Canagliflozin benefits may extend to primary prevention
medwireNews: Further analysis of the CANVAS trial suggests that the benefits of canagliflozin treatment are broadly consistent in type 2 diabetes patients with and without pre-existing cardiovascular disease (CVD).
The analysis, which is published in Circulation, showed no significant statistical interaction between CVD status and the effect of canagliflozin. In other words, there was no evidence that the effect of canagliflozin treatment on outcomes differed between these two groups.
The picture was clearest for the secondary outcomes of hospitalization for heart failure and the composite renal endpoint (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death). For these outcomes, the relative risk reductions with canagliflozin versus placebo were of similar size for the 3486 primary prevention and the 6656 secondary prevention patients during an average 188 weeks of treatment. For example, the respective hazard ratios for heart failure hospitalization were 0.64 and 0.68, although that for the primary prevention patients was nonsignificant due to the smaller numbers.
However, for the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, the secondary prevention patients had an 18% risk reduction with canagliflozin versus placebo, but there was just a 2% reduction among the primary prevention group.
In an accompanying editorial, Matthew Cavender (University of North Carolina, Chapel Hill, USA) and Mikhail Kosiborod (Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA) say that while it may be tempting to assume no benefit with respect to the primary outcome for patients without pre-existing CVD, “this would be an overly simplistic interpretation.”
They say that the statistical power to detect a difference is severely limited by the small number of events – 215 in the primary prevention group – reflected in the 95% confidence interval, which encompasses from a 26% risk reduction to a 30% risk increase for the primary composite endpoint.
“Accordingly, these results do not exclude the possibility of a benefit with canagliflozin in the ‘primary prevention’ subgroup – and the lack of statistical heterogeneity supports the concept that the results are similar in both populations,” they write.
Researcher Kenneth Mahaffey (Stanford University School of Medicine, California, USA) and team also found that the adverse effects of canagliflozin did not differ according to whether patients had pre-existing CVD. The risk increases for genital infections and lower extremity amputations observed in the primary analysis were present for both subgroups, although amputation rates were markedly higher among secondary than primary prevention patients.
The editorialists conclude that, while the evidence to date broadly supports a benefit of sodium–glucose cotransporter (SGLT)-2 inhibitors in primary prevention patients, a definitive answer will only come with the publication of DECLARE-TIMI 58, which is testing dapagliflozin versus placebo in more than 17,000 patients, including a large primary prevention cohort.
But in the meantime, they suggest that the clear benefits for endpoints such as heart failure “are also compelling for clinicians to favor SGLT-2 [inhibitors] over glucose-lowering therapies without proven cardiovascular benefits.”
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