Canagliflozin, a sodium–glucose cotransporter 2 inhibitor (SGLT-2), may provide cardiovascular and renal protection for type 2 diabetes patients at high risk for cardiovascular disease (CVD) or with an established history of it.

According to new findings reported by Bruce Neal, MB, ChB, PhD, of The George Institute for Global Health, and colleagues in the New England Journal of Medicine, canagliflozin was associated with a 14% lower risk of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke compared with placebo. Fewer canagliflozin recipients experienced these events: 26.9 vs 31.5 per 1000 patients per year. Those taking the medication also had a 33% lower risk of heart failure hospitalization.

With regard to renal outcomes, canagliflozin-treated patients experienced a 27% decreased risk of progression of albuminuria and a 40% decreased risk of a sustained 40% reduction in a composite outcome of estimated glomerular filtration rate (eGFR), need for renal replacement therapy, or death from renal causes. These decreases in risk were not statistically significant, however.

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The findings are from the CANVAS (Canagliflozin Cardiovascular Assessment Study, NCT01032629) and CANVAS-Renal (CANVAS-R) trials (NCT01989754), which involved 10,142 type 2 diabetes patients from 30 countries (mean age 63.3 years; 35.8% women) with an average diabetes duration of 13.5 years. Two-thirds (65.6%) had established CVD and one-third had several CVD risk factors. Participants were randomly assigned to receive canagliflozin (100 mg or 300 mg daily) or placebo and were followed for more than 3.5 years on average.

“Both patients and physicians should be tremendously reassured by the results,” co-author Vlado Perkovic, MB, BS, PhD, stated in a news release. “What we have done is show that the earlier results were not just a one off. This really is a game changer in the treatment of type 2 diabetes. It not only reduces the risk of heart disease, it also provides real protection against kidney decline which affects many people with diabetes.”

The paucity of end-stage renal disease cases prevented some analyses. Further evidence of kidney protection may be provided later this year when results from Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation trial (CREDENCE; NCT02065791) will be published.

“Several established effects of SGLT2 inhibitors on intermediate outcomes may contribute to cardiovascular and renal protection,” Dr Neal and colleagues noted in their paper. “Although pleiotropic effects have been inferred, improved glycemic control, lowering of blood pressure, decrease in intraglomerular pressure, reduction in albuminuria, and amelioration of volume overload are all plausible protective mechanisms.”

Among the drug’s adverse effects, the investigators reported a new warning about an increased risk of amputation, particularly at the level of the toe or metatarsal bone. Recipients were twice as likely to have an amputation: 6.3 vs 3.4 patients per 1000 per year. “We don’t know why there was an increased risk of amputation, and further work is needed in this area. But for now we urge caution in prescribing this drug to people at increased risk of suffering amputation,” Dr Neal stated in the news release.

The study was funded by Janssen Research and Development, the makers of canagliflozin (Invokana®)

Canaglifozin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), ESRD, or on dialysis.

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1. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Engl J Med doi: 10.1056/NEJMoa1611925 [Epub ahead of print]

2. Major study heralds new era in treatment of type 2 diabetes. George Institute for Global Health; June 12, 2017. [news release]