Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus

Abstract

The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis- and intravascular volume reduction-related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 100 mg and 300 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo (-4.3 mm Hg [-5.0 to -3.5], -5.0 mm Hg [-5.8 to -4.2], and -0.3 mm Hg [-1.2 to 0.5], respectively) and in diastolic BP (DBP; -2.5 mm Hg [-2.9 to -2.0], -2.4 mm Hg [-2.9 to -1.9], and -0.6 mm Hg [-1.1 to -0.02], respectively). Placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -4.0 mm Hg (-5.1 to -2.8) and -4.7 mm Hg (-5.8 to -3.5) and reductions in DBP were -1.9 mm Hg (-2.6 to -1.2) and -1.9 mm Hg (-2.6 to -1.1), respectively. Compared with the overall population, patients with elevated baseline SBP (≥140 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 100 mg and 300 mg and placebo (-12.8 mm Hg [-15.2 to -10.5], -14.2 mm Hg [-16.4 to -12.0], and -6.8 mm Hg [-9.1 to -4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP ≥90 mm Hg at baseline (-5.9 mm Hg [-8.2 to -3.6], -9.0 mm Hg [-11.1 to -6.9], and -7.4 mm Hg [-9.6 to -5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 100 mg and 300 mg were -6.0 mm Hg (-9.1 to -2.9) and -7.4 mm Hg (-10.4 to -4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg (-1.6 to 4.5) and -1.6 mm Hg (-4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 100 mg and 300 mg were associated with increased incidence of osmotic diuresis-related AEs (e.g., pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and 0.8%). The incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction.

Trial registration: ClinicalTrials.gov NCT01081834 NCT01106625 NCT01106677 NCT01106690.

Copyright © 2014 Wiley Periodicals, Inc.

Figures

Figure 1

Change in (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) for the overall population and for patients with SBP ≥140 mm Hg and DBP ≥90 mm Hg (last observation carried forward [LOCF]). LS indicates least‐squares; SE, standard error; CI, confidence interval; PBO, placebo; CANA, canagliflozin.

Figure 2

Proportion of patients with baseline systolic blood pressure (SBP) ≥140 mm Hg reaching SBP targets (last observation carried forward [LOCF]). PBO indicates placebo; CANA, canagliflozin. Patients with baseline SBP ≥140 mm Hg (PBO, n=134; CANA 100 mg, n=146; CANA 300 mg, n=166).

Figure 3

Change in (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) for patients taking antihypertensive medications (angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and/or diuretics) and not taking antihypertensive medications at baseline (last observation carried forward [LOCF]). LS indicates least‐squares; SE, standard error; CI, confidence interval; PBO, placebo; CANA, canagliflozin.

Figure 4

Kaplan‐Meier plot of time to first osmotic diuresis–related adverse event (AE). PBO indicates placebo; CANA, canagliflozin.