6This randomized, double-blind, placebo-controlled study evaluated the early effects of canagliflozin on blood pressure (BP) in patients with type 2 diabetes mellitus (T2DM) and hypertension. Patients were randomized to canagliflozin 300 mg, canagliflozin 100 mg, or placebo for 6 weeks and underwent 24-hour ambulatory BP monitoring before randomization, on day 1 of treatment, and after 6 weeks. The primary endpoint was change in mean 24-hour systolic BP (SBP) from baseline to week 6. Overall, 169 patients were included (mean age, 58.6 years; glycated hemoglobin, 8.1%; seated BP 138.5/82.7 mm Hg). At week 6, canagliflozin 300 mg provided greater reductions in mean 24-hour SBP than placebo (least squares mean À6.2 vs À1.2 mm Hg, respectively; P=.006). Numerical reductions in SBP were observed with canagliflozin 100 mg. Canagliflozin was generally well tolerated, with side effects similar to those reported in previous studies. These results suggest that canagliflozin rapidly reduces BP in patients with T2DM and hypertension. J Clin Hypertens (Greenwich). 2016;18:43-52. ª 2015 Wiley Periodicals, Inc.Hypertension is a common comorbidity of diabetes mellitus, affecting up to 60% of patients.1,2 Sodiumglucose cotransporter 2 (SGLT2) inhibitors, which have been shown to improve glycemic control in patients with type 2 diabetes mellitus (T2DM), may also reduce blood pressure (BP).3,4 In a meta-analysis of 27 randomized trials (most studies with a followup of 12-52 weeks), treatment with SGLT2 inhibitors was associated with significant reductions in systolic BP (SBP) and diastolic BP (DBP) from baseline. 5 Similarly, a pooled analysis of four randomized trials (duration of follow-up 26 weeks) showed significant placebo-corrected reductions in SBP when canagliflozin was given at doses of 300 mg and 100 mg in patients with T2DM and elevated SBP at baseline. 6 Most studies of SGLT2 inhibitors have evaluated changes in BP after 12, 26, or 52 weeks of therapy. 5-11The immediate effects (ie, less than 12 weeks) of SGLT2 inhibitors on BP have not been well characterized. The current 6-week study 12 was designed to evaluate the early effects of treatment with canagliflozin on BP, including a 24-hour BP assessment after the first dose, using ambulatory BP monitoring (ABPM). METHODS Study Design and Patient PopulationThis randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter study consisted of three phases: (1) a pretreatment phase comprising a screening visit and a 2-week single-blind, placebo runin; (2) a double-blind, 6-week treatment phase; and (3) a follow-up phase of 30 days after the last dose of the study drug. Protocol-specified inclusion and exclusion criteria were assessed at the screening visit (day À21).Patients aged from 18 years to less than 75 years were eligible for inclusion in the study if they had: (1) hypertension (defined as a seated office SBP ≥130 mm Hg and <160 mm Hg and seated office DBP ≥70 mm Hg) and were taking stable doses of one to three antihypertensive agents (includin...

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Background: Canagliflozin (CANA), a sodium glucose co-transporter 2 inhibitor, decreases renal glucose reabsorption and increases urinary glucose excretion. In 26-wk clinical studies consistent and sustained reductions in BP have been observed. This study used ABPM to assess reduction of BP after the initiation of CANA. Methods: In this 6-wk, placebo (PBO)-controlled study, 169 pts (mean [SD] age 58.6 [8.4] y, A1C 8.1% [0.9], seated SBP 138.5 mmHg [9.6], seated DBP 82.7 mmHg [8.1]), on 1-3 antihyperglycemic agents (required metformin; excluded insulin) and 1-3 antihypertensive agents (required ACEi or ARB; excluded loop diuretics) received ≥1 dose of the study medication (CANA 100 mg [n = 57], CANA 300 mg [n = 56], or PBO [n = 56]). Primary endpoint was change from baseline to Wk 6 (LOCF) in mean 24-hr SBP between CANA 300 mg and PBO. Primary efficacy analysis was based on an ANCOVA model which included terms for treatment and beta-blocker use and baseline mean 24-hr SBP as a covariate. Key secondary endpoints included change from baseline in mean 24-hr DBP, and mean day- and nighttime SBP and DBP for CANA 100 and 300 mg. Results: At Wk 6, CANA 300 mg provided greater reductions in mean 24-hr SBP vs PBO (-4.9 mmHg, p = 0.006, Fig.). Reductions in mean 24-hr SBP were also observed with CANA 100 mg (-3.3 mmHg) vs PBO. Reductions in mean 24-hr DBP were observed for both CANA 100 mg (-1.94 mmHg) and CANA 300 mg (-2.92 mmHg*) vs PBO. CANA 100 and 300 mg resulted in greater reductions in mean daytime SBP (PBO-adjusted changes -4.0 mmHg* and -5.4 mmHg*) and DBP (PBO-adjusted changes -2.2 mmHg* and -3.0 mmHg*). Higher incidences of orthostasis, volume depletion and osmotic diuresis adverse events were observed with CANA 300 mg vs CANA 100 mg and PBO. Conclusion: At Wk 6, CANA 300 mg provided a rapid and significant reduction in mean 24-hr SBP. Both CANA doses reduced daytime SBP and DBP, and demonstrated an overall safety profile consistent with clinical studies. *nominal p value (p < 0.05)