The cardiovascular advantages linked to the SGLT2 inhibitor drug canagliflozin appear to be dose-dependent, with some key clinical benefits, including reduced mortality, seen only at the higher 300 mg dose, according to new research presented at the 62nd European Renal Association Congress 2025.

“The benefit of canagliflozin on hard clinical endpoints might potentially 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 Center, in MONTREAL, Quebec.

While cardiovascular and renal benefits of SGLT2 inhibitors are well known,few studies have examined the impact of different doses on important clinical outcomes,except for the EMPA-REG OUTCOME trial with empagliflozin, according to ELENJICKAL.

To determine if dosage affects cardiovascular and renal endpoints, ELENJICKAL and his team conducted a post-hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS), wich was part of the pivotal CANVAS Program.

The CANVAS Program encompassed both the CANVAS and CANVAS-Renal studies, with results published together.

The CANVAS study involved 4330 patients with type 2 diabetes and a high cardiovascular risk,including those with known cardiovascular disease (CVD) or multiple CVD risk factors.

Participants were randomized in a 1:1:1 ratio to receive canagliflozin 100 mg, canagliflozin 300 mg, or a placebo.

The study participants had a median age of 61,with 66% being male,and the baseline characteristics were similar across all groups.

After an average follow-up of 74 months, the canagliflozin 300 mg group showed a significant decrease in the composite cardiovascular endpoint, including non-fatal myocardial infarction, stroke, or cardiovascular death, compared to the placebo group (hazard ratio [HR] 0.82; P = .04), after adjusting for age, sex, and CVD history.

However, no such differences were observed between the canagliflozin 100 mg group and the placebo group for the same 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, which 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).

The 300 mg dose group was also less likely to experience progression of albuminuria (A1 to A2, or A2 to A3) compared to the placebo group (HR, 0.83; P = .006), but this difference was not significant with the 100 mg dose (HR, 0.94; P = .33).

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

The incidence of acute kidney injury was similar across all groups, but the 300 mg group showed a trend toward fewer severe hyperkalemia episodes (adjusted HR, 0.61; P = .27).

Safety outcomes were similar across all dose groups.

Gender Differences observed

“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.”

A subgroup analysis revealed that gender may influence hospitalization rates for heart failure. Males in the 300 mg group had a significantly lower risk of heart failure hospitalization compared to placebo (HR, 0.62),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 showed a lower risk of heart failure hospitalization compared to females (HR, 0.65 vs HR,1.05; P for interaction .37).

ELENJICKAL cautioned that males had a higher prevalence of CVD at baseline (65% vs 46%).

“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.