Does SGLT1 Inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes?
2021; Lippincott Williams & Wilkins; Volume: 144; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.121.054442
ISSN1524-4539
AutoresBertram Pitt, Deepak L. Bhatt,
Tópico(s)Potassium and Related Disorders
ResumoHomeCirculationVol. 144, No. 1Does SGLT1 Inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBDoes SGLT1 Inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes? Bertram Pitt, MD and Deepak L. Bhatt, MD, MPH Bertram PittBertram Pitt University of Michigan, Ann Arbor (B.P.). and Deepak L. BhattDeepak L. Bhatt Correspondence to: Deepak L. Bhatt, MD, MPH, Brigham and Women's Hospital Heart and Vascular Center, 75 Francis St, Boston, MA 02115. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1278-6245 Brigham and Women's Hospital, Harvard Medical School, Boston, MA (D.L.B.). Originally published23 Apr 2021https://doi.org/10.1161/CIRCULATIONAHA.121.054442Circulation. 2021;144:4–6Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 23, 2021: Ahead of Print The SGLT2 (sodium-glucose cotransporter-2) inhibitors canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin have been shown to improve cardiac and cardiorenal outcomes in patients with—and in some cases without—type 2 diabetes (T2D) who have heart failure or chronic kidney disease.1 The mechanisms associated with their beneficial effects remain controversial. Although the effects of SGLT2 inhibitors on cardiac and cardiorenal outcomes in both patients with and without T2D are both statistically and clinically significant, recent data from the SOLOIST (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure)2 and SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk)3 trials with the dual SGLT1 (sodium-glucose cotransporter-1) and SGLT2 inhibitor sotagliflozin suggest that it may have important advantages compared with other SGLT2 inhibitors, at least in patients with T2D. Sotagliflozin provides greater inhibition of SGLT1 compared with all currently available SGLT2 inhibitors.SGLT2 is of primary importance for glucose reabsorption from the urinary filtrate, and SGLT1 is responsible for glucose absorption in the small intestine. In addition, SGLT1 is expressed in the distal proximal tubule where it contributes to glucose reabsorption, especially after SGLT2 inhibition, when tubular glucose concentrations are increased. A reduction in intestinal glucose absorption as a result of SGLT1 inhibition is associated with a sustained increase in circulating glucagon-like peptide-1 (GLP-1) and peptide YY.4 There may be advantages of SGLT1 inhibition in addition to its effects on glucose absorption. For example, heterozygosity for the missense variants in SLC5A1 (solute carrier family 5 member 1), which cause decreased SGLT1 function, was associated with decreased incidence of heart failure and death, as well as T2D.4 SGLT1 suppression is also linked to reductions in ventricular hypertrophy and myocardial fibrosis. These effects could further contribute to a reduction in heart failure, especially heart failure with preserved left ventricular function where both left ventricular hypertrophy and fibrosis are thought to play an important role.4 SGLT1 expression has been found to be elevated in patients with diabetes cardiomyopathy and in streptozotocin diabetes rats; inhibiting SGLT1 attenuates apoptosis and inhibits the development of diabetes cardiomyopathy. Therefore, SGLT1 inhibition might reduce the occurrence of heart failure independent of SGLT2 inhibition.The results of SOLOIST2 and SCORED3 suggest that additional SGLT1 inhibition on top of SGLT2 inhibition will impact cardiac and cardiorenal outcomes in ways similar to the SGLT2 inhibitors1—at least in patients with T2D. More so than with just SGLT2 inhibition, SGLT1 inhibition also reduces glucose and hemoglobin A1C levels in patients with an estimated glomerular filtration rate < 30 mL/(min·1.72 m2) to a similar degree as in those with an estimated glomerular filtration rate ≥ 30 mL/(min·1.72 m2).3 Thus, a relative increase in SGLT1 inhibition, such as that occurring with sotagliflozin, may have an advantage compared with currently available SGLT2 inhibitors in lowering hemoglobin A1C levels in patients with chronic kidney disease and preventing downstream microvascular complications of T2D.Furthermore, the relative increase in SGLT1 inhibition with sotagliflozin was associated with a significant reduction in total fatal and nonfatal myocardial infarction (MI; hazard ratio, 0.68 [95% CI, 0.52–0.89]; P=0.004) and total fatal and nonfatal stroke (hazard ratio, 0.66 [95% CI, 0.48–0.91]; P=0.012) in SCORED.3 Although it should be pointed out that the SCORED and SOLOIST trials were prematurely stopped and therefore may have overestimated the benefits of sotagliflozin, a meta-analysis by McGuire et al including EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes), CANVAS (Canagliflozin Cardiovascular Assessment Study), DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), CREDENCE (Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation), and VERTIS-CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) found that stroke was not reduced by the SGLT2 inhibitors (hazard ratio, 0.96; 95% CI, 0.87–1.07).1 Thus, in contrast to the currently available SGLT2 inhibitors, a relative increase in SGLT1 inhibition with sotagliflozin appears to provide protection against stroke across the spectrum of kidney function. In the meta-analysis by McGuire et al, the reduction in MI associated with the use of SGLT2 inhibitors was relatively modest (hazard ratio, 0.91; 95% CI, 0.84–0.99). DAPA-CKD (Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease) also demonstrated reduction in heart failure and kidney end points, although not in ischemic events.The explanation for the greater reduction in MI and stroke with sotagliflozin compared with the currently available SGLT2 inhibitors is uncertain but may relate to an SGLT1-induced increase in GLP-1,4 because an increase in native GLP-1 reduces thrombus formation at both venous and arterial flow shear rates.5 These findings are of potential importance because patients with T2D are prone to thrombosis and have an increased incidence of first and recurrent stroke, as well as a worse outcome after stroke, in comparison with patients without T2D. Although an increase in GLP-1 could explain, in part, the reduction of MI and stroke in SCORED, the level of GLP-1 increase associated with SGLT1 inhibition is relatively low in comparison with the GLP-1 receptor agonists; thus, there are likely effects of SGLT1 inhibition independent of an increase in GLP-1, because SGLT1 is expressed not only in the small intestines and kidneys, but also in other tissues, including the heart and brain (Figure).Download figureDownload PowerPointFigure. Sites of action of SGLT1 and SGLT2 inhibition in the kidneys, small intestines, heart, and brain. SGLT1 indicates sodium-glucose cotransporter-1; and SGLT2, sodium-glucose cotransporter-2.Adverse effects associated with the relatively greater degree of SGLT1 inhibition with sotagliflozin are mostly similar to those of the SGLT2 inhibitors. Both increase the risk of mycotic genital infections, lead to a small increase in incidence of diabetes ketoacidosis (often without hyperglycemia), and are associated with a transient hemodynamically mediated decrease in estimated glomerular filtration rate.1–3 The relative increase in SGLT1 inhibition, as anticipated from the effects of SGLT1 inhibition on intestinal glucose absorption, however, is associated with a 2.5% to 2.8% increase in diarrhea. Small but significant increases in volume depletion and hypotension were also noted.Thus, in addition to a reduction in hemoglobin A1C levels in patients with advanced kidney disease and T2D, the relative increase in SGLT1 inhibition with sotagliflozin may provide greater protection from MI and stroke than the currently available SGLT2 inhibitors that provide a lesser degree of SGLT1 inhibition. These observations suggest that dual SGLT1 and SGLT2 inhibition may provide an advantage over existent therapies in patients with T2D. The role of SGLT1 inhibition added to SGLT2 inhibition in patients without T2D will, however, require further prospective and comparative evaluation.Sources of FundingNone.Disclosures Dr Pitt served as co-chair of SOLOIST (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) and was on the executive committee of SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk), and received consulting fees from Sanofi/Lexicon. In addition, Dr Pitt discloses the following: consulting fees from Bayer, Astra Zeneca, Boehringer Ingelheim/Lilly, and Phasebio; consulting fees and stock options from SCPharmaceuticals, SQinnovations, G3pharmaceuticals, Relypsa/Vifor, Cereno scientific, KBP Pharmaceuticals, Sarfez, Tricida, Proton Intel, and Brainstorm Medical. Dr Pitt is chairman of the steering committee for the National Heart, Lung, and Blood Institute's TRANSFORM (Torsemide Comparison With Furosemide For Management of Heart Failure) trial and co-chair of SPIRRIT ([Spironolactone Initiation Registry Randomized Interventional Trial] from the National Heart, Lung, and Blood Institute–Swedish Heart Foundation). He holds US Patent No. 9931412 on site-specific delivery of eplerenone to the myocardium and has a pending US Patent (63/045,784) on histone acetylation–modulating agents for the treatment and protection of organ damage.Dr Bhatt served as the chair of SOLOIST and SCORED, with research funding from Sanofi and then Lexicon paid to Brigham and Women's Hospital. Dr Bhatt discloses the following relationships:– advisory board member for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, and Regado Biosciences; member of the Board of Directors for Boston Veteran Affairs Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair of the American Heart Association quality oversight committee; data monitoring committee member for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO [Portico Re-sheathable Transcatheter Aortic Valve System US IDE] trial, funded by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis], funded by Edwards), Contego Medical (Chair, PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE [Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation] trial, funded by Daiichi Sankyo), and Population Health Research Institute; Vice Chair, American College of Cardiology Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Atrial Fibrillation That Undergo a Percutaneous Coronary Intervention With Stenting] clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE [Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease] trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (Continuing Medical Education steering committees); Clinical Cardiology (Deputy Editor), NCDR-ACTION (National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network) Registry steering committee (Chair), Veterans Affairs Cardiovascular Assessment, Reporting, and Tracking research and publications committee (Chair); site co-investigator for Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), and Svelte; and trustee of the American College of Cardiology. Dr Bhatt also disclosures the following: honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News (https://www.acc.org); ; research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, MyoKardia, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); and unfunded research from FlowCo, Merck, and Takeda.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 6.https://www.ahajournals.org/journal/circCorrespondence to: Deepak L. Bhatt, MD, MPH, Brigham and Women's Hospital Heart and Vascular Center, 75 Francis St, Boston, MA 02115. Email [email protected]Harvard.eduReferences1. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, et al.. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis.JAMA Cardiol. 2021; 6:148–158. doi: 10.1001/jamacardio.2020.4511CrossrefMedlineGoogle Scholar2. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, et al.; SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure.N Engl J Med. 2021; 384:117–128. doi: 10.1056/NEJMoa2030183CrossrefMedlineGoogle Scholar3. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, et al.; SCORED Investigators. 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Chu Y, Zhang C and Xie M (2021) Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts, Frontiers in Aging, 10.3389/fragi.2021.681513, 2 Triposkiadis F, Xanthopoulos A, Bargiota A, Kitai T, Katsiki N, Farmakis D, Skoularigis J, Starling R and Iliodromitis E (2021) Diabetes Mellitus and Heart Failure, Journal of Clinical Medicine, 10.3390/jcm10163682, 10:16, (3682) July 6, 2021Vol 144, Issue 1Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.054442PMID: 33887961 Originally publishedApril 23, 2021 Keywordsmyocardial infarctionheart failurestrokediabetes mellitusPDF download Advertisement SubjectsDiabetes, Type 2Heart FailureMyocardial Infarction
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