Canagliflozin reduces risk for CVD, kidney disease in patients with type 2 diabetes

SAN DIEGO — Patients with type 2 diabetes at high risk for cardiovascular disease assigned the SGLT2 inhibitor canagliflozin saw a 33% reduction in risk for hospitalization for heart failure and were 40% less likely to experience renal decline vs. those assigned placebo, according to findings from the integrated CANVAS study presented here.

In a randomized, double blind, placebo-controlled trial conducted across 30 countries, researchers also noted that participants assigned canagliflozin (Invokana, Janssen) were twice as likely to experience an amputation, primarily at the toe or metatarsal, compared with those receiving placebo.

“The key question is how do the risks and the benefits balance up?” Bruce Neal, MB, ChB, PhD, scientific director at The George Institute for Global Health, said during a press conference announcing the findings. “For 1,000 individuals treated [with canagliflozin] for 5 years ... there would be 23 fewer deaths from vascular disease, 17 fewer hospitalizations for heart failure and 16 fewer serious declines in renal function. By contrast, there would be 15 more amputations, and ten of these would be at the toe or forefoot and five [would be] above the ankle.”

For the integrated CANVAS program, Neal and colleagues analyzed data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk, CANVAS (n = 4,330) and CANVAS-R (n = 5,812). The mean age for both trials was 63 years; 35.8% were women; mean duration of diabetes was 13.5 years; mean HbA1c, 8.2%; mean estimated glomerular filtration rate was 76.5 mL per minute per 1.73 m²; median urinary albumin-to-creatinine ratio was 12.3. Researchers randomly assigned participants in CANVAS to receive either 100 mg or 300 mg canagliflozin or placebo; participants in CANVAS-R received an initial dose of 100 mg canagliflozin daily with an optional increase to 300 mg at week 13, or matching placebo. Follow-up occurred every 3 months for the first year and at 6-month intervals thereafter, with follow-up by telephone between in-person appointments. Serum creatinine and eGFR rate were measured at least every 26 weeks in both trials; urinary albumin-to-creatinine ratio was assessed every 26 weeks in CANVAS-R and at week 12 and annually in CANVAS. Primary outcome was a composite of death from CVD, nonfatal myocardial infarction and nonfatal stroke. Final follow-up occurred in February 2017.

Within the cohort, 9,734 participants completed the trials; mean follow-up for both trials was 188.2 weeks, with a longer follow-up period in the CANVAS study (mean, 295.9 weeks). At baseline, 65.6% of participants had a history of CVD, 22.6% had microalbuminuria and 7.6% had macroalbuminuria.

Researchers found that the rate of primary outcome was lower in participants assigned canagliflozin vs. placebo, occurring in 26.9 per 1,000 patient-years vs. 31.5 per 1,000 patient-years (HR = 0.86; 95% CI, 0.75-0.97).

Researchers also observed a possible benefit with respect to progression to albuminuria in the canagliflozin group (HR = 0.73; 95% CI, 0.67-0.79), as well as the composite outcome of a sustained 40% reduction in the GFR, need for renal replacement therapy or renal death (HR = 0.6; 95% CI, 0.47-0.77).

Serious adverse events were less common in the canagliflozin group vs. placebo (104.3 events per 1,000 patient-years vs. 120 events per 1,000 patient-years); there were no between-group differences for adverse events leading to discontinuation. Researchers observed a higher risk for amputation of the toes, feet and legs in the canagliflozin group vs. placebo, with 6.3 participants with an amputation per 1,000 patient-years vs. 3.4 participants per 1,000 person-years; 71% of affected participants experienced their highest amputation at the toe or metatarsal, according to researchers.

“The highest absolute risk for amputation occurred among patients who had a history of peripheral vascular disease, but the relative risk of amputation with canagliflozin as compared with placebo was similar across subgroups,” the researchers wrote in their report, published simultaneously online in The New England Journal of Medicine.

In the press conference, Neal noted that clinicians use caution when prescribing canagliflozin to patients at increased risk for an amputation and said further work is needed in this area; however, the CANVAS program met its primary objective of demonstrating CV safety, while showing efficacy for the prevention of CV events.

“These data suggest a net overall benefit with canagliflozin for most patients with type 2 diabetes and high cardiovascular risk,” Neal said. – by Regina Schaffer

Reference:

Neal B, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611925.

Neal B, et al. 3-CT-SY26. Presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego.

Disclosures: Janssen Research and Development sponsored this study. Please see the full study for the researchers’ relevant financial disclosures.