Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes: A Mediation Analysis
Visual Abstract. Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes
Guidelines recommend albuminuria targets to guide treatment among patients with diabetes. This study examines the degree to which finerenone’s beneficial effects on kidney and cardiovascular outcomes can be explained by the drug’s effect in reducing early signs of kidney injury as measured by albuminuria.
Abstract
Background:
In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular and kidney failure outcomes. Finerenone also lowers the urine albumin-to-creatinine ratio (UACR). Whether finerenone-induced change in UACR mediates cardiovascular and kidney failure outcomes is unknown.
Objective:
To quantify the proportion of kidney and cardiovascular risk reductions seen over a 4-year period mediated by a change in kidney injury, as measured by the change in log UACR between baseline and month 4.
Design:
Post hoc mediation analysis using pooled data from 2 phase 3, double-blind trials of finerenone. (ClinicalTrials.gov: NCT02540993 and NCT02545049)
Setting:
Several clinical sites in 48 countries.
Patients:
12 512 patients with CKD and T2D.
Intervention:
Finerenone and placebo (1:1).
Measurements:
Separate mediation analyses were done for the composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline [approximately a doubling of serum creatinine], or kidney disease death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) outcomes.
Results:
At baseline, median UACR was 514 mg/g. A 30% or greater reduction in UACR was seen in 3338 (53.2%) patients in the finerenone group and 1684 (27.0%) patients in the placebo group. Reduction in UACR (analyzed as a continuous variable) mediated 84% and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively. When change in UACR was analyzed as a binary variable (that is, whether the guideline-recommended 30% reduction threshold was met), the proportions mediated for each outcome were 64% and 26%, respectively.
Limitation:
The current findings are not readily extendable to other drugs.
Conclusion:
In patients with CKD and T2D, early albuminuria reduction accounted for a large proportion of the treatment effect against CKD progression and a modest proportion of the effect against cardiovascular outcomes.
Primary Funding Source:
Bayer AG.
Get full access to this article
View all available purchase options and get full access to this article.
Supplemental Material
References
1.
Cockwell P, Fisher LA. The global burden of chronic kidney disease. Lancet. 2020;395:662-664. [PMID: 32061314] doi: 10.1016/S0140-6736(19)32977-0
2.
Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2016;12:73-81. [PMID: 26553517] doi: 10.1038/nrneph.2015.173
3.
Usman MS, Khan MS, Butler J. The interplay between diabetes, cardiovascular disease, and kidney disease. In: American Diabetes Association, ed. Chronic Kidney Disease and Type 2 Diabetes. American Diabetes Association; 2021:13-18.
4.
Chung H, Crowe CL, Kong SX, et al. Descriptive study of the economic burden among patients with type 2 diabetes mellitus, chronic kidney disease, and chronic kidney disease and type 2 diabetes mellitus in a large US commercially insured population. J Manag Care Spec Pharm. 2023;29:80-89. [PMID: 36580126] doi: 10.18553/jmcp.2023.29.1.80
5.
Bailey RA, Wang Y, Zhu V, et al. Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: Improving Global Outcomes (KDIGO) staging. BMC Res Notes. 2014;7:415. [PMID: 24990184] doi: 10.1186/1756-0500-7-415
6.
Gansevoort RT, Matsushita K, van der Velde M, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes: a collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80:93-104. [PMID: 21289597] doi: 10.1038/ki.2010.531
7.
Matsushita K, Coresh J, Sang Y, et al; CKD Prognosis Consortium. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3:514-525. [PMID: 26028594] doi: 10.1016/S2213-8587(15)00040-6
8.
Matsushita K, van der Velde M, Astor BC, et al; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-2081. [PMID: 20483451] doi: 10.1016/S0140-6736(10)60674-5
9.
de Zeeuw D, Remuzzi G, Parving H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309-2320. [PMID: 15149345] doi: 10.1111/j.1523-1755.2004.00653.x
10.
de Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation. 2004;110:921-927. [PMID: 15302780] doi: 10.1161/01.CIR.0000139860.33974.28
11.
Oshima M, Neuen BL, Li J, et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a posthoc analysis from the CREDENCE trial. J Am Soc Nephrol. 2020;31:2925-2936. [PMID: 32998938] doi: 10.1681/ASN.2020050723
12.
Waijer SW, Xie D, Inzucchi SE, et al. Short-term changes in albuminuria and risk of cardiovascular and renal outcomes in type 2 diabetes mellitus: a post hoc analysis of the EMPA-REG OUTCOME trial. J Am Heart Assoc. 2020;9:e016976. [PMID: 32893717] doi: 10.1161/JAHA.120.016976
13.
ElSayed NA, Aleppo G, Aroda VR, et al. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46:S191-S202. [PMID: 36507634] doi: 10.2337/dc23-S011
14.
Heerspink HJ, Kröpelin TF, Hoekman J, et al; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol. 2015;26:2055-2064. [PMID: 25421558] doi: 10.1681/ASN.2014070688
15.
Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229. [PMID: 33264825] doi: 10.1056/NEJMoa2025845
16.
Ruilope LM, Pitt B, Anker SD, et al. Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study. Nephrol Dial Transplant. 2023;38:372-383. [PMID: 35451488] doi: 10.1093/ndt/gfac157
17.
Agarwal R, Filippatos G, Pitt B, et al; FIDELIO-DKD and FIGARO-DKD Investigators. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474-484. [PMID: 35023547] doi: 10.1093/eurheartj/ehab777
18.
Ruilope LM, Agarwal R, Anker SD, et al; FIGARO-DKD Study Investigators. Design and baseline characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial. Am J Nephrol. 2019;50:345-356. [PMID: 31665733] doi: 10.1159/000503712
19.
Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Study Investigators. Design and baseline characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. Am J Nephrol. 2019;50:333-344. [PMID: 31655812] doi: 10.1159/000503713
20.
Pitt B, Filippatos G, Agarwal R, et al; FIGARO-DKD Investigators. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252-2263. [PMID: 34449181] doi: 10.1056/NEJMoa2110956
21.
Levey AS, Gansevoort RT, Coresh J, et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020;75:84-104. [PMID: 31473020] doi: 10.1053/j.ajkd.2019.06.009
22.
Levin A, Agarwal R, Herrington WG, et al; participant authors of the International Society of Nephrology’s 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020;98:849-859. [PMID: 32998816] doi: 10.1016/j.kint.2020.07.013
23.
Coresh J, Heerspink HJL, Sang Y, et al; Chronic Kidney Disease Prognosis Consortium and Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol. 2019;7:115-127. [PMID: 30635225] doi: 10.1016/S2213-8587(18)30313-9
24.
VanderWeele TJ. Explanation in Causal Inference: Methods for Mediation and Interaction. Oxford Univ Pr; 2015.
25.
Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. Psychol Methods. 2010;15:309-334. [PMID: 20954780] doi: 10.1037/a0020761
26.
Imai K, Keele L, Yamamoto T. Identification, inference and sensitivity analysis for causal mediation effects. Stat Sci. 2010;25:51-71. doi: 10.1214/10-STS321
27.
Gelfand LA, MacKinnon DP, DeRubeis RJ, et al. Mediation analysis with survival outcomes: accelerated failure time vs. proportional hazards models. Front Psychol. 2016;7:423. [PMID: 27065906] doi: 10.3389/fpsyg.2016.00423
28.
Fulcher IR, Tchetgen Tchetgen E, Williams PL. Mediation analysis for censored survival data under an accelerated failure time model. Epidemiology. 2017;28:660-666. [PMID: 28574921] doi: 10.1097/EDE.0000000000000687
29.
Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137-150. [PMID: 23379553] doi: 10.1037/a0031034
30.
SAS Institute. SAS/STAT 15.1: user's guide. Accessed at https://support.sas.com/en/software/sas-stat-support.html#9948ba40-e79f-48c4-8268-760b53b13955 on 1 February 2023.
31.
Kolkhof P, Jaisser F, Kim SY, et al. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol. 2017;243:271-305. [PMID: 27830348] doi: 10.1007/164_2016_76
32.
American Diabetes Association. Standards of Medical Care in Diabetes-2022 abridged for primary care providers. Clin Diabetes. 2022;40:10-38. [PMID: 35221470] doi: 10.2337/cd22-as01
33.
Kolkhof P, Joseph A, Kintscher U. Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - new perspectives for combination therapy. Pharmacol Res. 2021;172:105859. [PMID: 34461222] doi: 10.1016/j.phrs.2021.105859
34.
Heerspink HJL, Greene T, Tighiouart H, et al; Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019;7:128-139. [PMID: 30635226] doi: 10.1016/S2213-8587(18)30314-0
35.
Heerspink HJL, Xie D, Bakris G, et al; on behalf of the SONAR Investigators. Early response in albuminuria and long-term kidney protection during treatment with an endothelin receptor antagonist: a prespecified analysis from the SONAR trial. J Am Soc Nephrol. 2021;32:2900-2911. [PMID: 34551995] doi: 10.1681/ASN.2021030391
36.
Bayer AG. KERENDIA (finerenone) prescribing information. Accessed at https://labeling.bayerhealthcare.com/html/products/pi/Kerendia_PI.pdf on 5 September 2023.
37.
Localio AR, Meibohm AR, Guallar E. Finding the pathway: mediation analyses in randomized controlled trials. Ann Intern Med. 2020;172:553-557. [PMID: 32203981] doi: 10.7326/M20-0887
38.
Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204-2213. [PMID: 23121378] doi: 10.1056/NEJMoa1208799
39.
Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369:1892-1903. [PMID: 24206457] doi: 10.1056/NEJMoa1303154
40.
Mann JF, Green D, Jamerson K, et al; ASCEND Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527-535. [PMID: 20167702] doi: 10.1681/ASN.2009060593
41.
Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553. [PMID: 18707986] doi: 10.1016/S0140-6736(08)61236-2
Information & Authors
Information
Published In
Annals of Internal Medicine
Volume 176 • Number 12 • December 2023
Pages: 1606 - 1616
History
Published online: 5 December 2023
Published in issue: December 2023
Keywords
Copyright
© 2023 American College of Physicians.
Authors
Metrics & Citations
Metrics
Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
Download article citation data for:
Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes: A Mediation Analysis. Ann Intern Med.2023;176:1606-1616. [Epub 5 December 2023]. doi:10.7326/M23-1023
Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes: A Mediation Analysis. Ann Intern Med.2023;176:1606-1616. [Epub 5 December 2023]. doi:10.7326/M23-1023
Media
Figures
Visual Abstract. Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes
Guidelines recommend albuminuria targets to guide treatment among patients with diabetes. This study examines the degree to which finerenone’s beneficial effects on kidney and cardiovascular outcomes can be explained by the drug’s effect in reducing early signs of kidney injury as measured by albuminuria.
Other
Tables
Get Access
Get Access
Get Access
Login Options:
Purchase
You will be redirected to acponline.org to sign-in to Annals to complete your purchase.
Access to EPUBs and PDFs for FREE Annals content requires users to be registered and logged in. A subscription is not required. You can create a free account below or from the following link. You will be redirected to acponline.org to create an account that will provide access to Annals. If you are accessing the Free Annals content via your institution's access, registration is not required.
Create your Free Account
You will be redirected to acponline.org to create an account that will provide access to Annals.
References
References
1.
Cockwell P, Fisher LA. The global burden of chronic kidney disease. Lancet. 2020;395:662-664. [PMID: 32061314] doi: 10.1016/S0140-6736(19)32977-0
2.
Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol. 2016;12:73-81. [PMID: 26553517] doi: 10.1038/nrneph.2015.173
3.
Usman MS, Khan MS, Butler J. The interplay between diabetes, cardiovascular disease, and kidney disease. In: American Diabetes Association, ed. Chronic Kidney Disease and Type 2 Diabetes. American Diabetes Association; 2021:13-18.
4.
Chung H, Crowe CL, Kong SX, et al. Descriptive study of the economic burden among patients with type 2 diabetes mellitus, chronic kidney disease, and chronic kidney disease and type 2 diabetes mellitus in a large US commercially insured population. J Manag Care Spec Pharm. 2023;29:80-89. [PMID: 36580126] doi: 10.18553/jmcp.2023.29.1.80
5.
Bailey RA, Wang Y, Zhu V, et al. Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: Improving Global Outcomes (KDIGO) staging. BMC Res Notes. 2014;7:415. [PMID: 24990184] doi: 10.1186/1756-0500-7-415
6.
Gansevoort RT, Matsushita K, van der Velde M, et al; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes: a collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011;80:93-104. [PMID: 21289597] doi: 10.1038/ki.2010.531
7.
Matsushita K, Coresh J, Sang Y, et al; CKD Prognosis Consortium. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 2015;3:514-525. [PMID: 26028594] doi: 10.1016/S2213-8587(15)00040-6
8.
Matsushita K, van der Velde M, Astor BC, et al; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-2081. [PMID: 20483451] doi: 10.1016/S0140-6736(10)60674-5
9.
de Zeeuw D, Remuzzi G, Parving H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309-2320. [PMID: 15149345] doi: 10.1111/j.1523-1755.2004.00653.x
10.
de Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation. 2004;110:921-927. [PMID: 15302780] doi: 10.1161/01.CIR.0000139860.33974.28
11.
Oshima M, Neuen BL, Li J, et al. Early change in albuminuria with canagliflozin predicts kidney and cardiovascular outcomes: a posthoc analysis from the CREDENCE trial. J Am Soc Nephrol. 2020;31:2925-2936. [PMID: 32998938] doi: 10.1681/ASN.2020050723
12.
Waijer SW, Xie D, Inzucchi SE, et al. Short-term changes in albuminuria and risk of cardiovascular and renal outcomes in type 2 diabetes mellitus: a post hoc analysis of the EMPA-REG OUTCOME trial. J Am Heart Assoc. 2020;9:e016976. [PMID: 32893717] doi: 10.1161/JAHA.120.016976
13.
ElSayed NA, Aleppo G, Aroda VR, et al. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46:S191-S202. [PMID: 36507634] doi: 10.2337/dc23-S011
14.
Heerspink HJ, Kröpelin TF, Hoekman J, et al; Reducing Albuminuria as Surrogate Endpoint (REASSURE) Consortium. Drug-induced reduction in albuminuria is associated with subsequent renoprotection: a meta-analysis. J Am Soc Nephrol. 2015;26:2055-2064. [PMID: 25421558] doi: 10.1681/ASN.2014070688
15.
Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219-2229. [PMID: 33264825] doi: 10.1056/NEJMoa2025845
16.
Ruilope LM, Pitt B, Anker SD, et al. Kidney outcomes with finerenone: an analysis from the FIGARO-DKD study. Nephrol Dial Transplant. 2023;38:372-383. [PMID: 35451488] doi: 10.1093/ndt/gfac157
17.
Agarwal R, Filippatos G, Pitt B, et al; FIDELIO-DKD and FIGARO-DKD Investigators. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474-484. [PMID: 35023547] doi: 10.1093/eurheartj/ehab777
18.
Ruilope LM, Agarwal R, Anker SD, et al; FIGARO-DKD Study Investigators. Design and baseline characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease trial. Am J Nephrol. 2019;50:345-356. [PMID: 31665733] doi: 10.1159/000503712
19.
Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Study Investigators. Design and baseline characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. Am J Nephrol. 2019;50:333-344. [PMID: 31655812] doi: 10.1159/000503713
20.
Pitt B, Filippatos G, Agarwal R, et al; FIGARO-DKD Investigators. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252-2263. [PMID: 34449181] doi: 10.1056/NEJMoa2110956
21.
Levey AS, Gansevoort RT, Coresh J, et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am J Kidney Dis. 2020;75:84-104. [PMID: 31473020] doi: 10.1053/j.ajkd.2019.06.009
22.
Levin A, Agarwal R, Herrington WG, et al; participant authors of the International Society of Nephrology’s 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials. International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney Int. 2020;98:849-859. [PMID: 32998816] doi: 10.1016/j.kint.2020.07.013
23.
Coresh J, Heerspink HJL, Sang Y, et al; Chronic Kidney Disease Prognosis Consortium and Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies. Lancet Diabetes Endocrinol. 2019;7:115-127. [PMID: 30635225] doi: 10.1016/S2213-8587(18)30313-9
24.
VanderWeele TJ. Explanation in Causal Inference: Methods for Mediation and Interaction. Oxford Univ Pr; 2015.
25.
Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. Psychol Methods. 2010;15:309-334. [PMID: 20954780] doi: 10.1037/a0020761
26.
Imai K, Keele L, Yamamoto T. Identification, inference and sensitivity analysis for causal mediation effects. Stat Sci. 2010;25:51-71. doi: 10.1214/10-STS321
27.
Gelfand LA, MacKinnon DP, DeRubeis RJ, et al. Mediation analysis with survival outcomes: accelerated failure time vs. proportional hazards models. Front Psychol. 2016;7:423. [PMID: 27065906] doi: 10.3389/fpsyg.2016.00423
28.
Fulcher IR, Tchetgen Tchetgen E, Williams PL. Mediation analysis for censored survival data under an accelerated failure time model. Epidemiology. 2017;28:660-666. [PMID: 28574921] doi: 10.1097/EDE.0000000000000687
29.
Valeri L, VanderWeele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18:137-150. [PMID: 23379553] doi: 10.1037/a0031034
30.
SAS Institute. SAS/STAT 15.1: user's guide. Accessed at https://support.sas.com/en/software/sas-stat-support.html#9948ba40-e79f-48c4-8268-760b53b13955 on 1 February 2023.
31.
Kolkhof P, Jaisser F, Kim SY, et al. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol. 2017;243:271-305. [PMID: 27830348] doi: 10.1007/164_2016_76
32.
American Diabetes Association. Standards of Medical Care in Diabetes-2022 abridged for primary care providers. Clin Diabetes. 2022;40:10-38. [PMID: 35221470] doi: 10.2337/cd22-as01
33.
Kolkhof P, Joseph A, Kintscher U. Nonsteroidal mineralocorticoid receptor antagonism for cardiovascular and renal disorders - new perspectives for combination therapy. Pharmacol Res. 2021;172:105859. [PMID: 34461222] doi: 10.1016/j.phrs.2021.105859
34.
Heerspink HJL, Greene T, Tighiouart H, et al; Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019;7:128-139. [PMID: 30635226] doi: 10.1016/S2213-8587(18)30314-0
35.
Heerspink HJL, Xie D, Bakris G, et al; on behalf of the SONAR Investigators. Early response in albuminuria and long-term kidney protection during treatment with an endothelin receptor antagonist: a prespecified analysis from the SONAR trial. J Am Soc Nephrol. 2021;32:2900-2911. [PMID: 34551995] doi: 10.1681/ASN.2021030391
36.
Bayer AG. KERENDIA (finerenone) prescribing information. Accessed at https://labeling.bayerhealthcare.com/html/products/pi/Kerendia_PI.pdf on 5 September 2023.
37.
Localio AR, Meibohm AR, Guallar E. Finding the pathway: mediation analyses in randomized controlled trials. Ann Intern Med. 2020;172:553-557. [PMID: 32203981] doi: 10.7326/M20-0887
38.
Parving HH, Brenner BM, McMurray JJ, et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204-2213. [PMID: 23121378] doi: 10.1056/NEJMoa1208799
39.
Fried LF, Emanuele N, Zhang JH, et al; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369:1892-1903. [PMID: 24206457] doi: 10.1056/NEJMoa1303154
40.
Mann JF, Green D, Jamerson K, et al; ASCEND Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527-535. [PMID: 20167702] doi: 10.1681/ASN.2009060593
41.
Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553. [PMID: 18707986] doi: 10.1016/S0140-6736(08)61236-2
Submit a Comment
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.