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Canagliflozin associated with fewer CV events, higher amputation risk in patients with T2D and high CV risk

Roshini Claire Anthony
14 Jun 2017
Professor Bruce Neal

The sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin was associated with better cardiovascular (CV) outcomes compared with placebo in individuals with type 2 diabetes and high CV risk, though it was also linked to an elevated risk of amputation, according to findings from the CANVAS* Program.

“The CANVAS Program met its primary objective of demonstrating [CV] safety, and also showed efficacy of canagliflozin for the prevention of CV events,” said study investigator Professor Bruce Neal from The George Institute of Global Health, New South Wales, Australia, who presented the findings at the 77th Scientific Sessions of the American Diabetes Association (ADA 2017) held in San Diego, California, US.

“The primary adverse effect that we observed that was unanticipated was amputations. There was an approximate doubling of the risk of amputations in the participants treated with canagliflozin compared to placebo and about two-thirds of these were amputations of the toe or forefoot and about one-third amputations above the level of the ankle,” he said.

Participants in the CANVAS Program which comprised the CANVAS and CANVAS-R** studies were 9,734 individuals with type 2 diabetes (mean age 63.3 years, 35.8 percent female, mean diabetes duration 13.5 years) from 667 centres in 30 countries. About 66 percent of participants had a history of CV disease. Participants were randomized to daily doses of canagliflozin (100 mg or 300 mg in the CANVAS study or 100 mg with the option of increase to 300 mg at week 13 in the CANVAS-R study) or placebo and followed up for a mean 188.2 weeks.

The incidence of the primary outcome (composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) was lower among patients on canagliflozin compared with those on placebo (26.9 vs 31.5 participants per 1,000 patient-years, hazard ratio [HR], 0.86, 95 percent confidence interval [CI], 0.75–0.97; p<0.001 for noninferiority and p=0.0158 for superiority). [N Engl J Med 2017;doi:10.1056/NEJMoa1611925]

Patients on canagliflozin also had a lower incidence of hospitalization for heart failure (HR, 0.67, 95 percent CI, 0.52–0.87) and CV death or hospitalization for heart failure (HR, 0.78, 95 percent CI, 0.67–0.91) compared with those on placebo.

There was a 40 percent reduction in the composite of estimated glomerular filtration rate, end-stage renal disease, or renal-related death (5.5 vs 9.0 participants per 1,000 patient-years, HR, 0.60, 95 percent CI, 0.47–0.77), though these findings were not significant.

While the incidence of serious adverse events was less frequent among patients on canagliflozin compared with placebo (104.3 vs 120.0 participants per 1,000 person-years, HR, 0.93, 95 percent CI, 0.87–1.00), patients on canagliflozin had an elevated risk of lower extremity amputations compared with those on placebo (6.3 vs 3.4 participants per 1,000 person-years, HR, 1.97, 95 percent CI, 1.41–2.75), 71 percent of which involved the toe or metatarsal and 29 percent above-ankle amputations.

To estimate the risks vs benefits of canagliflozin, in an estimate of 1,000 patients treated for 5 years, there would be 23 fewer deaths from CV disease, nonfatal heart attacks, or nonfatal strokes, 17 fewer hospitalizations for heart failure, and 16 fewer serious declines in renal function, but 15 more amputations, said Neal.

“These data suggest net overall benefit of canagliflozin for most patients with type 2 diabetes and high CV risk,” he said, and recommended that physicians take into account the amputation risk when planning diabetes care for their patients.

 

 

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Most Read Articles
02 Dec 2017
The risk of congenital heart disease (CHD) Is significantly higher in foetuses conceived through in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), according to a recent study.
Pearl Toh, 5 days ago
A higher dose of pitavastatin can benefit Japanese patients with stable coronary artery disease (CAD) compared with a low-dose pitavastatin, even though cardiovascular (CV) event incidence is known to be lower in Asian than Western patients, according to the REAL-CAD study presented at the AHA Scientific Sessions 2017.
01 Apr 2014
The basic life support (BLS) termination of resuscitation (TOR) rule recommends transport and continued resuscitation when cardiac arrest is witnessed by EMT-Ds, or there is a return of spontaneous circulation, or a shock is given.
03 Dec 2017
Treatment with the triple combination of amlodipine, losartan and rosuvastatin appears to be an effective therapeutic strategy for lowering blood pressure and low-density lipoprotein (LDL)-C levels in patients with comorbid hypertension and dyslipidaemia, according to a study.