Canagliflozin Benefits Patients With Type 2 Diabetes in Both Primary and Secondary Prevention: Presented at AHA

By Walter Alexander

ANAHEIM, California – November 15, 2017 -- Canagliflozin should be considered for the management of diabetes mellitus in patients who are at high risk for cardiovascular events, according to results of the Canagliflozin Cardiovascular Assessment Study (CANVAS), presented at the 2017 Annual Scientific Sessions of the American Heart Association (AHA).

“Canagliflozin reduced cardiovascular and renal outcomes overall, with no statistical evidence of heterogeneity of canagliflozin effects across the primary- and secondary-prevention participants,” noted lead author Kenneth W. Mahaffey, MD, Stanford University School of Medicine, Stanford, California.

Dr. Mahaffey and the CANVAS investigators compared the effects of canagliflozin versus placebo on cardiovascular, renal, and safety outcomes among secondary and primary prevention participants. Participants at 667 centres in 30 countries (n = 10,142) were required to have an estimated glomerular filtration rate (eGFR) at entry of more than 30 ml per minute per 1.73 m2 of body-surface area and to meet a range of other criteria (below).

After a 2-week placebo run-in, the researchers randomised subjects to receive either canagliflozin (300 mg or 100 mg) or placebo. Previously reported initial CANVAS results for the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke favoured canagliflozin over placebo with a 14% reduction (hazard ratio [HR] 0.86 [95% confidence interval {CI} 0.75 to 0.97]; P = .02).

The current analysis compared canagliflozin effects among secondary- (n = 6,656) and primary-prevention (n = 3,486) participants. Mean follow-up was 188 weeks.

Patients in the secondary-prevention analysis had high rates of prior myocardial infarction (44%), hospitalisation for unstable angina (11%), coronary revascularisation (54%), percutaneous coronary intervention (38%) and bypass graft surgery (21%), and stroke (19%). Hazard ratios for the primary endpoint for canagliflozin versus placebo in the secondary- and primary-prevention groups were 0.82 (95% CI: 0.72 to 0.95) and 0.98 (95% CI: 0.74 to 1.30), respectively, without a significant interaction (P = .18). Hazard ratios for heart failure were 0.68 and 0.64, respectively, and for renal composite were 0.59 and 0.63, respectively. Interactions were not significant.

An analysis demonstrated that the number of events prevented in 1,000 patients over 5 years was 23 for the primary endpoint, 16 for heart-failure hospitalisation, 18 for renal improvement (40% reduction in eGFR, renal replacement therapy, or renal death), with an increase of 15 lower-extremity amputations (10 toe or metatarsal, 5 above the ankle) (HR 2.85; 95% CI, 1.95 to 4.16). The mechanism for this unexpected increase is not understood, but Dr. Mahaffey noted that physicians must exercise caution with canagliflozin among patients at risk for amputations.

Participants in this study were men and women with type 2 diabetes (glycated haemoglobin level, ≥7.0 percent and ≤10.5 percent) who were either 30 years of age or older with a history of symptomatic atherosclerotic cardiovascular disease or 50 years of age or older with 2 or more of the following risk factors for cardiovascular disease: duration of diabetes of at least 10 years, systolic blood pressure higher than 140 mm Hg while receiving 1 or more antihypertensive agent(s), current smoker, microalbuminuria or macroalbuminuria, or high-density lipoprotein (HDL) cholesterol level of < 1 mmol per litre (38.7 mg/decilitre).

Type 2 diabetes mellitus is associated with a high risk for cardiovascular and renal disease. Inhibitors of sodium-glucose cotransporter 2, like canagliflozin, have shown favourable effects on biomarkers, including glycaemia, blood pressure, weight, intrarenal haemodynamics, and albuminuria. These inhibitors may also reduce the risk of serious cardiovascular complications, kidney disease, and death, Dr. Mahaffey stated.
Further study with longer follow-up is needed, the team concluded.

[Presentation title: Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events in Type 2 Diabetes: Results From the CANVAS Program.]

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