKD progresses and therapeutic options become limited, treatment with insulin is often required. Insulin therapy is often complicated by weight gain, hypoglycemia, and increase mortality in older patients where aggressive glycemic goals are targeted.

CREDENCE Trial Just Beginning With Canagliflozin

Most newer agent for diabetes will require dose adjustment in diabetic renal disease because they are renally excreted, and 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, said Dr Davies.

The current license for SGLT-2 inhibitors precludes their use in patients with renal failure (eGFRs of less than 60 in some cases or less than 45 in others). However, despite their being handled by the kidney, there is a great deal of excitement about the potential of the SGLT inhibitors to provide a renoprotective effect. One of these agents, canagliflozin (Invokana, Janssen) is being tested in a diabetic kidney disease population.

The large multicenter randomized Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE) trial will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care, Dr Scott told Medscape Medical News. They will be randomized to canagliflozin 100 mg daily or placebo for 5 years, and results are not expected until 2019.

"There's a lot of excitement about this trial, because it's one of the few trials that are evaluating an antidiabetic agent for an additional benefit of renoprotection independent of its glycemic effects," Dr Scott noted.

CHMP Positive Opinion Based on LIRA-RENAL Results

The positive opinion for the expanded indication for liraglutide was based on the LIRA-RENAL trial, in which patients with type 2 diabetes and moderate renal impairment (eGFR 30–59 mL/min/1.73m2) received liraglutide injected at a dose of 1.8 mg (n=140) or placebo (n=137) 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, 35.7% vs 17.5% with placebo, and there was a higher withdrawal due to adverse events in the liraglutide group (13.6%) compared with placebo (2.9%).

There were also increases from baseline in lipase and amylase levels in the liraglutide group that were not seen in the placebo group, which are "of unknown clinical relevance," according to the poster of the data presented at the ADA meeting.

However, at the end of the trial, there were no patients in the active treatment group who developed pancreatitis.

There were no other unexpected safety or tolerability issues, including, importantly, 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.

The findings mean another option for diabetic patients with chronic kidney disease is hoped to be sanctioned soon, at least in Europe, providing clinicians who currently have limited options with one more choice, Dr Davies concluded.

Dr Davies has acted as consultant, advisory board member, and speaker for Novo Nordisk, Sanofi, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen and as a speaker for Mitsubishi Tanabe Pharma. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi, and Lilly. Dr Scott reports being on advisory panels for Novo Nordisk, Novartis, and Boehringer Ingelheim and receiving research support from Novo Nordisk.

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