Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Macroalbuminuria | Review

New strategies to improve clinical outcomes for diabetic kidney disease

Authors: Thomas Forst, Chantal Mathieu, Francesco Giorgino, David C. Wheeler, Nikolaos Papanas, Roland E. Schmieder, Atef Halabi, Oliver Schnell, Marina Streckbein, Katherine R. Tuttle

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

Background

Diabetic kidney disease (DKD), the most common cause of kidney failure and end-stage kidney disease worldwide, will develop in almost half of all people with type 2 diabetes. With the incidence of type 2 diabetes continuing to increase, early detection and management of DKD is of great clinical importance.

Main body

This review provides a comprehensive clinical update for DKD in people with type 2 diabetes, with a special focus on new treatment modalities. The traditional strategies for prevention and treatment of DKD, i.e., glycemic control and blood pressure management, have only modest effects on minimizing glomerular filtration rate decline or progression to end-stage kidney disease. While cardiovascular outcome trials of SGLT-2i show a positive effect of SGLT-2i on several kidney disease-related endpoints, the effect of GLP-1 RA on kidney-disease endpoints other than reduced albuminuria remain to be established. Non-steroidal mineralocorticoid receptor antagonists also evoke cardiovascular and kidney protective effects.

Conclusion

With these new agents and the promise of additional agents under clinical development, clinicians will be more able to personalize treatment of DKD in patients with type 2 diabetes.
Literature
1.
2.
Xu G, Liu B, Sun Y, Du Y, Snetselaar LG, Hu FB, et al. Prevalence of diagnosed type 1 and type 2 diabetes among US adults in 2016 and 2017: population based study. BMJ. 2018;362:k1497.PubMedPubMedCentralCrossRef
3.
4.
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.PubMedCrossRef
5.
Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol. 2016;5:49–56.PubMed
6.
7.
Li H, Lu W, Wang A, Jiang H, Lyu J. Changing epidemiology of chronic kidney disease as a result of type 2 diabetes mellitus from 1990 to 2017: estimates from Global Burden of Disease 2017. J Diabetes Investig. 2021;3:346–56.CrossRef
8.
Górriz JL, Soler MJ, Navarro-González JF, García-Carro C, Puchades MJ, D'Marco L, et al. GLP-1 receptor agonists and diabetic kidney disease: a call of attention to nephrologists. J Clin Med. 2020;9:947.PubMedCentralCrossRef
9.
Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson A-M, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379:633–44.PubMedCrossRef
10.
Alicic RZ, Johnson EJ, Tuttle KR. Inflammatory mechanisms as new biomarkers and therapeutic targets for diabetic kidney disease. Adv Chronic Kidney Dis. 2018;25:181–91.PubMedCrossRef
11.
12.
Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Ren Physiol. 2017;312:F716–f31.CrossRef
13.
Cappelli C, Tellez A, Jara C, Alarcón S, Torres A, Mendoza P, et al. The TGF-β profibrotic cascade targets ecto-5'-nucleotidase gene in proximal tubule epithelial cells and is a traceable marker of progressive diabetic kidney disease. Biochim Biophys Acta Mol basis Dis. 2020;1866:165796.PubMedCrossRef
14.
Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, et al. Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant. 2008;23:3946–52.PubMedCrossRef
15.
Benzing T, Salant D. Insights into glomerular filtration and albuminuria. N Engl J Med. 2021;384:1437–46.PubMedCrossRef
16.
Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, et al. Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. J Hypertens. 2011;29:1802–9.PubMedCrossRef
17.
Dwyer JP, Parving HH, Hunsicker LG, Ravid M, Remuzzi G, Lewis JB. Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: Results from the DEMAND study. Cardiorenal Med. 2012;2:1–10.PubMedCrossRef
18.
19.
Tervaert TWC, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21:556–63.PubMedCrossRef
20.
21.
American Diabetes Association. 11. Microvascular complications and foot care: Standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S135–s51.CrossRef
22.
Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150.CrossRef
23.
Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, et al. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol. 2007;18:1353–61.PubMedCrossRef
24.
Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, et al. A unifying approach for gfr estimation: recommendations of the NKF-ASN task force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2022;79:268–88 e1.PubMedCrossRef
25.
Williams WW, Hogan JW, Ingelfinger JR. Time to eliminate health care disparities in the estimation of kidney function. N Engl J Med. 2021;385:1804–6.PubMedCrossRef
26.
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New creatinine- and cystatin c-based equations to estimate gfr without race. N Engl J Med. 2021;385:1737–49.PubMedPubMedCentralCrossRef
27.
Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98:S1–s115.CrossRef
28.
Chen DC, Shlipak MG, Scherzer R, Bauer SR, Potok OA, Rifkin DE, et al. Association of intraindividual difference in estimated glomerular filtration rate by creatinine vs cystatin c and end-stage kidney disease and mortality. JAMA Netw Open. 2022;5:e2148940.PubMedPubMedCentralCrossRef
29.
Bargnoux A-S, Piéroni L, Cristol J-P, Kuster N, Delanaye P, Carlier M-C, et al. Multicenter evaluation of cystatin c measurement after assay standardization. Clin Chem. 2017;63:833–41.PubMedCrossRef
30.
Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303:423–9.PubMedCrossRef
31.
Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073–81.PubMedPubMedCentralCrossRef
32.
American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S66–s76.CrossRef
33.
34.
Kidney Disease Improving Global Outcomes Blood Pressure Work Group. KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int. 2021;99:S1–s87.CrossRef
35.
American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2021. Diabetes Care. 2020;44:S125–S50.CrossRef
36.
Kidney Disease Improving Global Outcomes Lipid Work Group. KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013;3:259–305.CrossRef
37.
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317:703–13.PubMedCentralCrossRef
38.
Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15:569–89.PubMedCrossRef
39.
Lv W, Wang X, Xu Q, Lu W. Mechanisms and characteristics of sulfonylureas and glinides. Curr Top Med Chem. 2020;20:37–56.PubMedCrossRef
40.
Hsia DS, Grove O, Cefalu WT. An update on SGLT2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24:73–9.PubMedPubMedCentral
41.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.PubMedCrossRef
42.
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394:131–8.PubMedCrossRef
43.
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou F-F, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.PubMedCrossRef
44.
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.PubMedCrossRef
45.
Zinman B, Inzucchi SE, Lachin JM, Wanner C, Ferrari R, Fitchett D, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014;13:102.PubMedPubMedCentralCrossRef
46.
Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.PubMedCrossRef
47.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018;380:347–57.PubMedCrossRef
48.
Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383:1425–35.PubMedCrossRef
49.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24.PubMedCrossRef
50.
Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc (2003). 2009;49(Suppl 1):S16–29.CrossRef
51.
Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839–48.PubMedCrossRef
52.
Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519–29.PubMedCrossRef
53.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.PubMedCrossRef
54.
Clegg LE, Penland RC, Bachina S, Boulton DW, Thuresson M, Heerspink HJL, et al. Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial. Cardiovasc Diabetol. 2019;18:138.PubMedPubMedCentralCrossRef
55.
Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat Rev Nephrol. 2021;17:227–44.PubMedCrossRef
56.
Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6:605–17.PubMedCrossRef
57.
Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474–84.PubMedCrossRef
58.
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.PubMedCrossRef
59.
Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA. 2016;316(6):602–10.PubMedPubMedCentralCrossRef
60.
Gerstein HC, Sattar N, Rosenstock J, Ramasundarahettige C, Pratley R, Lopes RD, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med. 2021;385:896–907.PubMedCrossRef
61.
Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab. 2009;23:479–86.PubMedCrossRef
62.
Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs. 2003;63:1373–405.PubMedCrossRef
63.
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53.CrossRef
64.
Wyatt CM, Cattran DC. Intensive glycemic control and the risk of end-stage renal disease: an ADVANCE in the management of diabetes? Kidney Int. 2016;90:8–10.PubMedCrossRef
65.
66.
67.
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383:2219–29.PubMedCrossRef
68.
Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021;385:2252–63.PubMedCrossRef
69.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.PubMedCrossRef
70.
Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–30.PubMedPubMedCentralCrossRef
71.
Caruso I, Giorgino F. SGLT-2 inhibitors as cardio-renal protective agents. Metabolism. 2022;127:154937.PubMedCrossRef
72.
Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int. 2019;96:302–19.PubMedCrossRef
73.
Grune J, Beyhoff N, Smeir E, Chudek R, Blumrich A, Ban Z, et al. Selective mineralocorticoid receptor cofactor modulation as ,molecular basis for finerenone’s antifibrotic activity. Hypertension. 2018;71(4):599–608.PubMedCrossRef
74.
Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42(2):152–61.PubMedCrossRef
75.
Frimodt-Møller M, Persson F, Rossing P. Mitigating risk of aldosterone in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2020;29:145–51.PubMedCrossRef
Metadata
Title
New strategies to improve clinical outcomes for diabetic kidney disease
Authors
Thomas Forst
Chantal Mathieu
Francesco Giorgino
David C. Wheeler
Nikolaos Papanas
Roland E. Schmieder
Atef Halabi
Oliver Schnell
Marina Streckbein
Katherine R. Tuttle
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02539-2

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Research article

Association of ideal cardiovascular health with cardiovascular events and risk advancement periods in a Mediterranean population-based cohort

Opinion

Heterogeneity in pragmatic randomised trials: sources and management

Research article

Improving on-treatment risk stratification of cancer patients with refined response classification and integration of circulating tumor DNA kinetics

Forum

The impact of race and ethnicity in breast cancer—disparities and implications for precision oncology

Research article

Prioritising attributes for tuberculosis preventive treatment regimens: a modelling analysis

Research article

Childhood diabetes mellitus and early-onset kidney diseases later in life: a nationwide population-based matched cohort study