Gradient of Risk and Associations With Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney Function
2020; Lippincott Williams & Wilkins; Volume: 143; Issue: 6 Linguagem: Inglês
10.1161/circulationaha.120.051901
ISSN1524-4539
AutoresDavid Z.I. Cherney, Darren K. McGuire, B Charbonnel, Francesco Cosentino, Richard E. Pratley, Samuel Dagogo‐Jack, Robert Frederich, Mario Maldonado, Jie Liu, Annpey Pong, Chih‐Chin Liu, Christopher P. Cannon,
Tópico(s)Diabetes Management and Research
ResumoHomeCirculationVol. 143, No. 6Gradient of Risk and Associations With Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney Function Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBGradient of Risk and Associations With Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney FunctionObservations From VERTIS CV David Z.I. Cherney, MD, PhD, Darren K. McGuire, MD, MHSc, Bernard Charbonnel, MD, Francesco Cosentino, MD, PhD, Richard Pratley, MD, Samuel Dagogo-Jack, MD, DSc, Robert Frederich, MD, Mario Maldonado, MD, Jie Liu, MD, PhD, Annpey Pong, PhD, Chih-Chin Liu, PhD, Christopher P. Cannon, MD and On behalf of the VERTIS CV Investigators David Z.I. CherneyDavid Z.I. Cherney Dr David Z.I. Cherney, Division of Nephrology, University of Toronto, Toronto General Hospital, 585 University Avenue, 8N-845, Toronto, Ontario, M5G 2N2, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4164-0429 Division of Nephrology, University of Toronto, Canada (D.Z.I.C.). , Darren K. McGuireDarren K. McGuire https://orcid.org/0000-0002-6412-7989 Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, and Parkland Health and Hospital System, Dallas (D.K.M.). , Bernard CharbonnelBernard Charbonnel Department of Endocrinology and Diabetes, University of Nantes, France (B.C.). , Francesco CosentinoFrancesco Cosentino https://orcid.org/0000-0002-6967-5685 Unit of Cardiology, Karolinska Institute and Karolinska University Hospital Solna, Stockholm, Sweden (F.C.). , Richard PratleyRichard Pratley https://orcid.org/0000-0002-2912-1389 AdventHealth Translational Research Institute, Orlando, FL (R.P.). , Samuel Dagogo-JackSamuel Dagogo-Jack Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis (S.D.-J.). , Robert FrederichRobert Frederich Research and Development, Pfizer Inc, Collegeville, PA (R.F.). , Mario MaldonadoMario Maldonado Diabetes and Endocrinology, MSD Limited, London, United Kingdom (M.M.). , Jie LiuJie Liu Diabetes and Endocrinology (J.L.), Merck & Co., Inc., Kenilworth, NJ. , Annpey PongAnnpey Pong Biostatistics (A.P., C.-C.L.), Merck & Co., Inc., Kenilworth, NJ. , Chih-Chin LiuChih-Chin Liu Biostatistics (A.P., C.-C.L.), Merck & Co., Inc., Kenilworth, NJ. , Christopher P. CannonChristopher P. Cannon Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.P.C.). and On behalf of the VERTIS CV Investigators Originally published13 Nov 2020https://doi.org/10.1161/CIRCULATIONAHA.120.051901Circulation. 2021;143:602–605Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 13, 2020: Ahead of Print SGLT2 (sodium-glucose cotransporter-2) inhibitors reduce the risk of cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus (T2DM) with or without established cardiovascular or kidney disease.1,2 Decreases in the urine albumin-to-creatinine ratio (UACR) after SGLT2 inhibition are associated with a lower risk of major adverse cardiovascular events and kidney outcomes.3 Despite the prognostic importance of kidney disease for cardiovascular outcomes, patients with T2DM are rarely risk-stratified by kidney measures in cardiology practice, with these measures being absent from commonly used cardiovascular risk prediction algorithms.We report results from prespecified exploratory analyses from the VERTIS CV study (Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease; URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881), assessing effects of ertugliflozin on cardiovascular events by baseline kidney function (estimated glomerular filtration rate [eGFR] and chronic kidney disease [CKD] stage), UACR, and Kidney Disease Improving Global Outcomes CKD risk category (KDIGO CKD), which combines eGFR and UACR to assess the risk for CKD progression. Analyses include testing of treatment group-by-subgroup interactions without adjustment for multiple testing.VERTIS CV primary results have been published.4 The study was conducted in accordance with principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. Informed consent was obtained from all individuals. In VERTIS CV, 8246 patients were randomized to placebo (n=2747) or ertugliflozin (n=5499; 5- and 15-mg doses). In this analysis of the intention-to-treat population, cardiovascular-related outcomes included time to first major adverse cardiovascular event, hospitalization for heart failure (HHF), cardiovascular death, and a composite of HHF or cardiovascular death.The proportions of patients with CKD stages 1, 2, and 3 at baseline were 25%, 53%, and 22%, respectively. A total of 60% and 40% of patients had normal and elevated albuminuria, respectively. A total of 49%, 32%, and 19% were classified into the KDIGO CKD low, moderate, and high/very high risk categories, respectively.Event rates were higher for all reported cardiovascular outcomes with more advanced kidney disease (Table). Interactions were suggested for UACR and KDIGO CKD classifications by treatment for the composite of HHF/cardiovascular death and for HHF (P<0.05). A similar trend was observed in subgroups by CKD stage for HHF, but the interaction was not significant. Risk reductions with ertugliflozin versus placebo achieved nominal significance for HHF and the composite of HHF/cardiovascular death in the CKD stage 3 subgroup, in patients with elevated albuminuria, and in the KDIGO CKD moderate and high/very high risk categories, with the highest absolute event rate reductions in these subgroups. Absolute event rate differences (per 1000 patient-years) and relative risk reductions with ertugliflozin for HHF and for a composite of HHF/cardiovascular death were highest in the CKD stage 3, KDIGO CKD moderate risk, high/very high risk, and elevated albuminuria subgroups.Table. Cox Proportional Hazards for Cardiovascular Outcomes, by Baseline Kidney Function CategoriesEnd pointSubgroup categoryPlacebo, number of events (incidence)Ertugliflozin, number of events (incidence)Absolute event rate reduction (per 1000 p-y)Hazard ratio (95% CI)P value for interactionMACEAll patients368 (40.3)735 (40.0)−0.30.99 (0.88, 1.12)—CKD stage 172 (31.2)135 (28.7)−2.50.92 (0.69, 1.22)0.58CKD stage 2193 (39.7)380 (38.5)−1.20.97 (0.82, 1.16)CKD stage 3103 (52.8)220 (58.0)5.21.10 (0.87, 1.39)Normoalbuminuria169 (31.1)344 (31.8)0.71.02 (0.85, 1.23)0.66Elevated albuminuria193 (55.6)375 (53.6)−2.00.96 (0.81, 1.15)KDIGO low risk130 (29.0)254 (28.4)−0.60.98 (0.79, 1.21)0.99KDIGO moderate risk125 (44.7)256 (44.7)0.01.00 (0.81, 1.24)KDIGO high/very high risk107 (66.0)208 (65.4)−0.60.99 (0.79, 1.25)Hospitalization for heart failure and cardiovascular deathAll patients250 (26.6)444 (23.4)−3.20.88 (0.75, 1.03)—CKD stage 132 (13.3)81 (16.9)3.61.27 (0.84, 1.91)0.13CKD stage 2126 (25.0)222 (21.8)−3.20.87 (0.70, 1.08)CKD stage 392 (46.5)141 (35.6)−10.90.76 (0.59, 1.00*)Normoalbuminuria83 (14.8)190 (17.1)2.31.16 (0.89, 1.50)0.01Elevated albuminuria163 (45.8)244 (33.5)−12.30.73 (0.60, 0.89)KDIGO low risk57 (12.3)139 (15.2)2.91.24 (0.91, 1.68)0.03KDIGO moderate risk88 (30.3)138 (23.1)−7.20.76 (0.58, 0.99)KDIGO high/very high risk100 (61.1)155 (47.0)−14.10.77 (0.60, 0.99)Cardiovascular deathAll patients184 (19.0)341 (17.6)−1.40.92 (0.77, 1.11)—CKD stage 126 (10.7)68 (13.9)3.21.30 (0.83, 2.05)0.26CKD stage 294 (18.2)162 (15.5)−2.70.85 (0.66, 1.10)CKD stage 364 (30.8)111 (27.1)−3.70.88 (0.64, 1.19)Normoalbuminuria72 (12.6)155 (13.7)1.11.08 (0.82, 1.43)0.13Elevated albuminuria110 (29.4)180 (24.0)−5.40.81 (0.64, 1.03)KDIGO low risk50 (10.6)109 (11.7)1.11.10 (0.79, 1.54)0.44KDIGO moderate risk63 (21.0)113 (18.5)−2.50.88 (0.65, 1.20)KDIGO high/very high risk68 (38.8)111 (32.2)−6.60.83 (0.61, 1.12)Hospitalization for heart failureAll patients99 (10.5)139 (7.3)−3.20.70 (0.54, 0.90)—CKD stage 17 (2.9)19 (4.0)1.11.36 (0.57, 3.23)0.08CKD stage 247 (9.4)75 (7.4)−2.00.79 (0.55, 1.13)CKD stage 345 (22.7)45 (11.4)−11.30.50 (0.33, 0.76)Normoalbuminuria23 (4.1)51 (4.6)0.51.12 (0.69, 1.83)0.02Elevated albuminuria74 (20.8)83 (11.4)−9.40.55 (0.40, 0.75)KDIGO low risk14 (3.0)38 (4.2)1.21.38 (0.75, 2.54)0.03KDIGO moderate risk33 (11.3)34 (5.7)−5.60.50 (0.31, 0.81)KDIGO high/very high risk50 (30.6)62 (18.8)−11.80.61 (0.42, 0.89)The 3 baseline kidney function classification schemes were as follows: (1) estimated glomerular filtration rate (eGFR) categories: chronic kidney disease (CKD) stage 1 (eGFR ≥90 mL/min/1.73 m2), CKD stage 2 (eGFR ≥60 and <90 mL/min/1.73 m2), and CKD stage 3 (eGFR <60 mL/min/1.73 m2); (2) Kidney Disease Improving Global Outcomes (KDIGO) CKD risk category: low risk (eGFR ≥60 mL/min/1.73 m2 with urine albumin-to-creatinine ratio [UACR] <30 mg/g), moderate risk (eGFR 45 to <60 mL/min/1.73 m2 with UACR 300 mg/g or eGFR 45 to 59 mL/min/1.73 m2 and UACR >30 mg/g or eGFR <45 mL/min/1.73 m2); (3) albuminuria category: normal (UACR <30 mg/g) or elevated (UACR ≥30 mg/g) albuminuria. MACE indicates major adverse cardiovascular events (composite of first event of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke); and p-y, patient-years.* Upper 95% CI = 0.995. All analyses were performed on the intention-to-treat population.Determination of cardiovascular risk is achieved using risk prediction algorithms complemented by biomarkers. Creatinine-based estimates of glomerular filtration rate are also recognized as a cardiovascular risk factor, particularly for HHF. UACR measurements are part of guideline-based clinical practice recommendations for diabetic kidney disease screening and also a predictor of cardiorenal risk and clinical responses to treatments such as SGLT2 inhibitors.3 The routine use of UACR testing in patients with T2DM in general practice remains low and UACR testing is not part of standard care in cardiology practice. These results support the importance of risk stratifying by both eGFR and albuminuria status, such as by the KDIGO CKD risk classification.The effect of ertugliflozin on HHF and the composite of HHF/cardiovascular death differed on the basis of the severity of kidney disease using classifications that included UACR. The presence of significant interactions for both the KDIGO CKD and UACR classifications suggests greater benefits in patients with higher risk profiles on the basis of kidney measures for HHF and HHF/cardiovascular death. Owing to small sample sizes and low numbers of events in some subgroups, interpretability of results for these subgroups is limited, and assessment of within-subgroup statistical significance was not the aim of the analyses. The low number of events deserves emphasis, especially in lower risk subgroups, such as eGFR ≥90 mL/min/1.73 m2, which were considered separately in this analysis, rather than being included in the eGFR ≥60 mL/min/1.73 m2 group, which showed significant interaction for the eGFR <60 mL/min/1.73 m2 group with respect to reduction of HHF events.5 Further exploration of the association between cardiovascular disease, CKD, and SGLT2 inhibition is warranted in dedicated kidney disease cohorts.In patients with T2DM and atherosclerotic cardiovascular disease, ertugliflozin reduced the risk of HHF, with greater relative risk reductions and absolute event rate reductions in patients in the KDIGO CKD moderate and high/very high risk categories and with elevated albuminuria at baseline. These results highlight the potential value of stratifying kidney disease risk by both UACR and measures of kidney function in patients with T2DM to predict cardiovascular risk and response to ertugliflozin.AcknowledgmentsEditorial support was provided by Moamen Hammad, PhD, MPharm, of Scion, and was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, in collaboration with Pfizer Inc., New York, NY.Sources of FundingThis study was sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, in collaboration with Pfizer Inc, New York, NY.Disclosures Dr Cherney has received consulting fees or speaking honorarium, or both, from Bristol Myers Squibb, Novo Nordisk, Mitsubishis-Tanabe, Maze, Janssen, Bayer, Boehringer Ingelheim–Eli Lilly, AstraZeneca, Merck & Co., Inc., Prometic, and Sanofi, and has received operating funds from Janssen, Boehringer Ingelheim–Eli Lilly, Sanofi, AstraZeneca, and Merck & Co., Inc. Dr McGuire has had leadership roles in clinical trials for AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co., Inc., Novo Nordisk, CSL Behring, and Sanofi USA, and has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly USA, Merck & Co., Inc., Pfizer, Novo Nordisk, Metavant, Afimmune, and Sanofi. Dr Charbonnel has received fees for advisory boards from AstraZeneca, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, Novo-Nordisk, Sanofi, and Servier; and speaker bureau: AstraZeneca, Eli Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, NovoNordisk, Sanofi, and Takeda. Dr Cosentino has received fees from Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, Novo Nordisk, and Pfizer, as well as research grants from Swedish Research Council, Swedish Heart & Lung Foundation, and the King Gustav V and Queen Victoria Foundation. Dr Pratley has received the following (directed to his institution): speaker fees from Novo Nordisk; consulting fees from Merck & Co., Inc., Novo Nordisk, Pfizer, Sanofi, Scohia Pharma Inc, and Sun Pharmaceutical Industries; and grants from Lexicon Pharmaceuticals, Hanmi Pharmaceutical Co, Novo Nordisk, Poxel SA, and Sanofi. Dr Dagogo-Jack has led clinical trials for AstraZeneca, Novo Nordisk, Inc, and Boehringer Ingelheim; has received fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co., Inc., and Sanofi; and holds equity interests in Jana Care, Inc and Aerami Therapeutics. Dr Frederich is an employee and shareholder of Pfizer Inc. Dr Maldonado is an employee of MSD UK and may own stock and stock options in Merck & Co., Inc., Kenilworth, NJ. Drs J. Liu, Pong, and C.-C. Liu are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, and may own stock and stock options in Merck & Co., Inc., Kenilworth, NJ. Dr Cannon reports grants and personal fees from Pfizer Inc and Merck & Co., Inc., during the conduct of the study; grants and personal fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, and Janssen; grants from Daiichi Sankyo; and personal fees from Aegerion, Alnylam, Amarin, Applied Clinical Therapeutics, Ascendia, Corvidia, HLS Therapeutics, Innovent, Kowa, Sanofi, Eli Lilly, and Rhoshan outside the submitted work.Footnoteshttps://www.ahajournals.org/journal/circREGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.The sponsor's data sharing policy is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to clinical study data can be submitted through the website or by email ([email protected]com).This work was presented as an abstract at the American Heart Association Scientific Sessions, November 13–17, 2020.This manuscript was sent to John J.V. McMurray, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.Dr David Z.I. Cherney, Division of Nephrology, University of Toronto, Toronto General Hospital, 585 University Avenue, 8N-845, Toronto, Ontario, M5G 2N2, Canada. Email david.[email protected]caReferences1. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, Mahaffey KW, Charytan DM, Wheeler DC, Arnott C, et al.. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019; 7:845–854. doi: 10.1016/S2213-8587(19)30256-6CrossrefMedlineGoogle Scholar2. 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. 2020;e204511. doi: 10.1001/jamacardio.2020.4511Google Scholar3. 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Cherney D, Cosentino F, Pratley R, Dagogo‐Jack S, Frederich R, Maldonado M, Liu J, Pong A, Liu C and Cannon C (2022) The differential effects of ertugliflozin on glucosuria and natriuresis biomarkers: Prespecified analyses from VERTIS CV , Diabetes, Obesity and Metabolism, 10.1111/dom.14677, 24:6, (1114-1122), Online publication date: 1-Jun-2022. Waijer S, Vart P, Cherney D, Chertow G, Jongs N, Langkilde A, Mann J, Mosenzon O, McMurray J, Rossing P, Correa-Rotter R, Stefansson B, Toto R, Wheeler D and Heerspink H (2022) Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial, Diabetologia, 10.1007/s00125-022-05694-6, 65:7, (1085-1097), Online publication date: 1-Jul-2022. 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Zhao L, Zhan Z, Ning J and Qiu M (2022) Network Meta-Analysis on the Effects of SGLT2 Inhibitors Versus Finerenone on Cardiorenal Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease, Frontiers in Pharmacology, 10.3389/fphar.2021.751496, 12 February 9, 2021Vol 143, Issue 6Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.051901PMID: 33186063 Originally publishedNovember 13, 2020 Keywordscardiovascular diseasediabetic nephropathiesrenal insufficiency, chronicdiabetes mellitus, type 2kidney diseasesheart failurePDF download Advertisement SubjectsAtherosclerosisClinical StudiesHeart Failure
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