More CREDENCE for SGLT2 Inhibition

HomeCirculationVol. 140, No. 18More CREDENCE for SGLT2 Inhibition Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBMore CREDENCE for SGLT2 Inhibition Subodh Verma, MD, PhD and Deepak L. Bhatt, MD, MPH Subodh VermaSubodh Verma Subodh Verma, MD, PhD, FRCSC Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, Canada, M5B 1W8. Email E-mail Address: [email protected] Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada (S.V.). and Deepak L. BhattDeepak L. Bhatt Brigham and Women's Hospital Heart & Vascular Center, Harvard Medical School, Boston, MA (D.L.B.). Originally published11 Jun 2019https://doi.org/10.1161/CIRCULATIONAHA.119.041181Circulation. 2019;140:1448–1450Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 11, 2019: Ahead of Print Although rates of ischemic complications in type 2 diabetes mellitus seem to be declining, some of the most feared and costly complications, namely end-stage kidney disease, heart failure, and lower limb amputations, remain on the rise. Herein, we discuss how the results from the CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy) trial may change this calculus.1The development of chronic kidney disease in type 2 diabetes mellitus marks the beginning of a sharp increase in cardio-renal complications.2 Indeed, in type 2 diabetes mellitus, chronic kidney disease is one of the strongest determinants of atherosclerotic vascular events and heart failure, with a hazard that parallels the degree/stage of kidney insufficiency. Thus, it is imperative that treatment goals of diabetic kidney disease (DKD) involve both kidney protection and cardiovascular risk reduction, particularly because many patients with DKD will have a cardiovascular event before developing end-stage kidney disease.Although DKD is a heterogeneous disease, the principles of treatment have uniformly involved glycemic control, inhibition of the renin-angiotensin-aldosterone system, and blood pressure reduction.3 Although tight glycemic control is associated with a slowing of DKD progression, the ongoing decline in estimated glomerular filtration rate (eGFR) presents a challenge with respect to the selection of antihyperglycemic agents. The incretin class of agents (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) have been studied in large cardiovascular outcome trials of patients with type 2 diabetes mellitus and increased cardio-renal risk, but short of a decrease in albuminuria, they have not shown any significant reductions in hard kidney outcomes.3 With respect to renin-angiotensin-aldosterone system blockers, seminal renoprotective data from the IDNT (Irbesartan Diabetic Nephropathy Trial) and RENAAL (Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan) trials showed kidney preservation with irbesartan and losartan, respectively, in patients with DKD. These benefits were believed to be independent of blood pressure lowering through favorable effects on renal hemodynamics. Although this was a big advance for the field, concerns around hyperkalemia and acute kidney injury arose, particularly in those with progressive decline in eGFR.3Sodium-glucose transport protein 2 inhibitors (SGLT2i), originally thought to be solely antihyperglycemic agents, have emerged as powerful therapies for cardio-renal protection in type 2 diabetes mellitus.4 Cumulative data from 3 cardiovascular outcome trials with empagliflozin, canagliflozin, and dapagliflozin demonstrated a large, consistent benefit on cardiovascular death and heart failure hospitalizations in people with type 2 diabetes mellitus and an eGFR>30 mL/min/1.73m2 (Table).4 This benefit was observed in patients with and without established atherosclerosis or heart failure, although the magnitude of heart failure hospitalization reduction seemed to be greater in those with a lower eGFR. Interestingly, these trials also demonstrated large declines in kidney end points, primarily related to preservation of eGFR, which were secondary outcomes. However, these trials did not recruit many patients who were at high renal risk, and the number of patients who developed end-stage renal disease was small, precluding any definitive recommendations. Indeed, only 29 primary renal replacement therapy events were recorded in the EMPA-REG OUTCOME (Empagliflozin Removal of Excess of Glucose Outcome) trial and the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Therefore, a dedicated renal trial was required to confirm these observations.Table. Key Details of the SGLT2i Type 2 Diabetes Mellitus Cardiovascular Outcome Trials and Renal Outcome TrialTrial (ClinicalTrials.gov Identifier)Key Entry CriteriaStudy GroupsNumber of Participants and Median Duration of Follow-UpPrimary Efficacy Outcome(s)Renal OutcomesCREDENCE(NCT02065791)Type 2 diabetes mellitus eGFR ≥30 mL/min/1.73 m2 UACR 300-5000 mg/gCanagliflozin 100 mg Placebo4401 2.6 yearsESKD*, doubling of serum creatinine, or death attributable to kidney or CV cause ↓30%Secondary renal efficacy outcome‡ ↓34%CANVAS Program(NCT01032629)Type 2 diabetes mellitus with or without ASCVD eGFR >30 mL/min/1.73 m2Canagliflozin 100 mg/300 mg Placebo10142 3.1 yearsCV death/myocardial infarction/stroke ↓14%Exploratory renal outcomes Albuminuria progression ↓27% Albuminuria regression ↑70% Renal composite: 40% reduction in eGFR, ESKD, or kidney-related death ↓40%DECLARE-TIMI 58(NCT01730534)Type 2 diabetes mellitus with or without ASCVD CrCl ≥60 mL/minDapagliflozin 10 mg Placebo17160 4.2 yearsCV death/myocardial infarction/stroke† ↓7% hHF/CV death† ↓17%Secondary renal efficacy outcome§ ↓24%Prespecified renal composite outcome‖ ↓47%EMPA-REG OUTCOME(NCT01131676)Type 2 diabetes mellitus with ASCVD eGFR ≥30 mL/min/1.73 m2Empagliflozin 10 mg/25 mg Placebo7020 2.4 yearsCV death/myocardial infarction/stroke ↓14%Prespecified renal microvascular outcomes Incident or worsening nephropathy# ↓39% Incident or worsening nephropathy# or CV death ↓39% Progression to macroalbuminuria ↓39% Doubling of serum creatinine ↓44% Renal-replacement therapy ↓55% Incident albuminuria ↓5%ASCVD indicates atherosclerotic cardiovascular disease; CrCl, creatinine clearance; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; hHF, hospitalization for heart failure; and UACR, urinary albumin to creatinine ratio.*Kidney replacement therapy or eGFR<15 mL/min/1.73m2.†Dual primary efficacy end points.‡ESKD, doubling of serum creatinine, or death attributable to kidney cause.§Decrease (≥40%) in eGFR to <60 mL/min/1.73 m2, new ESKD, or death from kidney or CV cause.‖Decrease (≥40%) in eGFR to <60 mL/min/1.73 m2, ESKD, or death from kidney cause.#Progression to macroalbuminuria, doubling of creatinine, initiation of renal-replace therapy, or death from kidney disease.CREDENCE, the first trial of an SGLT2i designed to primarily assess kidney outcomes, randomized 4401 patients with type 2 diabetes mellitus and albuminuric chronic kidney disease (eGFR 30–90 mL/min/1.73m2 and urine albumin-to-creatinine ratio 300–5000 mg/g) to canagliflozin 100 mg versus placebo, on top of standard of care, which included stable renin-angiotensin-aldosterone system blockade for at least 4 weeks before randomization (Table).1 Mean age of the participants was ≈63 years, type 2 diabetes mellitus duration ≈16 years, ≈50% with established cardiovascular disease, and ≈15% with heart failure. Mean eGFR was ≈56 mL/min/1.73m2 and median urine albumin-to-creatinine ratio ≈930 mg/g. The trial was stopped early after a median of 2.6 years on the recommendation of the independent data monitoring committee that determined the primary end point had been met. Specifically, the primary outcome which included a composite of end-stage kidney disease (kidney replacement therapy or eGFR<15 mL/min/1.73m2), doubling of serum creatinine, or death attributable to kidney or cardiovascular cause was reduced by 30% (hazard ratio [HR], 0.70 [95% CI, 0.59–0.82]; P=0.0001). Key kidney components of the primary outcome, namely end-stage kidney disease and doubling of serum creatinine, were reduced by 32% (P=0.002) and 40% (P<0.001), respectively. Cardiovascular death was reduced by 22% (HR, 0.78 [95% CI, 0.61–1.00]; P=0.05), heart failure hospitalization by 39% (P<0.001), and the composite of cardiovascular death and heart failure hospitalization by 31% (P<0.001). The results were consistent across the eGFR strata (30–45, 45–60, and 60–90 mL/min/1.73m2). The traditional cardiovascular death/myocardial infarction/stroke outcome was reduced by 20% (P=0.01). The eGFR deterioration was slower in those using canagliflozin versus placebo with a difference of approximately 2.74 mL/min/1.73m2 of decline per year. There was no significant difference in the incidence of amputation or fractures, although the incidences of diabetic ketoacidosis and genital infections, as expected, were higher. Acute kidney injury and hyperkalemia were numerically lower with canagliflozin.CREDENCE is a landmark trial that has the following implications: (1) The absolute benefit across the broad primary renocardio end point was large, with a number needed to treat over 2.6 years of 22; (2) The rates of lower limb amputations were similar in the canagliflozin and placebo study groups; (3) The mechanism of renal and cardiac benefits are likely multifactorial but unlikely related to a reduction in glucose; and (4) An SGLT2i should now be strongly considered as an add-on to renin-angiotensin-aldosterone system blockers in nonfrail patients with type 2 diabetes mellitus and albuminuric chronic kidney disease. The United States Food and Drug Administration has now given canagliflozin an indication to slow the progression of diabetic nephropathy and reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and diabetic kidney disease.Whether these therapies will be effective in cardiorenal protection even in people without diabetes is an important question. Indeed, the first trial of SGLT2 inhibition in patients with heart failure and reduced ejection fraction demonstrated similar efficacy of dapagliflozin on cardiovascular death and worsening heart failure in people with and without diabetes.5AcknowledgmentsThe authors thank H. Teoh, (St. Michael's Hospital, Toronto, ON, Canada) for editorial assistance.DisclosuresDr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, and Sun Pharmaceuticals. He is also the is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Bhatt discloses the following relationships - Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate 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-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), 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 Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circSubodh Verma, MD, PhD, FRCSC Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, Canada, M5B 1W8. Email Subodh.[email protected]toReferences1. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380:2295–2306. doi: 10.1056/NEJMoa1811744CrossrefMedlineGoogle Scholar2. Naylor KL, Kim SJ, McArthur E, Garg AX, McCallum MK, Knoll GA. Mortality in incident maintenance dialysis patients versus incident solid organ cancer patients: a population-based cohort.Am J Kidney Dis. 2019; 73:765–776. doi: 10.1053/j.ajkd.2018.12.011CrossrefMedlineGoogle Scholar3. Muskiet MHA, Wheeler DC, Heerspink HJL. New pharmacological strategies for protecting kidney function in type 2 diabetes.Lancet Diabetes Endocrinol. 2019; 7:397–412. doi: 10.1016/S2213-8587(18)30263-8CrossrefMedlineGoogle Scholar4. Connelly KA, Bhatt DL, Verma S. Can we DECLARE a victory against cardio-renal disease in diabetes?Cell Metab. 2018; 28:813–815. doi: 10.1016/j.cmet.2018.11.010CrossrefMedlineGoogle Scholar5. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction [published online ahead of print September 19, 2019].N Engl J Med. doi: 10.1056/NEJMoa1911303Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByConnelly K, Mazer C, Puar P, Teoh H, Wang C, Mason T, Akhavein F, Chang C, Liu M, Yang N, Chen W, Juan Y, Opingari E, Salyani Y, Barbour W, Pasricha A, Ahmed S, Kosmopoulos A, Verma R, Moroney M, Bakbak E, Krishnaraj A, Bhatt D, Butler J, Kosiborod M, Lam C, Hess D, Rizzi Coelho-Filho O, Lafreniere-Roula M, Thorpe K, Quan A, Leiter L, Yan A and Verma S (2022) Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial, Circulation, 147:4, (284-295), Online publication date: 24-Jan-2023. Cardoso R, Graffunder F, Ternes C, Fernandes A, Rocha A, Fernandes G and Bhatt D (2021) SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: A systematic review and meta-analysis, EClinicalMedicine, 10.1016/j.eclinm.2021.100933, 36, (100933), Online publication date: 1-Jun-2021. Paul S, Bhatt D and Montvida O (2020) The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study, European Heart Journal, 10.1093/eurheartj/ehaa956, 42:18, (1728-1738), Online publication date: 7-May-2021. Bhatt D, Szarek M, Pitt B, Cannon C, Leiter L, McGuire D, Lewis J, Riddle M, Inzucchi S, Kosiborod M, Cherney D, Dwyer J, Scirica B, Bailey C, Díaz R, Ray K, Udell J, Lopes R, Lapuerta P and Steg P (2021) Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease, New England Journal of Medicine, 10.1056/NEJMoa2030186, 384:2, (129-139), Online publication date: 14-Jan-2021. Bhatt D, Szarek M, Steg P, Cannon C, Leiter L, McGuire D, Lewis J, Riddle M, Voors A, Metra M, Lund L, Komajda M, Testani J, Wilcox C, Ponikowski P, Lopes R, Verma S, Lapuerta P and Pitt B (2021) Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure, New England Journal of Medicine, 10.1056/NEJMoa2030183, 384:2, (117-128), Online publication date: 14-Jan-2021. Verma S, Anker S, Butler J and Bhatt D (2020) Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST‐WHF in perspective, ESC Heart Failure, 10.1002/ehf2.13148, 7:6, (3261-3267), Online publication date: 1-Dec-2020. Verma S, Klug E, Mareev V, Kobalava Z, Connelly K, Arici M, Berwanger O, Santoso A, Mehta R, Meglis G and Kosiborod M (2020) Sodium–glucose cotransporter 2 inhibitors at the intersection of cardiovascular, renal and metabolic care: an integrated and multidisciplinary approach to patient-centered care, Current Opinion in Cardiology, 10.1097/HCO.0000000000000774, 35:5, (589-601), Online publication date: 1-Sep-2020. Triggle C, Ding H, Marei I, Anderson T and Hollenberg M (2020) Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease, Canadian Journal of Physiology and Pharmacology, 10.1139/cjpp-2019-0677, 98:7, (415-430), Online publication date: 1-Jul-2020. Bhatt D, Eikelboom J, Connolly S, Steg P, Anand S, Verma S, Branch K, Probstfield J, Bosch J, Shestakovska O, Szarek M, Maggioni A, Widimský P, Avezum A, Diaz R, Lewis B, Berkowitz S, Fox K, Ryden L, Yusuf S, Aboyans V, Alings M, Commerford P, Cook-Bruns N, Dagenais G, Dans A, Ertl G, Felix C, Guzik T, Hart R, Hori M, Kakkar A, Keltai K, Keltai M, Kim J, Lamy A, Lanas F, Liang Y, Liu L, Lonn E, Lopez-Jaramillo P, Metsarinne K, Moayyedi P, O'Donnell M, Parkhomenko A, Piegas L, Pogosova N, Sharma M, Stoerk S, Tonkin A, Torp-Pedersen C, Varigos J, Verhamme P, Vinereanu D, Yusoff K and Zhu J (2020) Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease, Circulation, 141:23, (1841-1854), Online publication date: 9-Jun-2020. Silva‐Cardoso J, Sheikh O, Nashawi M, Pham S, Gallegos K, Dinkha L and Chilton R (2019) Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials, Journal of Diabetes, 10.1111/1753-0407.13007, 12:4, (279-293), Online publication date: 1-Apr-2020. Mitrofanova A, Sosa M and Fornoni A (2019) Lipid mediators of insulin signaling in diabetic kidney disease, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00379.2019, 317:5, (F1241-F1252), Online publication date: 1-Nov-2019. October 29, 2019Vol 140, Issue 18 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.041181PMID: 31181959 Originally publishedJune 11, 2019 Keywordskidney failure, chronicdiabetes mellitusdiabetic nephropathiescardiovascular diseasesPDF download Advertisement SubjectsCardiorenal SyndromeClinical StudiesVascular Disease