Sotagliflozin In Patients With Diabetes And Recent .
Sotagliflozin in Patients with Diabetes and RecentWorsening Heart Failure – The SOLOIST-WHF TrialDeepak L. Bhatt, MD, MPH, Michael Szarek, PhD, Ph. Gabriel Steg, MD,Christopher P. Cannon, MD, Lawrence A. Leiter, MD, Darren K. McGuire, MD, MHSc,Julia B. Lewis, MD, Matthew C. Riddle, MD, Adriaan A. Voors, MD, PhD,Marco Metra, MD, Lars H. Lund, MD, PhD, Michel Komajda, MD,Jeffrey M. Testani, MD, MTR, Christopher S. Wilcox MD, Piotr Ponikowski, MD,Renato D. Lopes, MD, PhD, Subodh Verma, MD, PhD, Pablo Lapuerta, MD,Bertram Pitt, MD, on Behalf of the SOLOIST-WHF Investigators
DisclosuresDr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier PracticeUpdate Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors:Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality OversightCommittee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for thePORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards),Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for theENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (SeniorAssociate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research(formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-IIexecutive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical andSurgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trialsteering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal ofInvasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinarycurriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute(for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer),Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care(Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION RegistrySteering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin,Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, FerringPharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Pfizer, PhaseBio,PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention:A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott),Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda.SOLOIST-WHF was initially sponsored by Sanofi and then by Lexicon.This presentation includes off-label and investigational uses of drugs.
The Evolution of SGLT2i in HF ManagementDiabetesDiabetes and No DiabetesWindow of opportunity for treatmentPre-clinical(subclinical) stageof the disease0 yearsClinical stageof the disease10 yearsCANVAS CLARE-TIMI 58Detectablecardiacinvolvement18-20 yearsDAPA-HFDELIVER HFpEFEMPEROR-PreservedEMPEROR-ReducedEMPA-REG OUTCOMEVERTIS CVHF Prevention HF TreatmentAdapted from Bhatt DL, Verma S, Braunwald E. Cell Metabolism. 2019;30:847-849.End-stageHeart Failure
The Evolution of SGLT2i in HF ManagementDiabetesDiabetes and No DiabetesWindow of opportunity for treatmentPre-clinical(subclinical) stageof the disease0 yearsClinical stageof the disease10 yearsCANVAS CLARE-TIMI 58EMPA-REG OUTCOMEDetectablecardiacinvolvement18-20 yearsDAPA-HFDELIVER RTIS CVHF Prevention HF TreatmentAdapted from Bhatt DL, Verma S, Braunwald E. Cell Metabolism. 2019;30:847-849.End-stageHeart FailureAcute HF?
SOLOIST-WHF: Addressing the Vulnerable Periodof an Admission for Worsening Heart FailureVerma S, Bhatt DL. 2020 (unpublished)
Diabetes Na -retentionHypervolemiaRAAS ActivationNeurohumoral ActivationInflammationIschemiaAltered Energetics SGLT2 InhibitorsConnelly KA, Bhatt DL, Verma S. Cell Metabolism. 2018;28:813-815.
Sotagliflozin: Dual SGLT1 and SGLT2 InhibitorSGLT2SGLT1 SGLT1 is the primary transporter forabsorption of glucose and galactose inthe GI tractPharmacologic inhibition by sotagliflozinis independent of insulin and does notdepend on kidney functionPotential effects on atherosclerotic risksSGLT1 SGLT2 is expressed in the kidney, whereit reabsorbs 90% of filtered glucosePharmacologic inhibition by sotagliflozinis independent of insulin but requireskidney function
Loss of funding during the onset of the COVID-19 pandemic Academic leadership did everything to ensure patient safetyand to honor the scientific contribution of the patientsBagiella E, Bhatt DL, Gaudino M. JACC 2020;76:342-345.
SOLOIST-WHF Study CommitteesExecutive CommitteeDeepak L. Bhatt, MD, MPH (Chair), Christopher P. Cannon, MD, Lawrence A. Leiter, MD, Julia B. Lewis, MD,Darren K. McGuire, MD, MHSc, Bertram Pitt, MD, Matthew C. Riddle, MD, Ph. Gabriel Steg, MDSteering CommitteeDeepak L. Bhatt MD, MPH (Chair), Michel Komajda, MD, Lars H. Lund, MD, PhD, Marco Metra MD,Bertram Pitt MD (Co-Chair), Piotr Ponikowski, MD, Jeffrey M. Testani, MD, MTR, Adriaan Voors, MD, PhD,Christopher Wilcox, MDData Monitoring CommitteeHertzel C. Gerstein, MD, MS (Chair), Gary S. Francis, MD, John E. Gerich, MD, Johannes F. E. Mann, MD,Weichung Joe Shih, PhD, James B. Young, MDTrial OperationsPhillip Banks, MS and Eshetu Tesfaye, PhD (Lexicon biostatistics and data management),Kenneth Kassler-Taub MD, Chris Warner, and Mark O’Neill (Lexicon clinical operations),Rosemary Molinari (Covance), Francesca Lawson, MD, Jean-Francois Tamby, MDAcademic StatisticianMichael Szarek, PhDBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
SOLOIST-WHF Study CommitteesNational CoordinatorsChristopher P. Cannon, Robert Mentz, Frank Peacock, and Barry Greenberg (United States), Subodh Vermaand Justin Ezekowitz (Canada), Stefan Janssens (Belgium), Jeroen Schaap (Netherlands), Andrew LawrenceClark (United Kingdom), Morten Schou (Denmark), Veli-Pekka Harjola (Finland), Lars H. Lund (Sweden),Andrejs Erglis (Latvia), Jelena Celutkiene (Lithuania), Jindrich Spinar (Czech Republic), Jan Murin (Slovakia),Béla Peter Merkely (Hungary), Jadwiga Maria Nessler (Poland), Hans-Dirk Dungen (Germany), Kurt Huber(Austria), Christian Eugen Muller (Switzerland), Nicolas Lamblin (France), Piergiuseppe Agostoni and MariaFrigerio (Italy), John Parissis (Greece), Gheorghe Andrei Dan (Romania), Maria Generosa Crespo-Leiro (Spain),Tuvia Ben-Gal (Israel), Cândida Fonseca (Portugal), Mehmet Birhan Yilmaz (Turkey), Olga Barbarash (Russia),José Carlos Nicolau (Brazil), Eduardo Roque Perna (Argentina), Ramon Luis Corbalan Herreros (Chile), KyuHyung Ryu (South Korea), Harvey D. White (Australia and New Zealand)Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Key Inclusion Criteria Admission with signs and symptoms of heart failureTreatment with intravenous diureticsStabilized, off oxygen, transitioning to oral diureticsBNP 150 pg/mL ( 450 pg/mL if atrial fibrillation) or NTproBNP 600 pg/mL ( 1800 pg/mL if atrial fibrillation) Type 2 diabetesBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Key Exclusion Criteria End-stage heart failure Recent ACS, stroke, PCI, or CABG eGFR 30 mL/min/1.73m2Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
CONSORT DiagramCountriesSitesScreenedN 154932306Screen Fails N 327Incl./Excl. criteria not met 289Death2Other36RandomizedN 1222 (79%)SotagliflozinN 608 (100%)(3 never received dose)Completed StudyN 588 (96.7%)PlaceboN 614 (100%)(3 never received dose)Completed StudyN 591 (96.3%)Early Discontinuation from StudyN 20 (3.3%)Early Discontinuation from StudyN 23 (3.7%)Exposed to treatment 80% of follow-upKnown vital statusActual vs. potential total follow-up time497 (81.7%)592 (97.4%)98.5%Exposed to treatment 80% of follow-upKnown vital statusActual vs. potential total follow-up time486 (79.2%)595 (96.9%)98.3%Bhatt DL, et al. NEJM. 2020.Median (Q1-Q3) follow up duration 9.0 (4.9-13.4) months, maximum 22.3 months
Baseline CharacteristicsSotagliflozin(N 608)Placebo(N 614)Age, years69 (63-76)70 (64-76)Female198 (32.6)214 (34.9)Geographic RegionEuropeAmericasRest of World399 (65.6)171 (28.1)38 (6.3)401 (65.3)175 (28.5)38 (6.2)LVEF, %35 (28-47)35 (28-45)eGFR, mL/min/1.73m249.2 (39.5-61.2)50.5 (40.5-64.6)NT-proBNP, pg/mL1817 (855-3659)1741 (843-3582)Any RAAS Inhibitor553 (91.0)563 (91.7)Any Glucose Lowering Medication522 (85.9)522 (85.0)First Dose Prior to Index Hospitalization Discharge290 (47.7)306 (49.8)Numbers in table are n (%) or median (Q1, Q3).Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Primary Efficacy: Total CV Death, HHF,and Urgent HF VisitBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Primary Efficacy: Total CV Death, HHF,and Urgent HF Visit – Significant by 28 DaysVery early effectSignificant by 28 Days:HR 0.61, P 0.035Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Total CV Death and HHFBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
First of CV Death or HHFBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Efficacy Testing HierarchySotagliflozinRate [Events]PlaceboRate [Events]HR (95% CI)P-valueTotal CV death, HHF, and urgent HF visit51.0 [245]76.3 [355]0.67 (0.52-0.85)0.0009Total HHF and urgent HF visit40.4 [194]63.9 [297]0.64 (0.49-0.83)0.0008CV death10.6 [51]12.5 [58]0.84 (0.58-1.22)0.36Total CV death, HHF, NFMI, and non-fatalstroke51.4 [247]71.0 [330]0.72 (0.56-0.92)0.008*Total CV death, HHF, urgent HF visit, andHF while hospitalized54.7 [263]80.6 [375]0.68 (0.54-0.86)0.001*All-cause death13.5 [65]16.3 [76]0.82 (0.59-1.14)0.23*Change in KCCQ-12 score, points17.713.64.1 (1.3-7.0)0.005*Change in eGFR, mL/min/1.73m2-0.34-0.18-0.16 (-1.30-0.98)0.78*Endpoint*Nominal p-value. Rate number of events per 100 patient-years. Values in table for change in KCCQ-12 score and changein eGFR are least squares means, difference in least squares means, and 95% CI for difference in least squares means
Adverse Events of Special InterestSotagliflozinN 605n (%)PlaceboN 611n (%)P-valueBone fractures12 (2.0)9 (1.5)0.52Diabetic ketoacidosis2 (0.3)4 (0.7)0.69Genital mycotic infections5 (0.8)1 (0.2)0.12Urinary tract infections52 (8.6)44 (7.2)0.40Volume depletion57 (9.4)54 (8.8)0.77Diarrhea42 (6.9)25 (4.1)0.032Pancreatitis03 (0.5)0.25Venous thrombotic events07 (1.1)0.015Malignancies4 (0.7)4 (0.7)1.00Adverse event leading to amputation4 (0.7)1 (0.2)0.22Severe hypoglycemia9 (1.5)2 (0.3)0.037Composite TermBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Improvement in KCCQ-12 to Month 4Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
Change in eGFROverallPrior to Week 4Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.After Week 4
Primary Efficacy SubgroupsEvents Per 100 pySubgroupPatientsSotagliflozin PlaceboHR (95% CI)OverallLVEF (%) 50 50Geographic RegionAmericasEuropeRest of WorldFirst Study Drug DoseBefore DischargeAfter DischargeSex122251.076.30.67 (0.52, 0.85)96625656.930.679.964.00.72 (0.56, 0.94)0.48 (0.27, 0.86)3468007668.344.148.4103.064.778.30.64 (0.43, 0.95)0.69 (0.50, 0.95)0.60 (0.23, 1.58)59662652.150.076.676.10.71 (0.51, 0.99)0.64 (0.45, 0.90)FemaleMaleAge (years) 65 6541281041.955.752.089.30.80 (0.51, 1.25)0.62 (0.47, 0.82)36485857.148.071.178.50.79 (0.51, 1.23)0.62 (0.47, 0.82)eGFR (ml/min/1.73m2) 60 6085436885.858.10.59 (0.44, 0.79)0.90 (0.58, 1.37)50.153.10.25Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.0.5Sotagliflozin Better12Placebo Better
Primary Efficacy SubgroupsEvents Per 100 pySubgroupPatientsSotagliflozin PlaceboHR (95% CI)OverallLVEF (%) 50 50Geographic RegionAmericasEuropeRest of WorldFirst Study Drug DoseBefore DischargeAfter DischargeSex122251.076.30.67 (0.52, 0.85)96625656.930.679.964.00.72 (0.56, 0.94)0.48 (0.27, 0.86)3468007668.344.148.4103.064.778.30.64 (0.43, 0.95)0.69 (0.50, 0.95)0.60 (0.23, 1.58)59662652.150.076.676.10.71 (0.51, 0.99)0.64 (0.45, 0.90)FemaleMaleAge (years) 65 6541281041.955.752.089.30.80 (0.51, 1.25)0.62 (0.47, 0.82)36485857.148.071.178.50.79 (0.51, 1.23)0.62 (0.47, 0.82)eGFR (ml/min/1.73m2) 60 6085436885.858.10.59 (0.44, 0.79)0.90 (0.58, 1.37)50.153.10.25Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.0.5Sotagliflozin Better12Placebo Better
Primary Efficacy SubgroupsEvents Per 100 pySubgroupPatientsSotagliflozin PlaceboHR (95% CI)OverallLVEF (%) 50 50Geographic RegionAmericasEuropeRest of WorldFirst Study Drug DoseBefore DischargeAfter DischargeSex122251.076.30.67 (0.52, 0.85)96625656.930.679.964.00.72 (0.56, 0.94)0.48 (0.27, 0.86)3468007668.344.148.4103.064.778.30.64 (0.43, 0.95)0.69 (0.50, 0.95)0.60 (0.23, 1.58)59662652.150.076.676.10.71 (0.51, 0.99)0.64 (0.45, 0.90)FemaleMaleAge (years) 65 6541281041.955.752.089.30.80 (0.51, 1.25)0.62 (0.47, 0.82)36485857.148.071.178.50.79 (0.51, 1.23)0.62 (0.47, 0.82)eGFR (ml/min/1.73m2) 60 6085436885.858.10.59 (0.44, 0.79)0.90 (0.58, 1.37)50.153.10.25Bhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.0.5Sotagliflozin Better12Placebo Better
LimitationsTrial was stopped early Nevertheless, robust reduction in primary endpoint Shortened duration limited the statistical power to seesignificant reductions in CV death or in kidney endpointsPrimary endpoint was changed while blinded to results However, original primary endpoint was also stronglypositiveInvestigator-reported events were used instead of adjudication Double-blind trial, with no reason to expect biasBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
ConclusionsIn patients with acute decompensated HF, sotagliflozinsignificantly reduced the composite of total CV deaths,hospitalizations for HF, and urgent HF visits by 33% With an early benefit that was significant by 1 month A Number Needed to Treat of only 4 patient-yearsWith careful patient selection and close monitoring, earlyinitiation of sotagliflozin was generally well tolerated (similar toplacebo) and safeThe benefits were consistent across subgroups, including: Initiation prior to or soon after hospital discharge In HF with reduced or preserved ejection fractionBhatt DL, Szarek M, Steg PG, et al., and Pitt B. N Engl J Med. 2020. Bhatt DL. AHA 2020, virtual.
A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. SOLOIST-WHF was initially sponsored by Sanofi and then by Lexicon.
Bruce W. Bode, MD, FACE Atlanta Diabetes Associates Atlanta, Georgia American Diabetes Association. Facts and Figures. Available at: http://www.diabetes.org/ada/facts.asp. Accessed January 18, 2000. Diagnosed Type 1 Diabetes 0.5 - 1.0 Million Diagnosed Type 2 Diabetes 10.3 Million Undiagnosed Diabetes 5.4 Million Prevalence of Diabetes in the US 3
Diabetes in the United States More than 29 million people in the U.S. have diabetes 8.1 million people with diabetes are undiagnosed 9.3% of the U.S. population 1.7 million Americans aged 20 years or older were newly diagnosed with diabetes in 2010 Every 19 seconds, someone is diagnosed with diabetes
Clinical Diabetes. 2017 Jan; 35(1)51-54. Speight J, Conn J, Dunning T, Skinner TC, Diabetes Australia. Diabetes Australia position statement. A new language for diabetes: improving communications with and about people with diabetes. Diabetes Res Clin Pract 2012 Sep; 97(3): 425- 31.
Type 2 Diabetes Type 2 diabetes, which used to be called adult-onset diabetes, can affect people at any age, even children. However, type 2 diabetes develops most often in middle-aged and older people. People who are overweight and inactive are also more likely to develop type 2 diabetes. Type 2 diabetes usually begins with insulin resistance—a
TABLE 57-3. Proposed Classification System for Diabetes in Pregnancy Gestational diabetes: diabetes diagnosed during pregnancy that is not clearly overt (type 1 or type 2) diabetes Type 1 Diabetes: Diabetes resulting from β-cell destruction, usually leading to absolute insulin deficiency a. Without vascular complications b.
diabetes distress in patients with type 2 diabetes. To find out the gender differences on diabetic self-care and diabetic distress in patients with type 2 diabetes. Hypotheses There is likely to be negative relationship between self-care and diabetes di
pre-diabetes that do not improve their diet and exercise levels are more likely to develop diabetes. Patients who take steps to improve their risk factors may be able to prevent pre-diabetes from developing into diabetes. In type 1 diabetes , which effects five to 10 percent of all Americans, the beta cells stop producing insulin. In
Diabetes Self-Management Education (DSME): The ongoing process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. Diabetes Self-Management Support (DSMS): Assist persons with diabetes in implementing and sustaining the behaviors to manage diabetes on an ongoing basis.
