The Canadian Diabetes Association Clinical Practice Guidelines issued a second interim update during the fall of 2016.  The first interim update in March 2016 was to share the results of EMPA-REG OUTCOME trial and how it has changed the recommendations around the management in Type II diabetes for individuals with cardiovascular risk factors.  Well, the second interim update was driven from the results of LEADER, a trial that evaluated the cardiovascular outcomes with liraglutide, otherwise known as Victoza®.

Liraglutide (Victoza®) is a long-acting glucagon-like peptide-1 receptor agonist. It binds to  same receptors as endogenous metabolic hormone GLP-1 thereby stimulating insulin secretion to help regulate blood glucose in diabetes.

LEADER at a Glance:

LEADER (Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes) was a randomized, double-blind, placebo-controlled trial which was published in the New England Journal of Medicine (N Eng J Med 2016;375:311-22). Some highlights to note:

  • 9340 patients were enrolled in the study with a median follow up of 3.8 years. Patients were recruited from 410 trial sites in 32 countries.

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  • Patients were randomized to Liraglutide 1.8mg subcut daily vs. placebo, added to existing therapy
  • Primary composite endpoint was first occurrence of death from cardiovascular causes, nonfatal MI or stroke
  • Results:
    • The primary outcome occurred in significantly few patients in the liraglutide group:
      • Liraglutide group: 608 of 4668 patients (13%)
      • Placebo group: 694 of 4672 (14.9%)
      • Hazard ratio =0.87; 95% confidence interval, 0.78-0.97; p<0.001 for non-inferiority;p=0.01 for superiority.
    • Few patients died from cardiovascular causes in the liraglutide group:
      • Liraglutide group: 219 patients (4.7%)
      • Placebo group: 278 patients (6%)
      • Hazard ratio =0.78; 95% confidence interval, 0.66 to 0.93; p=0.007
    • The rate of death from any cause was lower in the liraglutide group:
      • Liraglutide group: 381 (8.2%)
      • Placebo group: 447 (9.6%)
      • Hazard ratio = 0.85; 95% confidence interval, 0.74-0.97; p=0.02

Given the results of this trial demonstrating cardiovascular benefits of liraglutide, the Canadian Diabetes Association Clinical Practice Guidelines have updated the following recommendation in the latest interim update:

In adults with type 2 diabetes with clinical cardiovascular disease in whom glycemic targets are not met, an antihyperglycemic agent with demonstrated cardiovascular outcome benefit should be added to reduce the risk of major cardiovascular events (Grade 1, Level 1A for empagliflozin (2); Grade 1, Level 1A for liraglutide if age ≥50 years (3); Grade D, Consensus for liraglutide if age <50 years).

My thoughts about the interim update …. too early too soon.

  • While the results of this trial has demonstrated cardiovascular benefits with liraglutide, I feel it is too quick to add this agent to the recommendation in the interim update.  The benefits seen with liraglutide were not as impressive as empagliflozin.
  • Also it is interesting to note that many previous studies only demonstrated neutral results including  ELIXA which evaluated another glucagon-like peptide-1 receptor agonist (lixisenatide), so why this new trial is able to demonstrate cardiovascular benefits?
  • We also don’t have a good understanding of its safety profile yet. There were some documented adverse events related to hypothyroidism and / or pancreatic cancer during the study. It definitely warrants a closer monitoring through post-marketing surveillance.
  • Another point to note is that liruglutide is given as a subcutaneous injection. This has major implication for patients in terms of therapy adherance or compliance. Medication needs to be kept refrigerated prior to use.  Injection training and support may need to be provided for the patients.
  • Finally, liruglutide is more expensive compared to empagliflozin. Patients also need to pay for needles and other injection related supplies.  Lirauglutide is not currently listed for reimbursement in the Ontario Drug Benefits Program. However, this  may change very soon.

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The study was only published in Jun 2016 and already made its way into the guideline in Nov 2016. You can argue that given the cardiovascular benefits are demonstrated by this study, it should be endorsed immediately. However, I wonder how much of its speediness is related to the pharma company’s marketing plan for Victoza®. The endorsement by the Canadian Diabetes Association will have a great impact on the uptake of this medication by physicians  across Canada. The guideline endorsement will support the case to add this medication to the provincial formularies for coverage, thereby reaching a huge market with great potential for sales and revenues.

I am, however, not ready to ask my patients to poke themselves with a needle yet.

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