Consistency Breeds Confidence: The Continuing Story of SGLT2 Inhibitors

HomeCirculationVol. 147, No. 8Consistency Breeds Confidence: The Continuing Story of SGLT2 Inhibitors Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBConsistency Breeds Confidence: The Continuing Story of SGLT2 Inhibitors Ileana L. Piña Ileana L. PiñaIleana L. Piña Correspondence to: Ileana L. Piña, MD, MPH, Thomas Jefferson University, 925 Chestnut St, Third Floor, Philadelphia, PA 19107. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4986-7129 Sydney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, PA. Search for more papers by this author Originally published20 Feb 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063451Circulation. 2023;147:635–637This article is a commentary on the followingSex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVERRecently, clinical trialists have analyzed and reported sex differences related to the efficacy and safety of medications for heart failure (HF). The overall effects appear usually favorable in these trials. What, then, accounts for this recent increase on reporting by sex?Article, see p 624To answer this question, it is valuable to do a brief review on the status of reporting drug effects in women and the level of our knowledge on specifics of HF therapy in women. Although early HF randomized controlled trials (RCT) included a limited number of women (average 20%), analyses by sex were often an afterthought, not planned a priori, and recruitment of women was neither prospectively planned nor encouraged, and was therefore limited.1–5 Consequently, our earlier HF trials primarily represent White men, with limited enrollment and participation of both women and racially diverse populations, and we therefore had automatically extrapolated findings of therapies on White men to women, as well as to all races and ethnicities. Forest plots commonly had wide CIs indicative of the small number of women and, other than generating some hypotheses, not much else was reported or explored. Furthermore, such analyses among women were post hoc and without the weight needed to change guidelines and/or society recommendations. An example of this post hoc analysis is the meta-analysis of angiotensin-converting enzyme inhibitors which shows a beneficial trend for women that is clothed in uncertainty because of the small populations and wide CIs.6Recognizing the lack of data on women with specific diagnoses (eg, HF), the National Institutes of Health Revitalization Act of 1993 directed the inclusion of women participants in all National Institutes of Health–sponsored projects. Additionally, the Act specified that trials be designed and carried out with the goal of providing “valid analysis to determine whether the variables being studied[...] affect women or members of minority groups.”7 In 2001, policy updates were established in “Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research.” In spite of the National Institutes of Health’s recommendations, the pharmaceutical industry did not necessarily endorse these policy updates or adopt guidelines regarding the inclusion of women in their RCTs. The figure depicts a selection of HFrEF and HFpEF trials that have contributed to guidelines. As expected, there is a greater number of women in HFpEF trials involving the same drug (dapagliflozin) and target dose (10 mg daily),9–12 which supports the combined data-level analysis by Wang et al.8Download figureDownload PowerPointFigure. Heart failure with reduced ejection fraction and heart failure with preserved ejection fraction trials.1-6, 9-13 CHARM indicates Effects of Candesartan in Patients with Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DELIVER, Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age; EF, ejection fraction; EMPEROR Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; LVEF, left ventricular ejection fraction; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; PARAGON-HF, Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction; RALES, Randomized Aldactone Evaluation Study; RCT, randomized controlled trial; SOLVD, Studies of Left Ventricular Dysfunction; and TOPCAT, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist. Adapted from Hsich and Piña with permission. Copyright © 2009, Journal of the American College of Cardiology.6In the last 10 years, there has been increased clinician-led efforts to include more women into RCTs and to plan for the recruitment of women in sufficient numbers such that prespecified subgroup analyses by sex have sufficient statistical power. Recent studies give rise to the idea that remodeling may differ by left ventricular ejection fraction and that women may respond better to neurohormonal blockade than men. One such trial was PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction), which did not meet its primary endpoint but did show that women benefited to a greater degree in a hypothesis-generating secondary analysis.13 All of these efforts should result in a better research platform from which sex differences in HF can be explored, our knowledge of HF in women can be increased, and therapies having greater statistical certainty can be applied.In this issue of Circulation, the dapagliflozin investigator group reports on a large number of patients (11 007) using the combined datasets of the HFrEF and HFpEF RCTs, DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age), respectively.4,8,12 This type of analysis takes advantage of the increased prevalence of HFpEF in women—historically, a greater number of women were recruited for RCTs with EFs >40 (eg,TOPCAT [(Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) 51%], CHARM Preserved [40%], PARAGON-HF [51%])—as well as the administration of one agent in a class of drugs that is EF agnostic. Thus SGLT2i, as a class effect, (including HFmrEF, and HF with improved EF, as a continuation of GDMT) has been recommended by the American Heart Association/American College of Cardiologists/Heart Failure Society of America Guidelines.14 American College of Cardiologists Guidelines.14 The combined analysis allows for a 40 000-foot perspective stratified by sex and EF groups. A similar analysis has been published about empagliflozin, showing consistent effects in women across the range of EFs.15 Sex did not influence response to empagliflozin, just as it did not influence response to dapagliflozin. This consistency further enhances our data with these agents and adds support to the AHA/ACC/HFSA Guidelines, indicating a class effect of SGLT2 inhibitors in both HFrEF and HFpEF.Certainly, the results should be comforting and reassuring to female patients that benefits of dapagliflozin have been explored in women and men and sex did not modify the effect of dapagliflozin on outcomes. In addition, lower rates of cardiovascular mortality in women were replicated in this analysis once again.8 The safety of dapagliflozin is similar between men and women whether assessed by the overall rate of adverse events or by drug discontinuation attributable to adverse events.Beyond the trial outcomes, the investigator group should be congratulated on the expansive data tables provided in the Supplemental Material which present interesting and important EF- and sex-related observations. We are hence offered a landscape that is both interesting and consistent with previous literature and includes the presence of comorbidities, levels of biomarkers and renal function, and dimensions of health-related quality of life.Noted by others, female patients often present to the clinical care team at baseline with worse symptoms, more advanced disease state, and lower health status than their male counterparts. The difference in men’s and women’s Kansas City Cardiomyopathy Questionnaire scores remains unchanged across the range of EFs, with women having lower scores than men, although improvements after taking the drug are similar. Gaps are also noted in angiotensin-converting enzyme inhibitor therapy between men and women with EFs <40%—and in particularly, EFs <30%—although the gap is partly accounted for because of the use of angiotensin receptor blockers. The use of angiotensin receptor/neprilysin inhibitors is also lower in women throughout most EF levels, and particularly with EFs >60%, perhaps reflecting the results of the PARAGON-HF trial in those upper EF levels. Another significant difference is noted in the use of cardiac resynchronization therapy or implantable cardiac defibrillators, especially for EFs <40%. Notably, women respond better to cardiac resynchronization therapy and at a narrower QRS.In summary, the pooled analysis of patient-level data from Wang et al8 enhances our knowledge of how women respond to dapagliflozin across the spectrum of EFs. The authors carefully describe their complex analysis, with this description potentially serving as a model for future investigative reports.Although an excellent analysis and publication, the paucity of Black patients represents a significant limitation in the dataset. Black patients with HF present at younger ages, have higher rates of hospitalizations and need to be recruited and included in future trials. It is conceivable that investigators will take this observation as a challenge to expand research on SGLT2 (sodium-glucose cotransporter-2) inhibitors to a more racially diverse population that has high incidence and prevalence of HF with persistent risk of mortality.Article InformationDisclosures Dr Piña serves on the advisory boards for Astra Zeneca and Boehringer Ingelheim.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 637.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Ileana L. Piña, MD, MPH, Thomas Jefferson University, 925 Chestnut St, Third Floor, Philadelphia, PA 19107. Email ilppina@aol.comReferences1. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991; 325:293–302. doi: 10.1056/NEJM199108013250501CrossrefMedlineGoogle Scholar2. 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Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction.Eur Heart J. 2022; 43:416–426. doi: 10.1093/eurheartj/ehab798CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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