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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
Open accessAbstract
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/m 2 ). 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.
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“A recent meta-analysis including seven RCTs demonstrated that SGLT2 inhibitors were associated with an average reduction of 3.6/1.7 mmHg (systolic/diastolic) in 24 h ambulatory BP, which is comparable with efficacy of low-dose hydrochlorothiazide.”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [225]
In the citing paper
“SGLT2 inhibitors induced a larger BP decrease than did GLP-1 RAs without changing heart rate.”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [225]
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“This is further supported by favorable effects on arterial stiffness, vascular resistance, and BP variability in human clinical trials.[32][33][34]”
From Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial (2021) · cites this paper as [34]
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“Human clinical trials have shown that SGLT2 inhibitors exert favorable effects on arterial stiffness, vascular resistance, and endothelial and blood pressure variability (Kario et al., 2018; Chilton et al., 2015; Cherney et al., 2014a; Cooper et al., 2019).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Kario et al., 2018
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Metadata
- Authors
- Kario, K., Okada, K., Kato, M., Nishizawa, M., Yoshida, T., Asano, T., Uchiyama, K., Niijima, Y., Katsuya, T., Urata, H., Osuga, J.-I., Fujiwara, T., Yamazaki, S., Tomitani, N., Kanegae, H., Hoshide, S., Yamamoto, M., Eguchi, K., Mizuno, A., Nakano, S., Kemi, Y., Iwashita, C., Wada, K., Kaneko, A., & Ryan, N.
- Affiliations
- Jichi Medical University (JP)
- Kato Clinic of Internal Medicine, Tokyo, Japan (M.K.).
- Asano Kanamachi Clinic, Tokyo, Japan (T.A.).
- Uchiyama Clinic, Niigata, Japan (K.U.).
- Kan-etsu Chuoh Hospital, Gunma, Japan (Y.N.).
- The University of Osaka (JP)
- Fukuoka University (JP)
- Utsunomiya Higashi Hospital, Tochigi, Japan (J.O.).
- Corresponding author
- Kario, Kazuomi
- ORCID
- Venue
- Circulation
- Published
- 2019-04-30
- Volume
- 139
- Issue
- 18
- Pages
- 2089-2097
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6493695
- OpenAlex
- W2903192033
- Cited by
- 251
- References
- 37
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 23 · 2023: 40 · 2022: 45 · 2021: 42 · 2020: 37 · 2019: 20
- FWCI
- 26.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Circulation (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (16K09514)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- empagliflozin, SGLT2 inhibitors, nocturnal hypertension, type 2 diabetes, blood pressure reduction, ambulatory blood pressure monitoring, angiotensin receptor blockers, N-terminal pro-brain natriuretic peptide, atrial natriuretic peptide, body weight, HbA1c, cardiovascular risk, salt-sensitive hypertension, older adults
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