Canagliflozin and Systolic Blood Pressure Variability in Type 2 Diabetes

In patients with T2DM and chronic kidney disease, canagliflozin decreases systolic blood pressure without affecting systolic blood pressure variability.

Canagliflozin lowers systolic blood pressure (SBP) but offers little to no effect on SBP variability among patients with type 2 diabetes with chronic kidney disease (CKD) or high cardiovascular risk. An independent association exists between higher visit-to-visit SBP variability and risks of all-cause mortality or hospitalization for heart failure, according to study findings published in the Journal of the American Heart Association.

Investigators sought to evaluate visit-to-visit SBP variability in patients with type 2 diabetes mellitus (T2DM) with CKD or at high cardiovascular risk being treated with canagliflozin. Additionally, they aimed to assess the association of SBP variability with mortality, cardiovascular, and kidney outcomes.

They conducted a post-hoc analysis combining data from the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; Identifier: NCT02065791) trial  and CANVAS (Canagliflozin Cardiovascular Assessment Study; Identifiers: NCT01032629 and NCT01989754) Program. CREDENCE and CANVAS were multicenter, double-blind, placebo-controlled, randomized trials evaluating the effects of canagliflozin among patients (pooled N=14,543; mean age 63.1 years; 35.7% women; 60.3% prior cardiovascular disease) with T2DM with CKD or high cardiovascular risk. Previous pooled analyses have shown canagliflozin significantly reduced risk of cardiovascular and all-cause mortality, hospitalization for heart failure, and kidney failure over a median of 2.5 years follow-up.

In this analysis, the investigators evaluated the effect of canagliflozin on SBP variability among patients (N=11,551) with T2DM across 4 study visits spanning 1.5 years. They noted 3.9% of patients died due to cardiovascular disease or were hospitalized for heart failure, 3.8% died of any cause, and 5.4% experienced a major adverse cardiovascular event during median follow-up of 1 year.

Compared with placebo, canagliflozin reduced mean and maximum SBP in adjusted models (-4.04 mm Hg; 95% CI, -4.49 to -3.59; and -4.36 mm Hg; 95% CI, -4.90 to -3.82), respectively.

There was no effect on the coefficient of variation (0.02%; 95% CI, -0.12 to 0.16) or variability independent of the mean (0.08; 95% CI, -0.11 to 0.26 adjusting for correlation with mean SBP) with canagliflozin, though the standard deviation (SD) of SBP variability was slightly lowered (-0.25 mm Hg; 95% CI, -0.44 to -0.06).

Cardiorenal protection with sodium glucose cotransporter-2 inhibitors is unlikely to be substantively mediated by benefits on systolic blood pressure variability.

Each standard deviation increase in SD of SBP variability independently associated with higher risk of all-cause mortality (12% increased risk; hazard ratio [HR], 1.12; 95% CI, 1.01-1.25), higher risk for hospitalization for heart failure (19% increased risk; HR, 1.19; 95% CI, 1.02-1.38), and higher risk of cardiovascular death or hospitalization for heart failure (14% increased risk; HR, 1.14; 95% CI, 1.03-1.27). These findings were consistent with results for the coefficient of variation and variability independent of the mean.

There was no association between increases in SBP variability with kidney outcomes.

Limitations of the study include availability of SBP data being only at study visits and a relatively short follow-up.

“In people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease, higher visit-to-visit SBP variability is independently associated with risks of hospitalization for heart failure and all-cause mortality,” the study authors wrote.  “Canagliflozin has little to no effect on SBP variability, independent of its established SBP-lowering effect.”  They added, “Cardiorenal protection with sodium glucose cotransporter-2 inhibitors is unlikely to be substantively mediated by benefits on systolic blood pressure variability.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Fletcher RA, Arnott C, Rockenschaub P, et al. Canagliflozin, blood pressure variability, and risk of cardiovascular, kidney, and mortality outcomes: pooled individual participant data from the CANVAS and CREDENCE trials. J Am Heart Assoc. Published online June 22, 2023. doi:10.1161/JAHA.122.028516