Twenty-Four-Hour Blood Pressure-Lowering Effect of a Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Diabetes and Uncontrolled Nocturnal Hypertension: Results From the Randomized, Placebo-Controlled SACRA Study

Abstract

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy.

Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring).

Results: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m²). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mm Hg; P=0.004); between-group difference in change from baseline was -4.3 mm Hg (P=0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5, and -8.6 mm Hg, respectively; all P≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both P<0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; P=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [P=0.008] and -9.7% [P=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups.

Conclusions: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality.

Clinical trial registration: URL: https://www.

Clinicaltrials: gov. Unique identifier: NCT03050229.

Keywords: hypertension; natriuretic peptides; sodium-glucose transporter 2 inhibitors; type 2 diabetes mellitus.

Figure 1.

Study flow chart.

Figure 2.

Changes from baseline in nighttime, daytime, and 24-hour systolic (SBP) and diastolic (DBP) blood pressure (BP). Bars and values represent the change (mean and 95% CI) from baseline using the mixed-effects model with repeated measures adjusted for age and sex. *Between-group difference in the change from baseline.

Figure 3.

Changes from baseline in clinic and morning home BPs. A, clinic systolic BP (SBP) and diastolic BP (DBP); B, morning home SBP and DBP. Points and bar represent the least-square mean and standard error using the mixed-effects model with repeated measures adjusted for age and sex. P values are for the between-group difference change from baseline.

Figure 4.

Change from baseline in glycosylated hemoglobin (HbA1c), body weight, uric acid, and estimated glomerular filtration rate (eGFR). HbA1c (A), body weight (B), uric acid (C), and eGFR (D). Points and bar represent the least-square mean and standard error using the mixed-effects model with repeated measures adjusted for age and sex. P values are for the between-group difference change from baseline.