Impact of SGLT2 Inhibitors (SGLT2i) on Cardiovascular (CV) Risk and Estimated Glomerular Filtration Rate (eGFR) in the EXSCEL Placebo Group
Authors: CLEGG LINDSAY , HEERSPINK HIDDO L. , PENLAND ROBERT C. , TANG WEIFENG , BOULTON DAVID W. , BACHINA SRINIVAS , FOX ROBERT D. , FENICI PETER , THURESSON MARCUS , MENTZ ROBERT J. , HERNANDEZ ADRIAN F. , ANGELYN BETHEL M. , HOLMAN RURY R. 
Published: June 2018

SGLT2i, empagliflozin and canagliflozin, have been shown to reduce the incidence of major adverse CV events (MACE), all-cause mortality (ACM) and renal events in CV outcomes trials (CVOTs), with robust real-world evidence (RWE) suggesting class effect benefits. In the exenatide CVOT EXSCEL, ∼10% of patients took an SGLT2i with ∼5% use of dapagliflozin (DAPA). Effects of all SGLT2i, and DAPA alone, on MACE, ACM, and eGFR were analyzed in EXSCEL participants randomized to placebo.
Propensity-matched cohorts (including by study visit) of SGLT2i users and non-users (n=709 per group) were generated, based on their last measured characteristics before SGLT2i initiation. Subsequent time-to-first adjudicated MACE and ACM were compared using a Cox regression. Decline in eGFR over time (slope) was quantified in the matched cohorts using a mixed model repeated measurement (MMRM) analysis.
SGLT2i overall, and DAPA alone, numerically decreased the MACE hazard ratio, and SGLT2i significantly reduced the ACM risk (Table). The eGFR slope was improved significantly for SGLT2i overall and DAPA alone (Table).
This post-hoc EXSCEL analysis supports a beneficial class effect for SGLT2i on MACE, ACM, and renal function, consistent with published CVOTs, Real-World data, and for DAPA alone. DECLARE, the ongoing DAPA CVOT, will complete in 2018.Time-to-First Adjudicated EventPropensity-matched cohortnEventsSubject-years of follow-upCrude rate (events/100 subject-years)Unadjusted hazard ratio (95% CI)Adjusted hazard ratio (95% CI)MACEaNo SGLT2i709449904.45SGLT2i709288223.410.78 (0.48–1.27)0.79 (0.49–1.28)No DAPA354224844.54DAPA354114082.690.59 (0.28–1.24)0.55 (0.26–1.15)All-cause mortalityNo SGLT2i7093711083.34SGLT2i709148711.610.48 (0.26–0.89)0.50 (0.27–0.95)No DAPA354135382.42DAPA35474321.620.66 (0.25–1.69)0.66 (0.25–1.72)MMRM analysisPropensity matched cohorteGFR slope (standard error)Treatment effect (95% CI)p-valueeGFR slope (mL/min/1.73m2/year) No SGLT2i−0.91 (0.26)SGLT2i+0.87 (0.37)+1.78 (0.87–2.69)0.00013No DAPA−1.04 (0.37)DAPA+1.24 (0.54)+2.28 (1.01–3.54)0.0004aMACE: a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke

Disclosure
L. Clegg: Employee; Self; AstraZeneca. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research & Development, Fresenius SE & Co. KGaA. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. W. Tang: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. S. Bachina: Employee; Self; AstraZeneca. R.D. Fox: None. P. Fenici: Employee; Self; AstraZeneca. M. Thuresson: Consultant; Self; AstraZeneca. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.