Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus
2017; Lippincott Williams & Wilkins; Volume: 136; Issue: 12 Linguagem: Inglês
10.1161/circulationaha.117.029529
ISSN1524-4539
AutoresKristina Striepe, Agnes Jumar, Christian Ott, Marina V. Karg, Markus P. Schneider, Dennis Kannenkeril, Roland E. Schmieder,
Tópico(s)Pharmacology and Obesity Treatment
ResumoHomeCirculationVol. 136, No. 12Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus Kristina Striepe, MD, Agnes Jumar, MD, Christian Ott, MD, Marina V. Karg, MD, Markus P. Schneider, MD, Dennis Kannenkeril, MD and Roland E. Schmieder, MD Kristina StriepeKristina Striepe From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. , Agnes JumarAgnes Jumar From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. , Christian OttChristian Ott From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. , Marina V. KargMarina V. Karg From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. , Markus P. SchneiderMarkus P. Schneider From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. , Dennis KannenkerilDennis Kannenkeril From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. and Roland E. SchmiederRoland E. Schmieder From Department of Nephrology and Hypertension, University Hospital Erlangen, Bavaria, Germany. Originally published19 Sep 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029529Circulation. 2017;136:1167–1169From a clinical perspective, type 2 diabetes mellitus might also be regarded as a vascular disease, characterized by increased arterial stiffness. Empagliflozin is a selective sodium-glucose cotransporter 2 inhibitor shown to improve glycemic control after short- and long-term treatment.1 In the EMPA-REG OUTCOME study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), a prospective randomized double-blind study in patients with type 2 diabetes mellitus with established cardiovascular disease, treatment with empagliflozin reduced the primary combined cardiovascular end point (3P-MACE [3-point major adverse cardiovascular event]), as well as secondary end points of hospitalization because of heart failure, cardiovascular morbidity, total mortality, and renal end points.2 We tested the hypothesis that improvements of vascular function and stiffness are involved in the observed improved cardiovascular and renal outcomes with empagliflozin treatment.In this investigator-initiated prospective, double-blind, randomized, placebo-controlled, crossover, interventional single-center trial, 76 female and male patients (18–75 years of age) with diagnosed type 2 diabetes mellitus were randomized to either empagliflozin 25 mg orally once daily or placebo for 6 weeks, followed by the second 6-week treatment with the other compound (crossover). In 64 patients, any antidiabetic agent was withdrawn 4 weeks before the baseline examination. We analyzed the effects of empagliflozin on central hemodynamics and vascular function at baseline (untreated status), after 6 weeks with empafliflozin/placebo, and after another 6 weeks with the other compound. The study protocol was approved by the local ethics committee, and written informed consent was obtained.To measure central systolic pressure and central pulse pressure, radial artery waveforms were recorded by the SphygmoCor System (AtCor Medical), and corresponding central (aortic) waveforms were then automatically generated through a validated transfer function.3 During 24-hour ambulatory, daily-life conditions, brachial blood pressure (BP), and derived central (aortic) pressure curves (obtained through a validated transfer function) were assessed by the Mobilograph (IEM).4 Statistical analysis was performed in the per protocol population (N=71).All patients (59% males, 62±7 years of age) were white, and 10 patients had established cardiovascular disease. At baseline, HbA1c was 6.75±0.8%, body weight 89.2 kg, office BP 129±14/77±7.6 mm Hg, and ambulatory BP 129±10/79±7.1 mm Hg. Compared with placebo, empagliflozin effected a decrease of HbA1c (−0.26±0.44%, P=0.001), fasting glucose (−24.9±26 mg/dL, P<0.001), body weight (−1.08±1.5 kg, P<0.001), brachial office BP (−5.20±7.8/−1.70±6.1 mm Hg, P<0.001/P=0.021), and 24-hour ambulatory BP (−2.13±7.3/−1.93±5.1 mm Hg, P=0.017/0.002). No safety issues were noted throughout the study.Under office conditions, central systolic (primary objective) and central pulse were lower by 5.14 mm Hg (P<0.001) in the empagliflozin group than in the placebo group after 6 weeks of treatment (Figure). Accordingly, a decreased forward pressure wave amplitude and a reduced reflected pressure wave amplitude were observed after empagliflozin. Heart rate-corrected augmentation index was numerically lower after empagliflozin treatment (P=0.073) compared with placebo.Download figureDownload PowerPointFigure. Principle results. Comparison of primary (central systolic pressure [mm Hg]) and key secondary (central pulse pressure, forward wave amplitude, reflected wave amplitude [all mm Hg]) parameters under office (upper) and 24-hour ambulatory (central systolic [mm Hg] and diastolic pressure [mm Hg], 24-hour pulse wave velocity [m/sec]) (lower) conditions. Left, Changes from baseline in the 2 groups (blue, empagliflozin; red, placebo). Right, Difference of the changes from baseline between the 2 groups with corresponding P values (green).Under ambulatory conditions, 24-hour central systolic (P=0.059) and diastolic BP (P=0.001) were lower in the empagliflozin than in the placebo group (Figure). A significant difference in the average of the 24-hour ambulatory pulse wave velocity was also observed after 6-week treatment with empagliflozin.The selective sodium-glucose cotransporter 2 inhibitor empaglifozin, approved as an antidiabetic agent, emerged as a novel cardioprotective and nephroprotective treatment strategy.1 The potential underlying pathogenetic mechanisms are being intensely discussed. For the first time, the current study provides an in-depth analysis of the vascular effects of empagliflozin, going beyond our previous analysis with dapagliflozin.5 We could demonstrate that 6 weeks of treatment with empagliflozin resulted in lower central systolic pressure, both under office and 24-hour ambulatory conditions, compared with placebo. Central systolic BP is primarily determined by arterial stiffness of the large arteries and, considering the published evidence that central systolic blood pressure is an important surrogate parameter of afterload and strongly linked to future cardiovascular outcomes,3,4 these novel data may serve to explain the beneficial effects of empagliflozin as previously observed in the EMPA-REG OUTCOME study.Whereas central systolic BP is the integral of various components of arterial stiffness, several other parameters of arterial stiffness have also been found to be significantly improved after empagliflozin treatment, such as central pulse pressure, forward pressure wave amplitude, and backward (or reflected) pulse wave amplitude. Central pulse pressure is superior in the prediction of cardiovascular events compared with measurements of pulse pressure at the brachial level, and both forward and backward wave amplitudes are associated with increased risk for incident cardiovascular disease and all-cause mortality, respectively, in large prospective trials.1,3,4In conclusion, our study demonstrates that empagliflozin exerts beneficial effects on central systolic BP, central pulse pressure, and various vascular parameters of aortic stiffness after 6 weeks of treatment under office and ambulatory conditions. Our data support the concept that empagliflozin exerts its beneficial effects on cardiovascular complications, in particular on heart failure events, at least in part via improved vascular function.Kristina Striepe, MDAgnes Jumar, MDChristian Ott, MDMarina V. Karg, MDMarkus P. Schneider, MDDennis Kannenkeril, MDRoland E. Schmieder, MDAcknowledgmentsThe authors gratefully acknowledge the expert technical assistance of Ortrun Alter, Dorothea Bader-Schmieder, Ingrid Fleischmann, Kerstin Fröhlich-Endres, Ulrike Heinritz, Susanne Muck, Simone Pejkovic, Sabine Thümmler, and Laura Waldmann, employees of the University Hospital Erlangen, Department of Nephrology and Hypertension.Sources of FundingThis investigator-initiated trial was supported by a research grant provided by Boehringer Ingelheim Pharma GmbH & Co. KG.DisclosuresDr Schmieder has received speaker and advisory board fees from Boehringer Ingelheim Pharma GmbH & Co. KG during the conduct of the study. The other authors report no conflicts of interest.FootnotesCirculation is available at http://circ.ahajournals.org.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02471963.Correspondence to: Roland E. 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Chiang C, Lin S, Lin T, Wang T, Yeh H, Chen J, Tsai C, Hung Y, Li Y, Liu P, Chang K, Wang K, Chao T, Shyu K, Yang W, Ueng K, Chu P, Yin W, Wu Y, Cheng H, Shin S, Huang C, Chuang L, Lin S, Yeh S, Sheu W and Lin J (2018) 2018 consensus of the Taiwan Society of Cardiology and the Diabetes Association of Republic of China (Taiwan) on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases, Journal of the Chinese Medical Association, 10.1016/j.jcma.2018.01.001, 81:3, (189-222), Online publication date: 1-Mar-2018. September 19, 2017Vol 136, Issue 12 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.029529PMID: 28923906 Originally publishedSeptember 19, 2017 Keywordspulse wave analysiscentral systolic pressureSGLT-2 inhibitortype 2 diabetes mellitusempagliflozinPDF download Advertisement SubjectsDiabetes, Type 2
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