Are SGLT2 Inhibitors New Hypertension Drugs?

HomeCirculationVol. 143, No. 18Are SGLT2 Inhibitors New Hypertension Drugs? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBAre Kazuomi Kario, MD, PhD Keith C. Ferdinand, MD Wanpen VongpatanasinMD KarioKazuomi Kario PhD, Division of Cardiovascular Medicine, Department Jichi Medical University School 3311-1, Yakushiji, Shimotsuke Tochigi, 329-0498 Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8251-4480 Japan (K.K.). Search for more papers by this author , FerdinandKeith Ferdinand Tulane Heart and Vascular Institute, Orleans, LA (K.C.F.). VongpatanasinWanpen Vongpatanasin Section, Cardiology Division, Texas Southwestern Center, Dallas (W.V.). Originally published3 May 2021https://doi.org/10.1161/CIRCULATIONAHA.121.053709Circulation. 2021;143:1750–1753This article is a commentary on the followingBlood Pressure Effects Canagliflozin Clinical Outcomes in Type 2 Diabetes Chronic Kidney DiseaseArticle, see p 1735Recent large, randomized, placebo-controlled clinical trials have demonstrated that treatment with (sodium-glucose cotransport 2) inhibitors (SGLT2i) significantly reduces rate cardiovascular events (including heart failure [HF]) prevents progression renal dysfunction (and ultimately chronic kidney disease) patients or without diabetes who were already receiving optimal guideline-directed medical therapy, as recently reviewed.1 One these studies CREDENCE trial (Canagliflozin Renal Events With Established Nephropathy Evaluation) canagliflozin 100 mg/d versus placebo outcomes type nephropathy.This issue Circulation includes post hoc analysis data from examined office blood pressure (BP)–lowering effects canagliflozin, overall patient subgroups defined basis baseline systolic BP (SBP), number BP-lowering drug classes, history apparent treatment-resistant hypertension.2 recipients showed an early sustained reduction (–3.5 mm Hg baseline); was consistent across all subgroups, but smaller magnitude than reductions reported other SGLT2i (Tables 1 2). Although statistically significant, can really be described “modest” certainly not fully account 30% primary end point (composition end-stage disease, doubling serum creatinine, death causes) 39% HF. For example, it has previously been 10-mm during antihypertensive conventional pharmacotherapy led 20% risk major disease 28% HF largest meta-analysis trials.10 Indeed, mediation evaluation contribution event rates relatively small.2 Furthermore, associated outcomes. However, there significant interaction between SBP effect (P=0.04). The hazard ratio (95% CI) HF-related hospitalization 0.52 CI, 0.29–0.94) when <130 Hg, 0.36 0.19–0.66) 130 <140 0.58 0.32–1.04) 140 <150 1.00 0.65–1.54) ?150 Hg.2 fact no benefit those highest seems counterintuitive because had double groups, therefore might expected most therapy. A potential explanation finding unclear, population likely older, Black, prescribed calcium channel blockers ?-blockers. It possible lack adjustment unmeasured confounding factors along nonadherence study medication therapy may play role. In addition, observation exploratory nature.Table 1. Available Data Changes Ambulatory Blood During Treatment Sodium-Glucose Cotransporter InhibitorsDrug doseNumber patientsSGLT2i/placeboOffice (mm Hg)24-h ambulatory Hg)Nighttime Hg)Baseline*Change baselinePlacebo- subtracted change baselineBaseline*Change baselineKario et al, 2019 (SACRA)368/63141–9.9†–8.6‡139–10.0†–7.7‡130–6.3‡–4.3 Empagliflozin 10 mg/dFerdinand 2019478/72149–10.3–7.4‡146–10.3–8.4‡144–6.7–5.1§ 10–25 mg/dTikkanen 2015 (EMPA-REG BP)5276/271142–5.5–4.8†131–3.7–4.2†123–2.5–2.9† 25 mg/dPapadopoulou 2021643/42130NRNR129–5.8‡–5.7NRNRNR Dapagliflozin mg/dBP indicates pressure; NR, reported; SACRA, Inhibitor Angiotensin Receptor Blocker Combination Therapy Patients Uncontrolled Nocturnal Hypertension; SBP, SGLT2i, sodium-glucose inhibitor.* Baseline value active group.† P<0.001.‡ P<0.01.§ P<0.05.Table 2. Home SGLT2i/placeboOffice Hg)Home (morning-evening) Hg)*Nighttime home Hg)BaselineChange baselineBaselineChange 2018 (SHIFT-J)741/37143–6.6–3.0143–7.9–5.0134–5.2–4.2 mg/dKario 2020 (LUSCAR)847/NR132–6.1†NR128–4.6NRNRNRNR Luseogliflozin 2.5 mg/dKinguchi (Y-AIDA)985/NR142–4.9§NR137–8.9NR125–2.4‡NR 5 mg/dNR SHIFT-J, Study beneficial nocturnal Japanese T2DM patients; Y-AIDA, Yokohama Add-On Inhibitory Efficacy Albuminuria Diabetes.* Average morning evening levels.† P<0.05.Baseline group.Another important seen Ye al2 simply reflect regression mean. fall at 3 weeks 11 same time, group 7 Hg. contrast, increased both groups This highlights limitations analysis, prespecified planned 24-hour monitoring informative.It also note based underestimate SGLT2i-induced numerous observational established superiority independent predictor beyond alone.11,12 These recommendations many international guidelines incorporate out-of-office effective management hypertension.There growing body evidence BP. SACRA (SGLT2 Hypertension), 12 empagliflozin uncontrolled hypertension reduced nighttime SBP,3 regardless age (by 7.9 <75 years 4.2 ?75 age; corresponding mean –11.0 –8.7 Hg).13 after 24 Black (placebo-corrected difference, –5.2 [95% –9.2 –1.2]; P=0.0117; –8.4 –13.7 –3.0]; P=0.0025, respectively).4 EMPAREG substudy placebo-subtracted dose mg weeks.5 recent dapagliflozin brachial (mean±SD, ?5.8±9.5 Hg; placebo, mean±SD, ?0.1±8.7 P=0.005).6 Significant (SACRA study; –7.5 Hg),3 (SHIFT-J [Study patients]),7 luseogliflozin (LUSCAR [luseogliflozin function]),8 (Y-AIDA [Yokohama Diabetes]).9 Future needed focus identifying predictors response differential agents class Currently available currently are summarized Table, head-to-head comparisons provide definitive data.In trial, observed resistant treated mineralocorticoid receptor antagonist excluded participants antagonist, which now considered cornerstone hypertension. Similar antagonists possess only diuretic action vascular protection sympathoinhibitory effects.14 Reductions higher levels3,4,13 appear similar spironolactone PATHWAY-2 (home difference placebo).15 Nevertheless, appears several advantages over population, especially respect unwanted adverse effects.A unique feature inclusion additional determine role optimizing control reducing diabetes.Disclosures K.K. received research grants Asteras Pharma, Taisho Pharmaceutical, Boehringer Ingelheim Japan, honoraria AstraZeneca, Kowa, Sanofi, Mitsubishi Tanabe outside submitted work. authors report conflicts.FootnotesThe opinions expressed necessarily editors American Association.https://www.ahajournals.org/journal/circKazuomi protected]ac.jpReferences1. K, KC, O’Keefe JH. Control prevent disease.Prog Cardiovasc Dis. 2020; 63:249–262. doi: 10.1016/j.pcad.2020.04.003CrossrefMedlineGoogle Scholar2. 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Circulation. 2021;143:1735-1749 4, 2021Vol Issue 18Article InformationMetrics Download: 3,290 © 2021 Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.053709PMID: 33939525 publishedMay 3, Keywordssodium-glucose transporter inhibitorshypertensiondrug therapyEditorialsPDF download SubjectsHypertension