Canagliflozin CV Benefits Appear to Be Dose-Dependent

Cardiovascular benefits associated with the SGLT2 inhibitor drug canagliflozin appear to be dose-dependent, with benefits in some key clinical endpoints — including mortality — observed only in the higher of the two key doses of 300 mg and 100 mg of the drug, new research shows.

“The benefit of canagliflozin on hard clinical endpoints may be dose-dependent, with the 300 mg dose showing a higher efficacy and a similar safety profile,” said first author Elias Elenjickal, MD, of the Research Institute of the McGill University Heath Centre, in Montreal, Quebec, in presenting the findings at the 62nd European Renal Association Congress 2025.

Cardiovascular and renal benefits of SGLT2 inhibitor drugs are well established, and while dose-dependent effects have been reported in some pharmacokinetic studies, none — with the exception of the EMPA-REG OUTCOME trial (which was of empagliflozin) — have formally evaluated the impact of different doses on hard clinical endpoints, Elenjickal noted.

To investigate whether dose indeed plays a role in those cardiovascular and renal endpoints with canagliflozin, Elenjickal and colleagues conducted a post-hoc analysis of the double-blind Canagliflozin Cardiovascular Assessment Study (CANVAS) study, which was part of the pivotal CANVAS Program. 

The CANVAS Program included the CANVAS and CANVAS-Renal studies. The results of the two trials were published together as part of the CANVAS program, not independently. 

The CANVAS study included 4330 patients with type 2 diabetes and a high cardiovascular risk, including known cardiovascular disease (CVD) or more than 2 risk factors for CVD.

Those patients were randomized 1:1:1 to treatment with canagliflozin 100 mg, canagliflozin 300 mg, or placebo.

Patients in the study had a median age of 61 years, 66% were male, and baseline characteristics between the groups were similar.

With a mean follow-up of 74 months, those in the canagliflozin 300 mg group showed significantly greater reductions in the composite cardiovascular endpoint, including non-fatal myocardial infarction, stroke, or cardiovascular death, compared with placebo (hazard ratio [HR], 0.82; P = .04) after adjustment for factors including age, sex, and history of CVD.

However, these differences were not observed between canagliflozin 100 mg and placebo for the composite endpoint (HR, 0.95; P = .55). 

There were no significant differences between the two canagliflozin doses and the incidence of the composite renal endpoint that included doubling of serum creatinine, end-stage kidney disease, or renal death, compared with placebo (HR, 0.48 for canagliflozin 100 mg; P = .03; HR, 0.41 for canagliflozin 300 mg; P = .01). 

Those in the 300 mg dose group were less likely to have progression of albuminuria to a higher stage (A1 to A2, or A2 to A3), compared with placebo (HR, 0.83; P = .006), but the difference was not significant with the 100 mg dose (HR, 0.94; P = .33). 

Importantly, all-cause mortality was significantly lower with the 300 mg dose compared with placebo (HR, 0.78; P =.03), while the 100 mg group only showed a trend toward lower mortality (HR, 0.89; P = .29).

There were no significant differences between the two dose groups and placebo in terms of the incidence of acute kidney injury, while the 300 mg group had a trend towards fewer severe hyperkalemia episodes (adjusted HR, 0.61; P = .27).

There were no differences observed in safety outcomes between the two dose groups or placebo.

A Gender Difference? 

Of note, a further subgroup analysis showed an effect of gender on hospitalization rates for heart failure events: with males in the 300 mg group having a significantly decreased risk of heart failure hospitalization vs placebo (HR,.62), while females in the 300 mg group had an increased risk (HR, 1.72; P for interaction .03).

In the 100 mg group, males also had a lower risk for heart failure hospitalization vs females (HR, 0.65 vs HR, 1.05; P for interaction .37).

As a caveat, Elenjickal noted that males did have a higher burden of CVD at baseline (65% vs 46%).

“Overall, we found that canagliflozin 300 mg significantly reduced major adverse cardiac events, and reduction in all-cause mortality was observed only with a 300 mg dose: not with a 100 mg dose,” Elenjickal said.

“There is evidence of a dose-dependent effect with canagliflozin, which is unique among other SGLT2 inhibitors for hard clinical endpoints,” Elenjickal said. 

The CANVAS study was funded by Janssen Research and Development; ClinicalTrials.gov number NCT01032629. 

Elenjickal reported an educational grant from Pfizer. 

Nancy A. Melville is a Maine-based medical and science journalist with more than 25 years of writing experience in specialties including endocrinology, oncology, hematology, psychiatry, and neurology.