Greater absolute benefit of SGLT2 inhibitor in secondary vs primary prevention in T2DM
CANVAS - Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events in Type 2 Diabetes: Results from the CANVAS Program
Presented at AHA 2017 Scientific Sessions in Anaheim, CA, USA by Kenneth Mahaffey (Stanford Center for Clinical Research, Stanford, CA, USA)
The CANVAS program enrolled over 10000 patients with type 2 diabetes (T2DM), with HbA1c between 7.0 and 10.5% and eGFR ≥30 mL/min/1.73m2, who were randomized to treatment with the SGLT2 inhibitor canagliflozin or placebo after a 2-week placebo run-in period.
Previously, treatment with canagliflozin had been shown to significantly reduce a composite of CV death, non-fatal MI and non-fatal stroke (HR: 0.86, 95%CI: 0.75-0.97, P=0.02). Hospitalization for HF (HR: 0.67, 95%CI: 0.52-0.87), CV death or hospitalization for HF (HR: 0.78, 95%CI: 0.67-0.91), progression of albuminuria (HR: 0.73, 95%CI: 0.67-0.79) and a renal composite outcome (HR: 0.60, 95%CI: 0.47-0.77) were also significantly reduced.
The current prespecified analysis aimed to compare the effects of canagliflozin vs placebo on CV, renal and safety outcomes in secondary (history of a prior CV event, n=6656, 66%) and primary (≥2 CV risk factors, n=3486, 34%) prevention participants.
- In the secondary prevention cohort, an HR for the composite of CV death, nonfatal MI or nonfatal stroke of 0.82 (95%CI: 0.72-0.95) was observed over 6 years (median follow-up: 2.4 years) , while in the primary prevention cohort HR was 0.98 (95%CI: 0.74-1.30). P-interaction was 0.18. The event rate was higher in secondary prevention participants.
- Hospitalization for HF showed an HR of 0.68 (95%CI: 0.51-0.90) for secondary prevention and of 0.64 (95%CI: 0.35-1.15) for primary prevention. P-interaction was 0.91. Again event rates were higher in the secondary prevention cohort.
- The renal composite showed an HR of 0.59 (95%CI: 0.44-0.79) for secondary prevention, and HR: 0.63 (95%CI: 0.39-1.02) for primary prevention, with higher event rates in the former group. P-interaction was 0.73.
- Hazards of safety events (including genital infections, low-trauma fracture, volume depletion events, hypoglycemia and lower-extremity amputations) did not differ much between the primary and secondary prevention groups. No significant interactions were noted.
This analysis of CANVAS showed that patients with prior CV events, who received canagliflozin for secondary prevention, had greater absolute benefit of treatment on CV, renal and death outcomes than did those without a prior CV events. Canagliflozin reduced CV and renal outcomes overall, with no statistical evidence of heterogeneity of canagliflozin effects across the primary and secondary prevention participants. Further study with longer follow-up in a primary prevention population will provide further insights into the effect of canagliflozin (CREDENCE) and other SGLT2 inhibitors (DECLARE).
It should be noted that the trial was not designed with appropriate statistical power to show definitive treatment differences in the outcomes in primary and secondary prevention participants. Other limitations include that the primary and secondary prevention participants were categorized based on investigator-reported criteria, and since no screening for subclinical atherosclerotic vascular disease was performed, those with asymptomatic CV disease may have been included in the primary prevention group.
Discussant Angelyn Bethel (University of Oxford) compared these results to the findings of EMPA-REG OUTCOME, which evaluated the SGLT2-inhibitor empagliflozin, in a secondary prevention population only. The point estimates for MACE in secondary prevention are comparable, while a larger point estimate for all-cause mortality was seen in EMPA-REG OUTCOME. The observed effects with SGLT2 inhibition may be the result of something other than conventional risk factors, but the timeline is too short for atherosclerotic or glucose-mediated mechanisms. Not all outcomes appear to translate to primary prevention cohorts in the short term, or perhaps at all.
She repeated that no statistical heterogeneity between the primary and secondary prevention cohorts was seen for any outcome, but the MACE outcome was in fact inconsistent (HR: 0.98 in primary prevention), and no separation of curves was seen. It is a limitation that the only available evidence on SGLT2 inhibiton in primary prevention stems from the CANVAS program, which was neither designed, nor powered, to address the primary prevention question.
- Our reporting is based on the information provided at the AHA 2017 congress –