Reductions in Mean 24‐Hour Ambulatory Blood Pressure After 6‐Week Treatment With Canagliflozin in Patients With Type 2 Diabetes Mellitus and Hypertension

Abstract

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...

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

“…This effect has been confirmed with all SGLT2 inhibitors [29,40] : canagliflozin [41,42], dapagliflozin [43][44][45], empagliflozin [46], ertugliflozin [47] (Table 1). Generally, the reduction in systolic BP was greater (at least twofold) than the reduction in diastolic BP.…”

“…It has been suggested that circadian BP rhythm may represent a possible key target of SGLT2 inhibitors used for the treatment of Type 2 diabetes [48]. Circadian BP rhythm was maintained in these dedicated studies of SGLT2 inhibitors, with greater reductions in day-time versus night-time measurements observed for systolic BP [41,44,46] and diastolic BP [41,46]. Thus circadian BP rhythm may represent a possible key target of SGLT2 inhibitors [48].…”

Response to Stavropoulos

“…In addition, in a pooled analysis of six placebo-controlled trials (18 or 26 weeks in duration) with 4158 patients with type 2 diabetes including 165 patients self-identified as black/ African American, placebo-subtracted changes in SBP were dose-dependent in the black/African American cohort (À2.8 mm Hg and À5.1 mm Hg with canagliflozin 100 mg and 300 mg, respectively) and generally similar to those in the white 2 and Asian 3 cohorts. Stavropoulos and colleagues are correct to assume that glucose-induced diuresis contributes to initial weight loss with canagliflozin, 4 but longer treatment with canagliflozin is associated with continued weight loss, with two thirds of the weight loss accounted for by a reduction in fat mass.…”

Canagliflozin and Hypertension: Is It the Optimal Choice for All Hypertensive Patients?

“…The study efficiently demonstrated that canagliflozin seems to actually be an antihypertensive drug, which is in agreement with the results of several studies of impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on BP. 2 Of note, the study demonstrated almost similar 24-hour ambulatory BP monitoring (ABPM) and office BP reductions, 1 in contrast with data supporting that antihypertensive treatment leads to an ABPM reduction that is usually two-thirds of the office BP decrease. A meta-analysis of 44 studies assessing response to antihypertensive treatment with office and 24-hour BP measurements concluded that the average reductions in 24-hour systolic BP and diastolic BP were 36.5% and 36.8% less than the reduction in the office systolic BP and diastolic BP values, respectively.…”

“…We have read with great interest the study by Townsend and colleagues, 1 which provided important clinical data on the effect of canagliflozin on blood pressure (BP). Patients with type 2 diabetes are typically a group with difficult-to-control hypertension, most often in need of combination treatment to achieve BP control.…”