The cardiovascular and renal effects of treatment with canagliflozin in patients with type 2 diabetes are more prominent in those not taking metformin compared with patients treated with canagliflozin as an add-on to metformin, according to data from the CANVAS (CANagliflozin cardioVascular Assessment Study) Program presented at the American Association of Clinical Endocrinologists 28th Annual Scientific & Clinical Congress, held April 24 to 28 in Los Angeles, California.

The researchers noted that the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) showed different cardiovascular effects of empagliflozin according to concomitant use with metformin, as the sodium-glucose cotransporter 2 inhibitor treatment had a greater effect on cardiovascular mortality when given without metformin vs in combination with metformin.

The goal of the study was to investigate whether the cardiovascular and renal effects of canagliflozin were different when given with or without metformin, based on data from the CANVAS Program.

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The CANVAS Program enrolled 10,142 patients with type 2 diabetes at high risk for cardiovascular morbidity and mortality. The participants were randomly assigned to receive canagliflozin or placebo.

Of the entire cohort, 2317 patients (22.8%) were not treated with metformin at baseline. Participants not treated with metformin were more likely to be older and have a longer duration of diabetes with complications of the disease (all P <.0001).

In patients receiving metformin, adding treatment with canagliflozin had no significant effect on the primary outcome (hazard ratio [HR], 0.91; 95% CI, 0.77-1.06; P =.14 for heterogeneity), defined as a composite of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke. However, in the group of patients not on metformin, canagliflozin had a significant protective effect (HR, 0.76; 95% CI, 0.61-0.94).

The results were similar in each group for myocardial infarction, cardiovascular mortality, renal composite outcome, and all-cause mortality (P >.30 for heterogeneity for all). However, the risk for fatal or nonfatal stroke was reduced more significantly in patients not receiving metformin (HR, 0.52; 95% CI, 0.35-0.78) compared with patients receiving metformin (HR, 1.11; 95% CI, 0.84-1.48; P =.002 for heterogeneity).

In a similar fashion, the risk reduction in hospitalization for heart failure was greater in participants not receiving metformin (HR, 0.43; 95% CI, 0.28-0.65) compared with patients who received baseline treatment with metformin (HR, 0.88; 95% CI, 0.64-1.23; P =.005 for heterogeneity).

“This observation may be explained by chance, differences in participant characteristics, or may represent a true interaction. An adequately powered head-to-head trial comparing the effects of metformin [with sodium-glucose cotransporter 2] inhibition would resolve this uncertainty,” wrote the researchers.


Neuen B, Heerspink H, Neal B, et al. Cardiovascular and renal outcomes with canagliflozin in people with type 2 diabetes according to baseline use of metformin. Presented at: American Association of Clinical Endocrinologists 28th Annual Scientific & Clinical Congress; April 24-28, 2019; Los Angeles, CA.


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This article originally appeared on Endocrinology Advisor