CANVAS Program results confirm cardiovascular benefits are SGLT-2 Inhibitor Class effect.
It has been well established that patients with type 2 diabetes have an increased risk of renal disease and cardiovascular mortality. SGLT-2 Inhibitors, a relatively new class of oral antidiabetic medication, has shown promising results on the potential cardiovascular and renal benefits in previous studies. Canagliflozin, FDA approved in 2013, is the primary therapy studied in the CANVAS Program, the largest SGLT-2 Inhibitor study evaluating cardiovascular outcomes. This study provides important news for both patients and health care providers in regards to the use of canagliflozin in patients with type 2 diabetes.
The landmark CANVAS Program, consisting of 10,142 participants, is a combination of data from two studies; The Canagliflozin Cardiovascular Assessment Study (CANVAS) and The CANVAS on Renal Endpoints Trial (CANVAS-R). The purpose of the CANVAS Program was to evaluate the cardiovascular safety and efficacy with the use of canagliflozin in type 2 diabetics with a high risk or history of cardiovascular disease. Researchers were primarily interested in the composite of three components; death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke. Other outcomes of interest included death from any cause, progression of albuminuria, hospitalization of heart failure and a composite of renal outcomes. The three components of the renal outcomes include 40% reduction in eGFR, requirement for renal-replacement therapy or death from renal causes. In 2009, CANVAS enrolled 4,330 participants. These participants were randomized and given either placebo, 100 mg of canagliflozin or 300 mg of canagliflozin in a 1:1:1 ratio. CANVAS-R, a study initiated in 2014, enrolled 5,812 participants. These participants were randomized in a 1:1 ratio and received placebo or 100 mg of canagliflozin. In CANVAS-R, participants in the canagliflozin study group had the opportunity to titrate up to 300 mg of canagliflozin at week 13, if additional glycemic control was needed.
The canagliflozin study group showed a statistically significant reduction in the rate of primary outcome compared to placebo (26.9 vs 31.5 participants with an event per 1000 patient-years; HR: 0.86; 95% CI 0.75 to 0.97; p < 0.001 for non-inferiority; p = 0.02 for superiority). The use of canagliflozin also showed a lower risk of hospitalization for heart failure (5.5 vs 8.7 participants with an event per 1000 patient-years; HR: 0.67; 95% CI 0.52 to 0.87), less progression of albuminuria (89.4 vs 128.7 participants with an event per 1000 patient-years; HR: 0.73; 95% CI 0.67 to 0.79) and reduced the risk of adverse renal outcomes (5.5 vs 9.0 participants with an event per 1000 patient-years; HR: 0.60; 95% CI 0.47 to 0.77). However, the results did not show superiority over placebo in the death from any cause (HR: 0.87; 95% CI 0.74 to 1.01; p = 0.24). In general, the canagliflozin study group had less serious adverse events reported (104.3 vs 120.0 participants per 1000 patient-year; HR: 0.93; 95% CI 0.87 to 1.00; p = 0.04). One important adverse event of notable concern is the increase rate of amputation, particularly the toe or metatarsal, with the use of canagliflozin compared to placebo (6.3 vs 3.4 participants per 1000 patient-year; HR: 1.97; 95% CI 1.41 to 2.75; p < 0.001). In May 2017, the FDA made a statement requiring canagliflozin drug labels to include boxed warnings regarding the increase risk of leg and foot amputation.
The results of this study is clinically important because it correlates with previous findings of SGLT-2 Inhibitors being associated with decrease risk of adverse cardiovascular outcomes and renal disease. The first SGLT-2 Inhibitor to exhibit cardiovascular benefits came from the EMPA-REG OUTCOME trial in 2015, showing a reduction in cardiovascular death by 38%. Although canagliflozin did not show a reduction in cardiovascular death, it did reduce the risk of cardiovascular events by 14%, reduce the risk of heart failure hospitalization by 33% and reduce the rate of renal decline by 40%. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation trial (CREDENCE), a current ongoing clinical trial, will provide more evidence on the effect canagliflozin has on renal outcomes.
John Buse, MD, of the University of North Carolina, Chapel Hill, added that, “In addition, cardiovascular death was not significantly reduced in CANVAS, as it was in both EMPA-REG and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial of the glucagonlike peptide-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk).”
- Canagliflozin and other SGLT-2 Inhibitors are shown to have positive cardiovascular benefits in patients with type 2 diabetes.
- Canagliflozin also demonstrated renal protective effects in patients with type 2 diabetes, more evidence will be available at the completion of the CREDENCE trial.
- Healthcare providers should use clinical judgement and weigh the risks against benefits in the use of canagliflozin, particularly in patients at high risk or have a history of amputations.
Neal B, Perkovic V, Mahaffey K, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England Journal of Medicine. 2017. Epub 2017/06/12. doi: 10.1056/NEJMoa1611925
PRNewswire. Invokana® (canagliflozin) Significantly Reduces the Combined Risk of Cardiovascular Death, Myocardial Infarction and Stroke in the CANVAS Program. Press Release. Available at: http://www.prnewswire.com/news-releases/invokana-canagliflozin-significantly-reduces-the-combined-risk-of-cardiovascular-death-myocardial-infarction-and-stroke-in-the-canvas-program-300472679.html. Accessed June 15, 2017.
U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana®, Invokamet®, Invokamet XR®). Safety Announcement. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed June 15, 2017.
Zinman B, Wanner C, Lachin J, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. 2015;373(22):2117-28. doi: 10.1056/NEJMoa1504720
Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus