Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis

Abstract

BackgroundPhysiologic determinants, such as pulse pressure [difference between systolic blood pressure (SBP) and diastolic BP (DBP)], mean arterial pressure (2/3 DBP + 1/3 SBP), and double product [beats per minute (bpm) × SBP], are linked to cardiovascular outcomes. The effects of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on pulse pressure, mean arterial pressure, and double product were assessed in patients with type 2 diabetes mellitus (T2DM).MethodsThis post hoc analysis was based on pooled data from four 26-week, randomized, double-blind, placebo-controlled studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled, ambulatory BP monitoring (ABPM) study evaluating canagliflozin in patients with T2DM and hypertension (N = 169). Changes from baseline in SBP, DBP, pulse pressure, mean arterial pressure, and double product were assessed using seated BP measurements (pooled studies) or averaged 24-h BP assessments (ABPM study). Safety was assessed based on adverse event reports.ResultsIn the pooled studies, canagliflozin 100 and 300 mg reduced SBP (−4.3 and −5.0 vs −0.3 mmHg) and DBP (−2.5 and −2.4 vs −0.6 mmHg) versus placebo at week 26. Reductions in pulse pressure (−1.8 and −2.6 vs 0.2 mmHg), mean arterial pressure (−3.1 and −3.3 vs −0.5 mmHg), and double product (−381 and −416 vs −30 bpm × mmHg) were also seen with canagliflozin 100 and 300 mg versus placebo. In the ABPM study, canagliflozin 100 and 300 mg reduced mean 24-h SBP (−4.5 and −6.2 vs −1.2 mmHg) and DBP (−2.2 and −3.2 vs −0.3 mmHg) versus placebo at week 6. Canagliflozin 300 mg provided reductions in pulse pressure (−3.3 vs −0.8 mmHg) and mean arterial pressure (−4.2 vs −0.6 mmHg) compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters. Canagliflozin was generally well tolerated in both study populations.ConclusionsCanagliflozin improved all three cardiovascular physiologic markers, consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM. Trial registration ClinicalTrials.gov Identifier: NCT01081834 (registered March 2010); NCT01106677 (registered April 2010); NCT01106625 (registered April 2010); NCT01106690 (registered April 2010); NCT01939496 (registered September 2013)

Effects of canagliflozin on cardiovascular risk factors in patients with type 2 diabetes mellitus

“…55,56 Pooled data from four placebo-controlled studies showed that canagliflozin treatment was associated with reductions in pulse pressure, mean arterial pressure and double product (ie, heart rate × systolic BP) compared with placebo. 57 Similar results were observed in a 6-week ambulatory BP monitoring study in patients with T2DM and hypertension; BP reductions with canagliflozin occurred quickly, as early as 2 days after initiation of therapy. 58 These rapid effects on BP are likely due to osmotic diuresis, natriuresis and reduced intravascular volume.…”

“…Similar results were observed in a 6‐week ambulatory BP monitoring study in patients with T2DM and hypertension; BP reductions with canagliflozin occurred quickly, as early as 2 days after initiation of therapy . These rapid effects on BP are likely due to osmotic diuresis, natriuresis and reduced intravascular volume . Long‐term reductions in BP are likely a result of weight loss and changes in the renin‐angiotensin system .…”

“…58 These rapid effects on BP are likely due to osmotic diuresis, natriuresis and reduced intravascular volume. 57,58 Long-term reductions in BP are likely a result of weight loss and changes in the renin-angiotensin system. 58 Empagliflozin has been shown to reduce arterial stiffness in patients with type 1 diabetes mellitus, and it has been speculated that SGLT2 inhibitors may improve endothelial function or the elastic properties of various components of connective tissue.…”

Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data

“…Na,reabs-PT,NHE3 ϭ Na,reabs-PT,NHE3,0 ϫ ͑1 Ϫ SGLT2i_NHE3_inhibition͒ (26) We made no a priori assumption about the mechanism or degree of inhibition of NHE3. The degree of inhibition, SGLT2i_NHE3_inhibition, was initially set to 0.…”

“…Mathematical analyses suggest that the excess electrolyte-free water clearance associated with osmotic diuresis may result in greater clearance of interstitial fluid compared with other forms of diuretics (14). Other proposed mechanisms, such as improvements in fuel metabolism from fat oxidation to ketones (6) or reduced arterial stiffness (3,26,33), have a less clear link to these renal actions of SGLT2i.…”