Improvement in Cardiovascular Outcomes With Empagliflozin Is Independent of Glycemic Control
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 17 Linguagem: Inglês
10.1161/circulationaha.118.035759
ISSN1524-4539
AutoresSilvio E. Inzucchi, Mikhail Kosiborod, David Fitchett, Christoph Wanner, Uwe Hehnke, Stefan Kaspers, Jyothis T. George, Bernard Zinman,
Tópico(s)Diabetes Management and Research
ResumoHomeCirculationVol. 138, No. 17Improvement in Cardiovascular Outcomes With Empagliflozin Is Independent of Glycemic Control Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBImprovement in Cardiovascular Outcomes With Empagliflozin Is Independent of Glycemic Control Silvio E. Inzucchi, MD, Mikhail Kosiborod, MD, David Fitchett, MD, Christoph Wanner, MD, Uwe Hehnke, Dipl Stat, Stefan Kaspers, MD, Jyothis T. George, MBBS, PhD and Bernard Zinman, MD Silvio E. InzucchiSilvio E. Inzucchi Silvio E. Inzucchi, MD, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06520. Email E-mail Address: [email protected] Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.). , Mikhail KosiborodMikhail Kosiborod Saint Luke's Mid America Heart Institute, University of Missouri–Kansas City (M.K.). , David FitchettDavid Fitchett St Michael's Hospital, Division of Cardiology, University of Toronto, Canada (D.F.). , Christoph WannerChristoph Wanner Department of Medicine, Würzburg University Clinic, Germany (C.W.). , Uwe HehnkeUwe Hehnke Boehringer Ingelheim International GmbH, Germany (U.K., S.K., J.T.G.). , Stefan KaspersStefan Kaspers Boehringer Ingelheim International GmbH, Germany (U.K., S.K., J.T.G.). , Jyothis T. GeorgeJyothis T. George Boehringer Ingelheim International GmbH, Germany (U.K., S.K., J.T.G.). and Bernard ZinmanBernard Zinman Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Ontario, Canada (B.Z.). Originally published22 Oct 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035759Circulation. 2018;138:1904–1907Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes mellitus (T2DM).1 However, control of the major metabolic derangement of T2DM, hyperglycemia, as denoted by hemoglobin A1c (HbA1c), does not substantively impact its cardiovascular complications.2 In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) involving 7020 patients with T2DM and established CVD, the SGLT2 inhibitor empagliflozin reduced the risk of 3-point major adverse cardiovascular events (composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) by 14%.3 This effect was driven by a 38% reduction in cardiovascular death.3 Empagliflozin also reduced heart failure (HF) hospitalization by 35%.3 Until EMPA-REG OUTCOME, such cardiovascular benefits had not been demonstrated by any glucose-lowering agent, and the data led to a label indication for empagliflozin to reduce cardiovascular mortality.We have previously reported no heterogeneity in the cardiovascular effects of empagliflozin in subgroups by HbA1c < versus ≥8.5% at baseline.3,4 Building on this, we analyzed the risks of cardiovascular death, HF hospitalization, and the composite of HF hospitalization or cardiovascular death (1) in subgroups stratified by baseline HbA1c (<7%; 7% to <8%; 8% to <9%; ≥9%) and (2) after adjustment for HbA1c control (defined as <7.5%; yes/no) during the trial as a time-dependent factor. In the EMPA-REG OUTCOME trial, background glucose-lowering therapy was to remain unchanged for the first 12 weeks. We therefore also analyzed the risks of cardiovascular death, HF hospitalization, and HF hospitalization or cardiovascular death after week 12 in subgroups stratified by reduction in HbA1c from baseline to week 12 using 3 thresholds: (1) 0.5% (used by the American Diabetes Association and the European Association for the Study of Diabetes to categorize glucose-lowering efficacy as low versus intermediate); (2) 0.3% (the U.S. Food and Drug Administration definition for a minimal clinically meaningful reduction), and (3) the median reduction across all patients (0.4%). In subgroup analyses, P values were derived from tests of heterogeneity of treatment group differences without adjustment for multiple testing. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All patients provided written informed consent.The reductions in risks of cardiovascular death, HF hospitalization, and HF hospitalization or cardiovascular death with empagliflozin versus placebo were consistent across categories of baseline HbA1c (Figure). In analyses adjusted for HbA1c control at baseline and during the trial, the relative reductions were similar to those in the main analyses (Figure). At week 12, the median HbA1c reduction was 0.4% (placebo, 0.1%; empagliflozin, 0.6%). The benefits of empagliflozin on these outcomes were evident regardless of whether the reduction in HbA1c reached thresholds of 0.5%, 0.3%, or the median (Figure).Download figureDownload PowerPointFigure. Cardiovascular death (A), heart failure hospitalization (B), and heart failure hospitalization or cardiovascular death (C) by hemoglobin A1c (HbA1c; <7%, 7% to <8%, 8% to <9%, and ≥9%) at baseline, adjusted for time-dependent HbA1c control (HbA1c <7.5%) by change in HbA1c (reduction of ≥0.5% vs reduction of <0.5% or increase; reduction of ≥0.3% vs reduction of <0.3% or increase; reduction ≥median vs reduction <median) at week 12. Cox regression analyses in patients treated with ≥1 dose of study drug. Baseline HbA1c measurements were not available from 2 patients in the empagliflozin group. CI indicates confidence interval; and HR, hazard ratio.We conclude that the cardiovascular benefits of empagliflozin in the EMPA-REG OUTCOME trial occurred consistently across the spectrum of HbA1c subgroups. Our findings are consistent with a mediation analysis that suggested that changes in HbA1c played only a modest role in explaining the effects of empagliflozin on cardiovascular death.5 Collectively, these findings strongly suggest that glycemic control is not a significant effect modifier for the reduction in risks of cardiovascular death and HF hospitalization in this cohort.The relative importance of HbA1c as a surrogate for CVD prevention in patients with T2DM is a matter of debate. Large randomized, clinical trials have demonstrated that maintaining HbA1c close to normal reduces the long-term risks of microvascular complications, but has a largely neutral effect on cardiovascular risk, particularly in those with established CVD. However, in patients achieving improved glycemic control early in the course of T1DM (DCCT [Diabetes Control and Complications Trial]) or T2DM (UKPDS [United Kingdom Prospective Diabetes Study]), long-term cardiovascular risk appears to be improved. Our findings, however, support the notion that HbA1c is a poor proxy for CVD risk in patients with T2DM and prevalent CVD. They also suggest that HbA1c may not be an important factor in selecting patients most likely to derive a cardiovascular benefit from empagliflozin. Our analysis based on HbA1c change at week 12 could be the most meaningful to clinicians, because this reflects the usual timing of first reassessment of glycemic control in clinical practice. No significant relationship was found between the HbA1c change detected at this juncture and subsequent cardiovascular events. Therefore, from the perspective of cardioprotection, it might be reasonable to continue empagliflozin, irrespective of the initial HbA1c response to treatment.Our data also inform the discussion pertaining to treatment guidelines. Traditionally, recommendations from professional associations have focused almost entirely on HbA1c reduction (mainly to prevent microvascular complications). So, it is classically advised that glucose-lowering agents be added in sequence until target HbA1c (typically <7%) is achieved. However, our findings show that the cardiovascular benefits of empagliflozin are not conditional on HbA1c levels. Indeed, they were observed even in patients with HbA1c <7% at baseline, albeit based on a small number of patients. This supports the evolution of guidelines, such as the recent American Diabetes Association recommendations, supporting an approach where patients at high cardiovascular risk follow a distinct pathway.In summary, the benefits of empagliflozin on the risks of cardiovascular death and HF hospitalization were consistent irrespective of HbA1c before and during therapy. These data add to a growing body of evidence demonstrating only a minor impact of glycemic control on cardiovascular complications in patients with T2DM and established CVD.AcknowledgmentsMedical writing assistance, supported financially by Boehringer Ingelheim, was provided by Elizabeth Ng and Wendy Morris of FleishmanHillard Fishburn, London, United Kingdom, during the preparation of this article. The authors were fully responsible for all content and editorial decisions and were involved at all stages of manuscript development and have approved the final version.Sources of FundingThe EMPA-REG OUTCOME trial was sponsored by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.DisclosuresDr Inzucchi reports honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Janssen, Novo Nordisk, Sanofi/Lexicon, and VTV Therapeutics (modest) and Intarcia (significant). Dr Kosiborod reports research grants from AstraZeneca and Boehringer Ingelheim (significant), honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Sanofi, Merck (Diabetes), Novo Nordisk, Amgen, Eisai (significant), and GSK, Intarcia, and Glytec (modest). Dr Fitchett reports honoraria from Sanofi, Merck & Co, Amgen, AstraZeneca, Eli Lilly and Company (modest) and Boehringer Ingelheim (significant). Dr Wanner reports honoraria from Boehringer Ingelheim, Janssen, Lilly and Mitsubishi (modest). U. Hehnke, Dr Kaspers, and Dr George are used by Boehringer Ingelheim. Dr Zinman has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk (significant), honoraria from Janssen, Sanofi, and Eli Lilly and Company (modest), and honoraria from Boehringer Ingelheim, Novo Nordisk, and Merck (significant).FootnotesData sharing: The data that support the findings of this analysis are available from the corresponding author upon reasonable request.https://www.ahajournals.org/journal/circSilvio E. Inzucchi, MD, Section of Endocrinology, Yale University School of Medicine, New Haven, CT 06520. Email silvio.[email protected]eduReferences1. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J; Emerging Risk Factors Collaboration. 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