New strategies to improve clinical outcomes for diabetic kidney disease
BMC Medicine volume 20, Article number: 337 (2022)
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.
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.
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.
According to the International Diabetes Federation, 537 million adults (20–79 years of age) were living with diabetes mellitus worldwide in 2021, and this number is expected to increase to more than 780 million by the year 2045 . Of these, an estimated 90–95% have type 2 diabetes (T2D) [2, 3]. Among people with T2D, nearly half will develop diabetic kidney disease (DKD), previously termed “diabetic nephropathy” [4, 5]. DKD is the most common cause of kidney failure and end-stage kidney disease (ESKD) leading to the need for kidney replacement therapy (dialysis or transplant) in the world [6, 7]. Moreover, DKD is a leading cause of cardiovascular disease and overall mortality in people with diabetes [8, 9]. Given the ever-increasing prevalence of T2D, early detection and proper management of DKD is of great clinical importance. This review provides an update on DKD pathophysiology, clinical manifestations, and recent breakthroughs in DKD therapies.
Multiple diabetes-driven pathways including hyperglycemia and associated metabolic disturbances, glomerular hemodynamic changes, and proinflammatory and profibrotic factors contribute to kidney damage in DKD [10,11,12,13]. These pathways often lead to glomerular hyperfiltration accompanied by glomerular hypertrophy, and evidence suggests that this may further lead to sclerosis, particularly with comorbid hypertension . Obesity and systemic hypertension, common among people with T2D, also exacerbate glomerular hyperfiltration . Arteriolar hyalinosis along with tubulointerstitial inflammation and fibrosis are also dominant features of DKD (Figs. 1 and 2) . Increasing permeability to albumin, marked by high levels of albuminuria, results from progressive glomerular injury . Albuminuria typically develops prior to loss of filtration, but eGFR decline may also occur without the occurrence of albuminuria in DKD [16,17,18]. In people who experience a decline in eGFR without albuminuria, the kidney tissue typically shows prominent vascular lesions and interstitial fibrosis . Table 1 provides a description of typical findings of glomerular lesion biopsies common in DKD.
DKD often progresses to kidney failure or leads to cardiovascular events that cause death in about half of those affected [11, 20]. Therefore, early awareness, detection, and intervention are essential to improve clinical outcomes.
Diagnostic tools and laboratory practices for DKD
A persistent elevation in urinary albumin to creatinine ratio (UACR, ≥30mg/g [≥3 mg/mmol]), and/or a persistent reduction in eGFR (<60 mL/min/1.73m2) in a person with diabetes indicates DKD . To qualify as DKD, however, these lesions must be due only to diabetes-related factors .
The American Diabetes Association (ADA) Standards of Medical Care recommends that people with T2D be screened for DKD at their initial diagnosis and annually thereafter .
Stage A1, normal to mildly increased albuminuria: <30 mg/g (<3 mg/mmol) UACR in urine sample
Stage A2, moderately increased albuminuria, microalbuminuria: 30–300 mg/g (3–30 mg/mmol) UACR; occurring ≥2 times, 3–6 months apart . This low-grade albuminuria is a less effective predictor of disease progression than macroalbuminuria 
Stage A3, severely increased albuminuria, macroalbuminuria: >300 mg/g (>30 mg/mmol) UACR; occurring ≥2 times, 3–6 months apart 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is the most commonly used formula to estimate GFR from the serum creatinine. Recently, the American Society of Nephrology and the National Kidney Foundation have made recommendations to use race-agnostic methods excluding race in the equation to diagnose and classify chronic kidney disease as a path toward equitable healthcare [24, 25]. A major development is a new CKD-EPI 2021 eGFR equation. This new equation does not include a term for race, with the intent to increase awareness of chronic kidney disease as well as to encourage more timely detection and therapeutic interventions, for all groups of people. Addition of the serum cystatin-C to the CKD-EPI 2021 eGFR equation improves accuracy and precision . Although the serum cystatin-C test is available in some regions of the world, it is not widely used yet due to costs and lack of assay standardization [26,27,28,29]. Albuminuria and decreased eGFR, in both general and high-risk populations, are also associated with increased risks for cardiovascular events and mortality, as well as all-cause mortality [30, 31].Therefore, as a holistic approach to assess kidney and cardiovascular risks, these tests should be checked at least twice a year in people with diabetes and UACR >30 mg/g (>3 mg/mmol) and/or eGFR <60 mL/min/1.73 m2 .
In addition to monitoring for kidney damage and function, people with T2D should have their glycated hemoglobin (HbA1c) tested every 3–6 months to monitor their blood glucose control . The ADA recommends that people with T2D work with their physician to set an individualized goal for glycemic control avoiding hypoglycemia, but with a general target of HbA1c <7% (53 mmol/mol) .
Treatments and medications
Several strategies exist that can help prevent DKD development and slow its progression [8, 33]. While healthy lifestyle changes are foundational, achieving optimal glycemic, blood pressure, and cholesterol levels generally require use of medications. A summary of the Kidney Disease Improving Global Outcomes (KDIGO) guideline for people with chronic kidney disease and diabetes is shown in Fig. 4.
Current goals/targets for people with T2D are:
Manage glycemic control—goal HbA1C ≤7% (53 mmol/mol) 
Control blood pressure—the ADA recommends blood pressure below 140/90 mmHg for people with diabetes, with a lower target (e.g., 130/80 mmHg) potentially beneficial for those with macroalbuminuria . KDIGO recommends treating to a target systolic blood pressure of <120 mmHg, as tolerated, in people with chronic kidney disease with or without diabetes, but not those having had a kidney transplant or on dialysis . Measures to control blood pressure should include use of either:
Angiotensin-converting enzyme inhibitors (ACEi) or
Angiotensin II receptor blockers (ARB) 
Manage cholesterol levels—ideally, low density lipoprotein (LDL) of <100 mg/dL (2.59 mmol/L), total cholesterol of <150 mg/dL (3.88 mmol/L)
In addition to the beneficial effects that blood pressure lowering medications have on progression of DKD , other types of medications are also used to manage DKD in people with T2D. Table 2 lists classes, examples, and modes of action of these medications. Optimal management of blood glucose is the first step in preventing the onset of DKD. Both sodium glucose transport protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have shown beneficial effects on DKD, such as a reduction in albuminuria or lower risk of new-onset albuminuria, largely beyond glycemic control [44, 51].
SGLT-2i agents (Table 3)
Two double-blind, randomized, placebo-control trials, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE)  and Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) , included kidney disease endpoints as the primary outcome. In CREDENCE, participants assigned to canagliflozin had a 30% reduced risk (hazard ratio (HR)=0.70 [95% confidence interval (CI): 0.59–0.82]) of the primary kidney composite outcome (ESKD, doubling of serum creatinine from baseline sustained for at least 30 days, or death from kidney or cardiovascular disease causes) as compared with participants assigned to placebo . A similar effect was seen in DAPA-CKD, with participants assigned to dapagliflozin having a 39% reduced risk (HR=0.61 [95% CI: 0.51–0.72]) of the primary kidney composite outcome (>50% decline in eGFR from baseline or kidney- or CV-related death) as compared to those in the placebo arm . The majority of participants in both trials were already receiving ACEi or ARBs in maximum tolerated doses where possible. Approximately one third (n=1398) of the participants in DAPA-CKD did not have T2D .
Other clinical trials with SGLT-2i investigated kidney disease outcomes as a secondary outcome. Four trials, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) , Canagliflozin Cardiovascular Assessment Study (CANVAS, CANVAS-R) , Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) , and Empagliflozin Outcome Trial in Patients with Chronic Heart Failure, Reduced Ejection Fraction (EMPEROR REDUCED) , reported lower rates of kidney disease composite outcomes in those assigned to the active drug than to placebo (EMPA-REG OUTCOME HR=0.61 [95% CI: 0.53–0.70]; CANVAS, CANVAS-R HR=0.73 [95% CI: 0.67–0.79]; DECLARE-TIMI 58 HR=0.76 [95% CI: 0.67–0.87]; EMPEROR REDUCED HR=0.50 [95% CI: 0.32–0.77]) [44, 46, 47, 49]. Composite kidney disease outcomes were somewhat similar between studies (e.g., composite of sustained decrease in eGFR of 40% or more, to less than 60 mL/min/1.73 m2, incident ESKD, death from kidney or cardiovascular disease causes in DECLARE-TIMI 58 and incident chronic dialysis or kidney transplantation, profound and sustained reduction in eGFR in EMPEROR REDUCED) [47, 49]. One study, eValuation of ERTugliflozin effIcacy and safety – CardioVascular outcomes (VERTIS-CV) , reported no significant difference in their secondary kidney disease outcome (death due to kidney disease, kidney replacement therapy, or doubling of serum creatinine) between those randomized to ertugliflozin versus placebo (HR=0.80 [95% CI: 0.61–1.05] ).
GLP-1 RA agents (Table 4)
Cardiovascular outcome trials have also examined GLP-1 RA in people with T2D with kidney disease outcomes as secondary outcomes; to date, there are no published studies of GLP-1 RAs with kidney outcomes as a primary outcome. Randomized, placebo-controlled trials including Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) ; Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) ; Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes (Harmony Outcomes) ; Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) ; Exenatide Study of Cardiovascular Event Lowering (EXSCEL) ; Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) ; Assessment of Weekly Administration of dulaglutide in Diabetes (AWARD 7) ; and Effect of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O)  all reported significantly lower rates of kidney disease outcomes in participants assigned to the active drug as compared with those assigned to placebo, or active drug as compared to insulin in AWARD-7. LEADER, REWIND, and AMPLITUDE-O report significantly lower risk of composite kidney disease outcomes among those assigned to study drug versus placebo (LEADER HR=0.78 [95% CI: 0.67–0.92]; REWIND HR=0.85 [95% CI: 0.77–0.93]; AMPLITUDE-O HR=0.68 [95% CI: 0.57–0.79]) [42, 51, 60]. EXSCEL found no significant difference in risk of their composite outcome (HR=0.43 [95% CI: 0.15–1.22]) .
Other GLP-1RA studies reported on individual kidney disease measures. In Harmony Outcomes, there was a between-group difference (albiglutide vs. placebo) in change in eGFR at 8 months (mean difference=−1.11 [95% CI: −1.84 to 0.39]) and at 16 months (mean difference=−0.43 [95% CI: −1.26 to 0.41]) . SUSTAIN-6 reported significantly lower risk of new or worsening nephropathy (HR=0.64 [95% CI: 0.46–0.88]) or persistent macroalbuminuria (HR=0.54 [95% CI: 0.37–0.77]) among those assigned to semaglutide as compared with placebo . In ELIXA, participants assigned to lixisenatide had a 24% increase in UACR from baseline to study week 108 while those assigned to placebo had a 34% increase, a significant difference (p=0.004) . In AWARD 7, participants assigned to dulaglutide had higher eGFR at 52 weeks than those assigned to insulin glargine (eGFR least square means = 34.0 mL/min/1.73m2, p=0.005 for dulaglutide 1.5 mg, eGFR least square means = 33.8 mL/min/1.73 m2, p=0.009 for dulaglutide 0.75mg) . More details of these studies are provided in Table 4. As the kidney outcomes mentioned here were all secondary outcomes from cardiovascular outcomes or glycemic lowering trials, there is a clear need for studies with primary kidney disease outcomes in participants with T2D and DKD . The Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease (FLOW, NCT03819153) trial is investigating a GLP-1RA with a primary kidney disease outcome (≥50% eGFR decline, kidney failure, and death from kidney or CV disease) . A companion study, Renal Mode of Action of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease (REMODEL, NCT04865770), is examining the effect of semaglutide on kidney inflammation, perfusion, and oxygenation .
MRA agents (Table 5)
Two recent clinical trials report on the effects of a non-steroidal MRA, finerenone, on kidney disease outcomes. Finerenone demonstrated positive results in FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) with kidney disease endpoints as primary outcomes . In this study, participants assigned to finerenone had an 18% lower risk of the primary composite outcome (ESKD or eGFR <15 mL/min/1.73 m2, sustained decrease of ≥40% in eGFR from baseline for ≥4 weeks, or kidney disease death) as compared with those assigned to placebo (HR=0.82 [95% CI=0.73–0.93]) . FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease (FIGARO-DKD)  included kidney disease endpoints as secondary outcomes. Participants assigned to finerenone had a 23% lower risk of the composite kidney disease outcome of first occurrence of kidney failure, sustained decrease from baseline eGFR ≥57% for ≥4 weeks, or kidney disease death as compared to the placebo arm (HR=0.77 [95% CI: 0.60–0.99]) . Both of these clinical trials included participants with T2D and DKD who were on a maximally tolerated dose of an ACE inhibitor or ARB [67, 68]. The FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis (FIDELITY)  prespecified meta-analysis reported that finerenone significantly reduced risk of kidney disease outcomes (kidney failure, sustained ≥57% decrease in eGFR, or kidney disease death) by 23% and the risk of cardiovascular endpoints (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) by 14% versus placebo in >13,000 participants. Finerenone was well tolerated, but investigator-reported hyperkalemia (serum potassium concentration >5.5 mmol/l) was more common versus placebo (14.0% versus 6.9%, respectively) .
DKD is a frequent and serious complication in people with T2D and diabetes is the most common cause of ESKD and kidney failure worldwide . Glycemic control and blood pressure management, with preferential use of agents that attenuate the renin-angiotensin aldosterone system, have traditionally represented the cornerstone for prevention and treatment of DKD. Even though these measures may reduce albuminuria, their beneficial effects on GFR decline or progression to ESKD are modest [63, 64, 69, 70].
In recent studies, treatment with SGLT-2i and GLP-1 RA proved to reduce the risk for a combined major adverse cardiovascular event endpoint (including cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) [60, 71]. In the CREDENCE and the DAPA-CKD trials, treatment with canagliflozin and dapagliflozin were shown to reduce risks of substantial eGFR decline or kidney failure with a primary kidney disease outcome in adults with T2D who had DKD. These findings have inspired many organizations that produce clinical practice guidelines across the world to recommend these agents over other treatments in people with T2D and DKD and/or cardiovascular disease.
Despite these new therapeutic opportunities for treating people with T2D, the risk of DKD progression remains [11, 72]. There is evidence to support the role of the mineralocorticoid receptor through inflammation and fibrosis in the progression of DKD . Treatment of DKD with older steroidal MRAs has not been widely implemented because of their high rate of unfavorable side effects such as hyperkalemia . However, finerenone is a new non-steroidal MRA with less side effects and more potent anti-inflammatory and antifibrotic effects as compared with steroidal MRAs [73, 74]. Finerenone was shown to evoke kidney and cardiovascular protective effects in people with T2D and DKD [57, 67]. Therefore, promising new pharmacological drugs are available to be used in people with DKD.
Drugs like phosphodiesterase inhibitors, 5-hydroxytrytamine 2a receptor antagonists, aldosterone synthesis inhibitors, anti-inflammatory agents, and others are under clinical development. Such additional classes of agents might further increase the armamentarium in the treatment of DKD in the future [33, 75]. Even though new drugs will help to improve the prognosis of people with DKD, it becomes more and more a challenge for physicians to choose the most beneficial medication or combination of medications for an individual patient. There is a need to evaluate the kidney-protective effects of different treatment modalities based on individual characteristics. For example, it would be important to evaluate if different drugs might have a distinct efficacy in patients with DKD with and without albuminuria. Combination therapy with SGLT-2is and MRAs also need to be better explored to understand if benefits are additive. Additional clinical and real-world studies are warranted to elucidate best clinical practices.
It is important to emphasize the intention of this review, along with its limitations. We aimed to provide an overview on recent renal data of SGLT-2i, GLP-1 RAs, and MRAs. Most of the studies included in the review were cardiovascular outcome trials, with kidney outcomes as secondary outcomes. As such, they may not have sufficient power to provide confirmative answers on kidney-related endpoints, especially when examined by subgroups. Furthermore, for composite secondary kidney outcomes, examining each individual component of the composite outcome provided interesting information, but again, these results were underpowered to be considered confirmatory. With the composite renal outcomes of studies examining GLP-1 RAs driven primarily by reductions in albuminuria, the studies do not prove any beneficial effect of GLP-1 RA on kidney outcomes. Even though many of the results are not confirmatory, they are of interest to discuss potential effects in an exploratory sense. Results of these trials are thesis generating and should not be interpreted in a confirmatory sense. This highlights the need for future trials with kidney outcomes as primary outcomes of interest.
Availability of data and materials
Cited sources are available online
Angiotensin-converting enzyme inhibitor
American Diabetes Association
Effect of Efpeglenatide on Cardiovascular Outcomes
Angiotensin II receptor blocker
- AWARD 7:
Assessment of Weekly Administration of dulaglutide in Diabetes
Canagliflozin Cardiovascular Assessment Study
Chronic kidney disease
Chronic Kidney Disease Epidemiology Collaboration
Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation
Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease
- DECLARE-TIMI 58:
Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58
Diabetic kidney disease
Estimated glomerular filtration rate
Evaluation of Lixisenatide in Acute Coronary Syndrome
- EMPA-REG OUTCOME:
Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients
- EMPEROR REDUCED:
Empagliflozin Outcome Trial in Patients with Chronic Heart Failure, Reduced Ejection Fraction
End-stage kidney disease
Exenatide Study of Cardiovascular Event Lowering
FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease
FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analysis
FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease
Glomerular filtration rate
- GLP-1 RA:
Glucagon-like peptide-1 receptor agonist
- Harmony Outcomes:
Effect of albiglutide, when added to standard blood glucose lowering therapies, on major cardiovascular events in subjects with type 2 diabetes
Kidney Disease Improving Global Outcomes
Low density lipoprotein
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
Least square method
Modification of Diet in Renal Disease
Mineralocorticoid receptor antagonist
New York Heart Association
Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes
Sodium glucose transport protein 2 inhibitor
Sodium glucose transport protein 2
Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes
Type 2 diabetes
Urinary albumin to creatinine ratio
- VERTIS- CV:
EValuation of ERTugliflozin effIcacy and safety – CardioVascular outcomes
International Diabetes Federation. IDF Diabetes Atlas. https://diabetesatlas.org/2021. Accessed 30 Aug 2022.
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.
World Health Organization. Diabetes Available from: https://www.who.int/news-room/fact-sheets/detail/diabetes. Accessed 30 Aug 2022.
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.
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.
Fu H, Liu S, Bastacky SI, Wang X, Tian X-J, Zhou D. Diabetic kidney diseases revisited: a new perspective for a new era. Mol Metab. 2019;30:250–63.
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.
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.
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.
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.
Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12:2032–45.
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.
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.
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.
Benzing T, Salant D. Insights into glomerular filtration and albuminuria. N Engl J Med. 2021;384:1437–46.
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.
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.
Deng L, Li W, Xu G. Update on pathogenesis and diagnosis flow of normoalbuminuric diabetes with renal insufficiency. Eur J Med Res. 2021;26:144.
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.
Ballew SH, Matsushita K. Cardiovascular risk prediction in ckd. Semin Nephrol. 2018;38:208–16.
American Diabetes Association. 11. Microvascular complications and foot care: Standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S135–s51.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S66–s76.
Doshi SM, Friedman AN. Diagnosis and management of type 2 diabetic kidney disease. Clin J Am Soc Nephrol. 2017;12:1366–73.
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.
American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2021. Diabetes Care. 2020;44:S125–S50.
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.
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.
Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol. 2019;15:569–89.
Lv W, Wang X, Xu Q, Lu W. Mechanisms and characteristics of sulfonylureas and glinides. Curr Top Med Chem. 2020;20:37–56.
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.
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.
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.
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.
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.
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.
Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs. 2003;63:1373–405.
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.
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.
U.S. National Library of Medicine. A Reseach Study to See How Semaglutide Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW) 2022 https://clinicaltrials.gov/ct2/show/NCT03819153:ClinicalTirals.gov.
U.S. National Library of Medicine. A research study to find out how semaglutide works in the kidneys compared to placebo, in people with type 2 diabetes and chronic kidney disease (the REMODEL trial) 2022 https://clinicaltrials.gov/ct2/show/NCT048657702022.
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.
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.
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.
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.
Caruso I, Giorgino F. SGLT-2 inhibitors as cardio-renal protective agents. Metabolism. 2022;127:154937.
Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int. 2019;96:302–19.
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.
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.
Frimodt-Møller M, Persson F, Rossing P. Mitigating risk of aldosterone in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2020;29:145–51.
The authors would like to thank Karen Nunley, PhD (Syneos Health), for serving as the medical writer for this article; Joe Durrant (Syneos Health) for editorial assistance; and Nadja Faisst of Clinical Research Services (CRS).
This review was funded by Clinical Research Services.
Ethics approval and consent to participate
Consent for publication
TF provided advisory services to Astra Zeneca, Atrogi, Bayer, Cipla, Eli Lilly, Eysense, Fortbildungskolleg, Novo Nordisk, Pfizer, Sanofi, Remynd, and Roche. TF provided speaker services to Amarin, Astra Zeneca, Böhringer Ingelheim, Berlin Chemie, Cipla, Daiichi-Sankyo, Eli Lilly, Fortbildungskolleg, MSD, Novartis, Novo Nordisk, Sanofi, and Santis.
FG provided advisory services to AstraZeneca, Eli Lilly, Novo Nordisk, Roche Diabetes Care, and Sanofi; received speaker fees and served as a consultant for Boehringer Ingelheim, Lifescan, Merck Sharp & Dohme, Sanofi, AstraZeneca, Medimmune, Roche Diabetes Care, Sanofi, and Medtronic; and received research support from Eli Lilly and Roche Diabetes Care.
KRT is supported by NIH research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and CDC contract 75D301-21-P-12254; other support from Eli Lilly; personal fees and other support from Boehringer Ingelheim; personal fees and other support from AstraZeneca; grants, personal fees, and other support from Bayer AG; grants, personal fees, and other support from Novo Nordisk; grants and other support from Goldfinch Bio; other support from Gilead; and grants from Travere outside the submitted work.
RES is supported by grants from AstraZeneca, Boehringer Ingelheim, Lilly, and NovoNordisk to the Institution (University Hospital Eralngen); personal advisory and speaker fees were received from AstraZeneca, Bohringer Ingelheim, and NovoNordisk.
NP has been an advisory board member of AstraZeneca, Boehringer Ingelheim, MSD, NovoNordisk, Pfizer, Takeda, and TrigoCare International; has participated in sponsored studies by AstraZeneca, Eli Lilly, GSK, MSD, Novo Nordisk, Novartis, and Sanofi-Aventis; has received honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elpen, MSD, Mylan, NovoNordisk, Pfizer, Sanofi-Aventis, and Vianex; and attended conferences sponsored by TrigoCare International, Eli Lilly, Galenica, NovoNordisk, Pfizer, and Sanofi-Aventis.
DCW has an ongoing consultancy agreement with AstraZeneca. In the last 3 years, he has also received payments from Amgen, Astellas, Bayer, Boehringer Ingelheim, Janssen, Gilead, GlaxoSmithKline, Merck Sharp and Dohme, Mundipharma, Tricida, Vifor, and Zydus.
OS is founder and CEO of Sciarc GmbH, Germany.
CM serves or has served on the advisory panel for NovoNordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, and Vertex. Financial compensation for these activities has been received by KU Leuven; KU Leuven has received research support for CM from Medtronic, Imcyse, NovoNordisk, Sanofi, and ActoBio Therapeutics; CM serves or has served on the speaker’s bureau for NovoNordisk, Sanofi, Eli Lilly, Boehringer Ingelheim, AstraZeneca, and Novartis. Financial compensation for these activities has been received by KU Leuven.
AH and MS declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Forst, T., Mathieu, C., Giorgino, F. et al. New strategies to improve clinical outcomes for diabetic kidney disease. BMC Med 20, 337 (2022). https://doi.org/10.1186/s12916-022-02539-2