Therapeutic Advances in Diabetic Kidney Disease: 30 Years of Evidence and the Rise of the “Fantastic Four” in Nephrology

Abstract

Background

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease and kidney failure worldwide. Over the past 3 decades, management has evolved from strict glycemic and blood pressure control to targeted therapies that modify disease progression.

Summary

The DCCT/EDIC (1993) confirmed the impact of intensive glycemic and multifactorial risk factor management. But the early 1990s established the foundation of nephroprotective therapy with the Captopril Trial (1993) in type 1 diabetes and subsequent IRMA-1 (2001), IDNT (2001), and the RENAAL (2001) studies established renin-angiotensin-system blockade as the first disease-specific therapy. More than a decade later, sodium-glucose cotransporter-2 (SGLT2) inhibitors transformed care, with EMPA-REG OUTCOME (2015) and CANVAS (2017) studies first demonstrating kidney benefits as secondary outcomes, which were confirmed in subsequent dedicated kidney trials: CREDENCE (2019), DAPA-CKD (2020), and EMPA-KIDNEY (2022) studies, demonstrating consistent reductions in kidney failure and cardiovascular mortality. Finerenone further advanced outcomes in FIDELIO-DKD (2020) and FIGARO-DKD (2021), and combination therapy with SGLT2 inhibition showed additive benefit in the CONFIDENCE (2025) study. Most recently, the FLOW (2024) trial confirmed glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as promising fourth pillar of nephroprotective therapies.

Key Messages

Together, these advances, termed the “Fantastic Four,” have redefined standards of care in DKD. This review synthesizes pivotal clinical trials and highlights evolving strategies to guide individualized treatment and future research.

Introduction

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide, affecting approximately 30–40% of patients with diabetes [1–3]. Moreover, the global incidence of CKD attributable to type 2 diabetes mellitus increased by 74% in 2017 compared with 1990 [3]. DKD is characterized by persistent albuminuria, a progressive decline in glomerular filtration rate (GFR), and increased risk of cardiovascular (CV) morbidity and mortality [4]. Beyond glomerular lesions, tubulointerstitial fibrosis and vascular rarefaction are critical determinants of DKD progression [5]. Notably, up to one-third of patients may develop reduced GFR without overt albuminuria, underscoring the heterogeneity of DKD and the limitations of albuminuria as a sole marker [6, 7]. The pathophysiology involves metabolic and hemodynamic disturbances driven by chronic hyperglycemia, including glomerular hyperfiltration, podocyte injury, oxidative stress, advanced glycation end products, activation of the renin-angiotensin-aldosterone system, and maladaptive inflammatory and fibrotic responses. These processes link DKD with systemic vascular dysfunction, explaining the close overlap between renal and CV risk. Clinically, DKD progression is staged from microalbuminuria to macroalbuminuria, followed by declining GFR and eventual kidney failure, with current KDIGO guidelines recommending risk stratification based on both albuminuria and estimated GFR (eGFR) categories [8].

For decades, therapeutic strategies in diabetes focused primarily on glycemic control. Landmark trials such as the Diabetes Control and Complications Trial (DCCT) in patients with insulin-dependent diabetes mellitus [9] and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes [10] demonstrated that intensive glucose control significantly reduced the risk of microvascular complications.

A major breakthrough was achieved in the early 1990s with the demonstration that renin-angiotensin-aldosterone system (RAAS) blockade confers kidney-specific protection. The Captopril Trial (1993) demonstrated that angiotensin-converting enzyme (ACE) inhibition reduced the risk of serum creatinine doubling and progression to kidney failure in patients with DKD, independent of blood pressure control [11]. Subsequent trials, including IRMA-1, IDNT, and RENAAL (2001), firmly established angiotensin receptor blockers (ARBs) as nephroprotective agents in type 2 diabetes [12–14] (Fig. 1). These findings shaped international guidelines, which for more than a decade recommended ACE inhibitors or ARBs as the cornerstone of DKD management.

Fig. 1.

Landmark studies shaping the therapy and management of DKD (1990–2025). Each study is labeled with its acronym and publication year to avoid overlap. Blue: glycemic control, orange: ACE inhibitors/angiotensin II receptor antagonists, green: SGLT2 inhibitors, red: MRAs, purple: GLP-1 agonists.

However, from 2001 to 2015, progress stagnated (Fig. 1). Trials of novel agents such as bardoxolone (BEACON trial), an Nrf2 activator with anti-inflammatory and antioxidant effects, failed to improve hard renal outcomes and raised safety concerns [15]. The therapeutic landscape changed dramatically with the advent of sodium-glucose cotransporter-2 (SGLT2) inhibitors. Empagliflozin, as demonstrated in the EMPA-REG OUTCOME trial (2015) [16], subsequently canagliflozin in CANVAS (2017) [17] and dapagliflozin in DECLARE-TIMI 58 (2019) [18], reduced the risk of major CV events in patients with type 2 diabetes. However, the beneficial effects on kidney outcomes were specifically demonstrated in the landmark trials CREDENCE (2019) with canagliflozin [19], DAPA-CKD (2020) with dapagliflozin [20], and EMPA-KIDNEY (2023) with empagliflozin [21], which consistently established robust benefits in reducing albuminuria and slowing CKD progression.

More recently, nonsteroidal mineralocorticoid receptor antagonism with finerenone in FIDELIO-DKD and FIGARO-DKD further improved kidney and CV outcomes [22, 23]. The CONFIDENCE trial (2024) provided proof of concept for dual therapy with finerenone and empagliflozin, showing additive reductions in albuminuria [24, 25]. Parallel to these developments, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained worldwide attention. The FLOW trial (2024) demonstrated that semaglutide reduced the risk of adverse kidney outcomes in type 2 diabetes with CKD, marking another emerging therapeutic class [24].

Taken together, therapeutic advances over the past 30 years have transformed the care of DKD, evolving from glycemic control, monotherapy with RAS blockade to multidrug strategies incorporating SGLT2 inhibitors, nonsteroidal mineralocorticoid receptor antagonist (MRA), and GLP-1 RAs representing the “Fantastic Four in Nephrology.” Furthermore, the significantly positive results regarding CV outcomes have led to the widespread use of many of these medications for heart failure, irrespective of the presence of DKD, reflected within the “Fantastic Four in Cardiology” [26–28]. This review summarizes the evidence from pivotal RCTs, highlights clinical implications, and outlines future directions for individualized management of DKD.

Methods

This review was conducted as a narrative, structured synthesis of pivotal randomized controlled trials (RCTs) in DKD published over the past 3 decades. Our primary objective was to identify and summarize clinical evidence that has shaped current therapeutic practice in the management of DKD.

Search Strategy and Study Identification

We searched PubMed/MEDLINE and major bibliographic databases from 1990 to 2025 using the following keywords: “diabetic nephropathy”, “diabetic kidney disease”, “randomized controlled trial”, “albuminuria”, “end-stage kidney disease”, “SGLT2 inhibitors”, “finerenone”, “GLP-1 receptor agonists”. In addition, reference lists of relevant reviews, meta-analyses, and international guideline documents were manually screened.

Inclusion Criteria

Inclusion criteria were as follows:

• RCTs (phase III or IV) enrolling ≥500 patients with diabetes and kidney involvement (microalbuminuria, proteinuria, or reduced estimated GFR);

• published in journals with an impact factor >10 (Journal Citation Reports 2023);

• trials demonstrating clinically meaningful kidney outcomes, defined as progression of albuminuria, doubling of serum creatinine, kidney failure, or validated composite kidney endpoints;

• pivotal studies that changed clinical practice, irrespective of whether results were positive or neutral.

Exclusion Criteria

Exclusion criteria were as follows:

• phase II studies, pilot trials, or mechanistic studies without hard renal endpoints;

• abstract-only publications, conference proceedings, or unpublished data;

• trials focusing exclusively on CV outcomes without renal endpoints or pre-specified renal subanalyses.

Study Selection

Based on these criteria, we identified 15 pivotal RCTs conducted between 1993 and 2024. These include landmark studies of RAAS inhibition (Captopril, IRMA-1, IDNT, RENAAL), glycemic control (DCCT/EDIC, UKPDS), sodium-glucose cotransporter-2 (SGLT2) inhibitors (EMPA-REG OUTCOME, CANVAS, CREDENCE, DAPA-CKD, EMPA-KIDNEY), nonsteroidal MRAs (FIDELIO-DKD, FIGARO-DKD, CONFIDENCE), and glucagon-like peptide-1 receptor agonists (FLOW).

Data Extraction and Synthesis

For each trial, we extracted study design, patient population, sample size, intervention and comparator, primary renal outcomes, and key results. Trials were categorized as practice changing if their findings directly influenced international guidelines and standards of care. Results are presented along a historical timeline (1990–2025) to illustrate the evolution of therapeutic strategies in DKD.

Results

Glycemic and Multifactorial Control

The Diabetes Control and Complications Trial (DCCT, 1993) and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC), demonstrated that intensive glycemic control in type 1 diabetes substantially reduced the incidence of both microalbuminuria and overt DKD [9]. Similarly, the UK Prospective Diabetes Study (UKPDS, 1998) in type 2 diabetes showed that strict blood glucose and blood pressure management lowered the risk of microvascular complications, including early stages of kidney disease [10]. These trials established hyperglycemia and hypertension as modifiable drivers of diabetic nephropathy and formed the cornerstone of multifactorial management.

Renin-Angiotensin System Blockade

The Captopril Trial (1993) was the first to demonstrate beneficial effects of ACE inhibition in diabetic nephropathy [11]. It enrolled 409 patients with type 1 diabetes and overt nephropathy, defined as proteinuria ≥500 mg per 24 h and baseline serum creatinine ≤2.5 mg/dL. At baseline, the mean serum creatinine was approximately 1.3 mg/dL and average proteinuria was around 2.5 g/24 h. Over a median follow-up of 3 years, captopril significantly reduced the risk of the primary composite endpoint of doubling of serum creatinine or progression to kidney failure by 48% compared with placebo (p = 0.007). This effect was most pronounced in patients with higher baseline serum creatinine, reaching up to a 76% relative risk reduction in those with levels above 2.0 mg/dL. The annual decline in creatinine clearance was −11% in the captopril group versus −17% in the placebo group. Importantly, the treatment also halved the risk of the composite outcome of death, dialysis, or transplantation, independent of blood pressure reduction.

The Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA-1) trial randomized 590 patients with type 2 diabetes and persistent microalbuminuria, defined as urinary albumin excretion of 20–200 µg/min, while baseline renal function was preserved (creatinine in men <1.5 mg/dL, in women <1.1 mg/dL). Participants were assigned to receive either placebo, irbesartan 150 mg, or irbesartan 300 mg daily. Over a median follow-up of 2 years, progression to overt nephropathy occurred in 5.2% of patients in the 300 mg irbesartan group compared with 9.7% in the 150 mg irbesartan and 14.9% in the placebo group, corresponding to a hazard ratio (HR) of 0.30 (95% CI, 0.14–0.61; p < 0.001) and 0.61 (95% CI, 0.34–1.08; p = 0.08) for the two irbesartan groups, respectively. Treatment with irbesartan also reduced urinary albumin excretion in a dose-dependent manner, with decreases of 24% in the 150 mg group and 38% in the 300 mg group. Importantly, these renal benefits were observed without significant differences in systemic blood pressure compared with placebo, supporting the concept of a direct renoprotective effect [12].

The Irbesartan Diabetic Nephropathy Trial (IDNT, 2001) investigated the effects of angiotensin receptor blockade in 1,715 patients with type 2 diabetes, hypertension, and proteinuric CKD. At baseline, the mean serum creatinine was approximately 1.7 mg/dL and albuminuria 1.9 g/day. Patients were randomized to receive irbesartan, amlodipine, or placebo and were followed for a median of 2.6 years. Irbesartan significantly reduced the risk of the composite primary endpoint of doubling of serum creatinine, kidney failure, or death from any cause by 20% vs. placebo (p = 0.02) and by 23% vs. amlodipine (p = 0.006). By contrast, amlodipine did not confer renal protection despite similar blood pressure lowering, underscoring the independent benefit of RAAS blockade in DKD [13].

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL, 2001) trial evaluated the effects of losartan in 1,513 patients with type 2 diabetes, hypertension, and overt nephropathy. At study entry, the mean baseline serum creatinine was 1.9 mg/dL and median urinary albumin-to-creatinine ratio (UACR) 1.2g/g creatinine. Patients were randomized to losartan or placebo on top of conventional antihypertensive therapy and were followed for a mean of 3.4 years. Losartan reduced the risk of the composite primary endpoint (doubling of serum creatinine, kidney failure, or death) by 16% compared with placebo (p = 0.02). The risk of doubling of serum creatinine was reduced by 25% (p = 0.006), and the risk of progression to kidney failure was reduced by 28% (p = 0.002). Losartan also reduced proteinuria by 35% compared to placebo and decreased hospitalization for heart failure by 32%, highlighting both renal and cardiac benefits [14] (Table 1).

Table 1.

ACE inhibitors and ARBs

Group	Study (year)	Population (N)	Baseline kidney status	Intervention vs. comparator	Primary renal endpoint	Key secondary results
ACEi	Captopril Trial (1993) [11]	409 (T1D, overt DKD)	Mean serum creatinine 1.3 mg/dL; mean proteinuria 2,500 mg/24 h	Captopril vs. placebo	Doubling of serum creatinine: RRR: 48% overall (p = 0.007) –Baseline creatinine 2.0 mg/dL: RRR: 76% –Baseline creatinine 1.5 mg/dL: RRR: 55% –Baseline creatinine 1.0 mg/dL: RRR: 17%	Rate of decline in creatinine clearance: Captopril: 11±21% per year Placebo: 17±20% per year (p = 0.03) Among patients with baseline creatinine ≥1.5 mg/dL: captopril 23±25%/year vs. placebo 37±25%/year (p = 0.01)
				Median follow-up 3 years		Composite endpoint (death, dialysis, transplantation): 50% risk reduction, independent of small differences in blood pressure
ARB	IRMA (2001) [12]	590 (T2D, microalbuminuria, hypertensive)	Microalbuminuria: mean albumin excretion rate 55.5 µg/min; creatinine in men <1.5 mg/dL, in women <1.1 mg/dL	Irbesartan 300 mg (or 150 mg) vs. placebo	Progression to overt DKD (persistent albuminuria >200 µg/min + ≥30% above baseline)	Albuminuria reduction by irbesartan 300 mg: −38%, irbesartan 150 mg: −24%
				Median follow-up 2 years	Irbesartan 300 mg (or 150 mg) vs. placebo
				​	Irbesartan 150 mg: RRR of 35% vs. placebo
ARB	IDNT (2001) [13]	1,715 (T2D, hypertension, proteinuric CKD)	Overt DKD	Irbesartan vs. amlodipine vs. placebo (blood pressure targets similar, <135/85 mm Hg)	Composite of doubling baseline creatinine, kidney failure, or death from any cause: irbesartan: −20% risk vs. placebo (p = 0.02), −23% vs. amlodipine (p = 0.006)	Irbesartan: risk of doubling of serum creatinine −33% vs. placebo (p = 0.003), −37% vs. amlodipine (p < 0.001) RRR for kidney failure: 23% vs. placebo/other groups (p = 0.07) Blood pressure adjusted: effect independent of achieved blood pressure
			Mean UACR 1.9g/24h	Mean follow-up 2.6 years
			Mean serum creatinine 1.67 mg/dL
ARB	RENAAL (2001) [14]	1,513 (T2D, DKD)	Overt DKD; hypertensive	Losartan vs. placebo (on background blood pressure therapy)	Composite of a doubling baseline serum creatinine, kidney failure, death Composite endpoint: −16% RR vs. placebo (p = 0.02) Doubling of serum creatinine: −25% RR (p = 0.006) Kidney failure: −28% RR (p = 0.002) Effect independent of BP lowering	Proteinuria −35% losartan vs. placebo (p < 0.001)
			Median UACR 1.2 g/g creatinine	Mean follow-up 3.4 years
			Serum creatinine 1.9 mg/dL			Hospitalization for HF: −32% by losartan vs. placebo (p < 0.001)

T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; UACR, urinary albumin-to-creatinine ratio; RRR, relative risk reduction; RR, risk reduction; RRT, renal replacement therapy; HF, heart failure.

Sodium-Glucose Cotransporter-2 Inhibitors

The EMPA-REG OUTCOME trial enrolled 7,020 patients with type 2 diabetes and established CV disease, all with baseline eGFR above 30 mL/min/1.73 m² (mean eGFR 74 mL/min/1.73 m²). Albuminuria status at entry varied, with 60% normoalbuminuria, 29% microalbuminuria, and 11% macroalbuminuria. Participants received empagliflozin 10 or 25 mg daily or placebo, with a median follow-up of 3.1 years. Empagliflozin reduced progression to macroalbuminuria by 38%, doubling of serum creatinine by 44%, and initiation of renal replacement therapy by 55%. The composite nephropathy outcome was reduced with a HR of 0.61 (95% CI 0.53–0.70). In addition, major CV benefits were demonstrated, including a reduction in major adverse CV events (MACE) (HR 0.86; 95% CI 0.74–0.99), a 38% reduction in CV death, a 35% reduction in hospitalization for heart failure, and a 32% reduction in all-cause mortality [29].

The CANVAS Program combined data from two sister trials and randomized 10,142 patients with type 2 diabetes and high CV risk. The mean baseline eGFR was 76 mL/min/1.73 m², and median UACR was 12.3 mg/g, with 70% normoalbuminuria, 23% microalbuminuria, and 8% macroalbuminuria. Over a mean follow-up of 3.6 years, canagliflozin reduced progression of albuminuria by 31% and increased regression of albuminuria by 57%. The composite renal endpoint of sustained ≥40% decline in eGFR, need for renal replacement therapy, or renal death was reduced by 39%. CV outcomes demonstrated a significant reduction in MACE (HR 0.86; 95% CI 0.75–0.97) [17].

The CREDENCE trial enrolled 4,401 patients with type 2 diabetes and albuminuric CKD, with a mean eGFR of 56 mL/min/1.73 m² and UACR 300–5,000 mg/g. About half had established CV disease. Patients were randomized to canagliflozin 100 mg or placebo and followed for a median of 2.62 years. The primary composite endpoint – kidney failure (dialysis, transplantation, or sustained eGFR <15 mL/min/1.73 m²), doubling of serum creatinine, or death from renal or CV causes – was reduced by 30% with canagliflozin. Secondary endpoints included reductions in MACE (HR 0.80; 95% CI 0.67–0.95) and hospitalization for heart failure (HR 0.61; 95% CI 0.47–0.80) [19].

The DAPA-CKD trial investigated dapagliflozin in 4,304 patients with CKD, with or without diabetes. Baseline mean eGFR was 43.1 mL/min/1.73 m² and median UACR was 949 mg/g; 67.5% of participants had type 2 diabetes. Patients received dapagliflozin 10 mg daily or placebo, with a median follow-up of 2.4 years. The primary composite endpoint – a sustained ≥50% decline in eGFR, kidney failure, or death from renal or CV causes – was reduced by 37% with dapagliflozin. CV outcomes also improved, with a HR of 0.71 (95% CI 0.55–0.92) for the composite of CV death or hospitalization for heart failure [20].

The EMPA-KIDNEY trial randomized 6,609 patients with CKD, defined as eGFR 20–45 mL/min/1.73 m² or eGFR 45–90 with albuminuria. The mean baseline eGFR was 37.3 mL/min/1.73 m² and median UACR was 329 mg/g; 46% had diabetes. Patients received empagliflozin 10 mg daily or placebo, with a median follow-up of 2.0 years. The primary composite outcome – progression of CKD (kidney failure, sustained decrease in eGFR to <10 mL/min/1.73 m², decline of ≥40% in eGFR, or renal death) or CV death – was reduced by 23%. Secondary outcomes showed no significant effect on the composite of hospitalization for heart failure or CV death, although overall renal protection was consistent across subgroups [21]. Complementing these RCTs, the multinational DISCOVER-CKD study provided prospective real-world evidence. Despite guideline recommendations, a substantial proportion of patients with CKD, of whom nearly half had type 2 diabetes, were not treated with RAS blockade or SGLT2 inhibitors; yet those who received guideline-directed medical therapy experienced significantly fewer adverse renal outcomes, highlighting the ongoing treatment gap in clinical practice [30] (Table 2).

Table 2.

SGLT2 inhibitors

Group	Study (year)	Population (N)	Baseline kidney status	Intervention vs. comparator	Primary renal endpoint	Key cardiovascular results
Empagliflozin	EMPA-REG OUTCOME (2016) – renal microvascular analysis [29]	7,020 (T2D, CV disease, eGFR >30 mL/min/1.73 m2)	Mean eGFR ∼74 mL/min/1.73 m2 Albuminuria spectrum: <30 mg/g: 60.0% 30–300 mg/g: 28.9% >300 mg/g: 11.1%	Empagliflozin 10 mg vs. 25 mg vs. placebo	Progression to macroalbuminuria: RRR of 38% Doubling of the serum creatinine: RRR of 44% Initiation RRT: RRR of 55% HR 0.61 (95% CI 0.53–0.70) for nephropathy composite	MACE (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke): HR 0.86 (95% CI 0.74–0.99) CV death: RRR of 38% Hospitalization for HF: RRR of 35% All-cause mortality: RRR of 32%
				Median follow-up 3.1 years
Canagliflozin	CANVAS Program (2017) [17]	10,142 (T2D, high CV risk)	Mean eGFR 76 mL/min/1.73 m2 Median UACR 12.3 mg/g creatinine Albuminuria spectrum: UACR <30 mg/g: 69.8% UACR 30–300 mg/g: 22.6% UACR >300 mg/g: 7.6%	Canagliflozin vs. placebo	Progression of albuminuria: RRR of 30.6% Regression of albuminuria: relative increase of 56.5% Composite (sustained ≥40% eGFR reduction, RRT, or renal death): RRR of 38.9%	Major CV events (composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): HR 0.86 (95% CI 0.75–0.97)
				Mean follow-up 3.6 years
Canagliflozin	CREDENCE (2019) [19]	4,401 (T2D, albuminuric CKD)	Mean eGFR 56 mL/min/1.73 m2; UACR 300–5,000 mg/g (all patients); 50.4% had CV disease	Canagliflozin 100 mg vs. placebo	Composite of kidney failure (dialysis, transplantation, or a sustained estimated GFR of <15 mL per minute per 1.73 m2), a doubling of the serum creatinine, or death from renal or CV causes: RRR of 30%	Composite MACE (CV death, nonfatal MI, nonfatal stroke): HR 0.80 (0.67–0.95)
				Median follow-up of 2.62 years		HF hospitalization: HR 0.61 (0.47–0.80)
Dapagliflozin	DAPA-CKD (2020) [20]	4,304 (CKD with/without T2D, albuminuric)	Mean eGFR 43.1 mL/min/1.73 m2; median UACR 949 mg/g; 67.5% T2D	Dapagliflozin 10 mg vs. placebo	Composite of a sustained decline in the eGFR of at least 50%, kidney failure, or death from renal or CV causes: RRR of 36.9%	CV death or HF hosp.: HR 0.71 (0.55–0.92)
				Median follow-up of 2.4 years		Consistent benefit with/without diabetes
Empagliflozin	EMPA-KIDNEY (2023) [21]	6,609 (CKD, eGFR 20–45 or 45−90 w/albuminuria; with/without T2D)	Mean eGFR 37.3 mL/min/1.73 m2; median UACR 329 mg/g; 46% T2D	Empagliflozin 10 mg vs. placebo	Composite of progression of CKD (defined as kidney failure, decrease in eGFR to <10 mL/min 1.73 m2, decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from CV causes: RRR of 22.6%	No significant differences regarding the composite outcome of hospitalization for HF or death from CV causes
				Median follow-up of 2.0 years of

T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; UACR, urinary albumin-to-creatinine ratio; RRR, relative risk reduction; RR, risk reduction; RRT, renal replacement therapy; HF, heart failure.

Nonsteroidal Mineralocorticoid Receptor Antagonists

The FIDELIO-DKD trial enrolled 5,674 patients with type 2 diabetes and CKD already receiving ACE inhibitor or ARB therapy. The mean baseline eGFR was 44 mL/min/1.73 m², and median UACR was 852 mg/g, reflecting patients with advanced DKD. Patients were randomized to finerenone or placebo and followed for a median of 2.6 years. Finerenone significantly reduced the risk of the primary composite outcome – kidney failure, sustained ≥40% decline in eGFR, or renal death – with a HR of 0.82 (95% CI 0.73–0.93), corresponding to a relative risk reduction of 15.7%. Secondary outcomes showed a 12.2% relative risk reduction in the composite of CV death, myocardial infarction, stroke, or hospitalization for heart failure (HR 0.86; 95% CI 0.75–0.99) [22].

The FIGARO-DKD trial included 7,352 patients with type 2 diabetes and earlier stages of CKD. At baseline, mean eGFR was 68 mL/min/1.73 m², and median UACR was 308 mg/g. Participants were randomized to finerenone or placebo and followed for a median of 3.4 years. Finerenone reduced the risk of the composite renal outcome (kidney failure, sustained ≥40% eGFR decline, or death from renal causes), though the effect did not reach conventional statistical significance (HR 0.87; 95% CI 0.76–1.01; RRR 11.9%). For CV outcomes, finerenone significantly reduced the composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure (HR 0.87; 95% CI 0.76–0.98), a benefit driven primarily by a 29% reduction in heart failure hospitalization (HR 0.71; 95% CI 0.56–0.90) [23]. More recently, the large FINE-HEART pooled analysis, including nearly 19,000 patients with CKD and type 2 diabetes, confirmed and extended these findings [31]. Finerenone consistently reduced CV events, kidney outcomes, and mortality across a wide spectrum of eGFR and albuminuria categories, thereby broadening the evidence base for its use in routine practice.

The CONFIDENCE trial tested dual therapy with finerenone and the SGLT2 inhibitor empagliflozin in 800 patients with type 2 diabetes and CKD. Baseline mean eGFR was 54.2 mL/min/1.73 m², and median UACR was 579 mg/g. Patients were randomized to combination therapy versus either drug as monotherapy and followed for 180 days. Combination therapy achieved an additional 29% reduction in UACR compared with finerenone alone and a 32% greater reduction compared with empagliflozin alone [24] (Table 3).

Table 3.

Nonsteroidal MRA

Group	Study (year)	Population (N)	Baseline kidney status	Intervention vs. comparator	Primary renal endpoint	Key cardiovascular results
Finerenone	FIDELIO-DKD (2020) [22]	5,674 (T2D, CKD on ACEi/ARB)	Mean eGFR 44 mL/min/1.73 m2; median UACR 852 mg/g	Finerenone vs. placebo	Composite of kidney failure, sustained decrease in eGFR ≥40%, or renal death: HR 0.82 (95% CI 0.73–0.93); RRR 15.7%	Composite of CV death, MI, stroke, HF hospitalizations: HR 0.86 (95% CI 0.75–0.99); RRR 12.2%
				Median follow-up of 2.6 years
Finerenone	FIGARO-DKD (2021) [23]	7,352 (T2D, earlier CKD)	Mean eGFR 68 mL/min/1.73 m2; median UACR 308 mg/g	Finerenone vs. placebo	Composite: kidney failure or sustained ≥40% decrease in eGFR or death from renal causes: HR 0.87 (95% CI 0.76–1.01); RRR of 11.9%	Composite: CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF: HR 0.87 (95% CI 0.76–0.98); RRR of 12.3% Driven by lower HF hospitalizations: HR 0.71 (95% CI 0.56–0.90)
				Median follow-up of 3.4 years
Finerenone + empagliflozin	CONFIDENCE (2025) [24]	800 (T2D, CKD)	Mean eGFR 54.2 mL/min/1.73 m2; median UACR 579 mg/g	Finerenone + SGLT2i vs. respective monotherapy	UACR reduction: −29% greater vs. finerenone alone −32% greater vs. empagliflozin alone	NA
				Follow-up 180 days

T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; UACR, urinary albumin-to-creatinine ratio; RRR, relative risk reduction; RR, risk reduction; RRT, renal replacement therapy; HF, heart failure.

GLP-1 Receptor Agonists

The FLOW trial (2024) evaluated semaglutide 1 mg weekly vs. placebo in 3,533 patients with type 2 diabetes and CKD, with a mean eGFR of 47 mL/min/1.73 m² and a median UACR of 567.6 mg/g. Semaglutide significantly reduced the risk of the primary composite endpoint of major adverse kidney events (kidney failure, ≥50% eGFR decline, or renal/CV death) with a HR of 0.76 (95% CI 0.66–0.88). CV death was also reduced with a HR of 0.71 (95% CI, 0.56–0.89) (Table 4).

Table 4.

GLP-1 receptor agonist

Group	Study (year)	Population (N)	Baseline kidney status	Intervention vs. comparator	Primary renal endpoint	Key cardiovascular results
Semaglutide	FLOW (2024) [32]	3,533 (T2D, CKD)	Mean eGFR 47 mL/min/1.73 m2; median UACR 567.6 mg/g	Semaglutide 1.0 mg weekly vs. placebo (standard care)	Composite of major kidney events (kidney failure, ≥50% eGFR decline, or renal/CV death)	CV death (HR 0.71; 95% CI 0.56–0.89)
				Median follow-up was 3.4 years	HR 0.76 (95% CI 0.66–0.88); RRR 19.3%

T1D, type 1 diabetes mellitus; T2D, type 2 diabetes mellitus, ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; UACR, urinary albumin-to-creatinine ratio; RRR, relative risk reduction; RR, risk reduction; RRT, renal replacement therapy; HF, heart failure.

Discussion

Over the past 3 decades, the therapeutic landscape of DKD has shifted from monotherapy approaches to multidrug strategies that target both renal and CV risk. The evidence summarized in this review underscores how glycemic and blood pressure control, RAAS blockade, SGLT2 inhibitors, nonsteroidal MRAs, and GLP-1 receptor agonists have progressively redefined the standard of care. Together, these interventions represent a paradigm shift toward comprehensive cardiorenal-metabolic protection.

This evolving paradigm aligns with the recent American Heart Association Presidential Advisory on cardiovascular-kidney-metabolic (CKM) health, which calls for a unified approach to prevent and manage the intertwined risks of diabetes, CKD, and CV disease. Framing DKD within the broader CKM construct underscores the need for integrated, multidrug strategies that simultaneously address metabolic, renal, and CV pathways [33].

RAAS and SGLT2 inhibitors derive their kidney-protective effect primarily from the reduction of intraglomerular pressure and glomerular hyperfiltration. RAAS inhibitors act by blocking angiotensin II-mediated efferent arteriolar vasoconstriction, thereby lowering glomerular capillary pressure. In addition, RAAS inhibition attenuates maladaptive cellular signaling pathways involved in inflammation and fibrosis, contributing further to structural protection of the nephron [34]. SGLT2i, on the other hand, reduce glucose and sodium reabsorption in the proximal tubule, which increases sodium delivery to the macula densa and restores tubuloglomerular feedback. This results in afferent arteriolar vasoconstriction and a reduction in intraglomerular pressure. In parallel, SGLT2 inhibitors have been shown to stimulate erythropoietin production, leading to increases in hematocrit and potentially enhanced systemic oxygen delivery [35]. Beyond their hemodynamic actions, SGLT2 inhibitors may confer additional kidney and CV protective effects by reducing systemic uremic toxin levels [36] and improving renal tissue oxygenation, thereby attenuating hypoxia-related kidney inflammation, fibrosis, and progressive nephron loss [35, 37, 38]. Finerenone as a selective, nonsteroidal MRA confers kidney protection predominantly through anti-inflammatory and anti-fibrotic pathways [22]. Spironolacton as a steroidal MRA also reduces albuminuria, supporting mineralocorticoid receptor blockade as a promising nephroprotective strategy [39]. However, it is more likely associated with hyperkalemia, especially in advanced CKD stages [40].

Despite these advances, residual risk remains substantial [41]. Even in contemporary landmark trials such as CREDENCE, DAPA-CKD, FIDELITY, and FLOW, many patients progressed to kidney failure or experienced major CV events. This highlights the need for earlier detection and intervention as well as the development of additional therapeutic classes. Moreover, real-world data suggest that implementation of evidence-based therapy remains suboptimal. In the USA, fewer than 15% of eligible patients with type 2 diabetes and ASCVD receive an SGLT2 inhibitor or GLP-1 RA, with prescription rates of only 7.2% and 7.9%, respectively [42]. In the UK, finerenone has only recently been recommended by NICE [43], underscoring how slowly novel therapies are adopted into practice. Even ACEi/ARB uptake in the USA for DKD historically lagged at 25–40% before more recent improvements to ∼70% [44]. Compounding this, less than half of patients with diabetes undergo annual albuminuria testing [45], limiting opportunities for early initiation of the “Fantastic Four.” Uptake is also low worldwide, particularly in in low- and middle-income regions where access is even more restricted. Closing these gaps and inequities is critical if the benefits demonstrated in clinical trials are to be translated into population health.

Another challenge is the heterogeneity of DKD. Traditional staging based on albuminuria and eGFR fails to fully capture disease variability. Up to one-third of patients may experience GFR decline without significant albuminuria [46], and these non-albuminuric phenotypes are underrepresented in current trials. Certain patient groups also remain understudied in contemporary trials; i.e., elderly patients, who represent a large proportion of the CKD population, are frequently underrepresented despite their high risk of adverse outcomes and polypharmacy. Similarly, individuals with advanced CKD (eGFR <20 mL/min/1.73 m²) are typically excluded from pivotal trials, leaving uncertainty about efficacy and safety in this vulnerable group.

Also, most modern RCTs enrolled patients with type 2 diabetes, leaving a knowledge gap in type 1 diabetes and in more advanced CKD stages. Although the concept of the “Fantastic Four” represents a major paradigm shift in the management of DKD, it is important to emphasize that the supporting evidence is predominantly derived from large randomized controlled trials in patients with type 2 diabetes. Robust outcome data exist for the combined use of RAAS inhibition, SGLT2 inhibitors, nonsteroidal MRAs, and GLP-1 receptor agonists in this population, allowing for an approach analogous to guideline-directed medical therapy as established in heart failure. In contrast, the applicability of this comprehensive therapeutic framework to DKD in type 1 diabetes remains limited by a substantial lack of dedicated clinical trial data.

To date, the Captopril Trial remains the only landmark randomized study demonstrating kidney protective effects in patients with type 1 diabetes and overt diabetic nephropathy. In contrast to type 2 diabetes, individuals with type 1 diabetes have been largely excluded from contemporary DKD outcome trials evaluating SGLT2 inhibitors, MRAs, and GLP-1 receptor agonists, resulting in a significant evidence gap. Consequently, the extrapolation of combination strategies or “quadruple therapy” to type 1 diabetes cannot currently be supported by high-quality outcome data and should be approached with caution.

Nevertheless, renewed interest in advancing therapeutic strategies for DKD in type 1 diabetes is emerging. In this context, acetazolamide has recently gained attention as a potential kidney protective agent, supported by early experimental and clinical evidence suggesting favorable effects on tubular workload, glomerular hemodynamics, relieving glomerular hyperfiltration, and intraglomerular pressure [47]. While these findings remain preliminary and require confirmation in adequately powered outcome trials, they highlight a growing effort to develop disease-modifying therapies tailored specifically to DKD in type 1 diabetes.

Taken together, these observations underscore that, while guideline-directed medical therapy-like approaches are now well supported for DKD in type 2 diabetes, substantial unmet needs persist in type 1 diabetes. Future clinical trials specifically designed for this population are urgently required to establish evidence-based therapeutic strategies and to close the longstanding translational gap in DKD care.

There is an urgent need for biomarkers that reflect active injury, inflammation, and fibrosis to guide risk stratification and therapy selection beyond albuminuria [48–50]. Recent work has highlighted urinary Dickkopf-3 as a promising tubular stress biomarker that predicts short-term eGFR decline and fibrosis even in the absence of albuminuria [51]. Notably, the association of RAAS inhibition with lower Dickkopf-3 levels suggests that this biomarker may reflect treatment-responsive tubular stress, thereby offering potential value not only for early risk stratification but also for monitoring the effectiveness of nephroprotective therapy in routine clinical practice [32].

The question of optimal sequencing and combination of therapies also remains unanswered. While SGLT2 inhibitors are widely recommended as foundational therapy, the potentially distorting effect of the high level of recommendation for SGLT2 inhibitors for all types of chronic heart failure must also be taken into account. On the other hand, the integration of finerenone and GLP-1 receptor agonists into clinical practice raises issues of drug sequencing, additive benefit, and long-term safety. The CONFIDENCE trial provided proof of concept for combination therapy, but larger, longer trials are required. Recently, a modeling study by Neuen et al. [52] projected that combined use of an SGLT2 inhibitor, GLP-1 receptor agonist, and nonsteroidal MRA in patients with type 2 diabetes and albuminuria could substantially extend lifetime survival free of kidney failure and CV events compared with conventional care. Mechanistically, this “pillared” approach is attractive because each class targets complementary pathways: SGLT2 inhibitors reduce intraglomerular pressure and improve hemodynamics, nonsteroidal MRAs attenuate inflammation and fibrosis, and GLP-1 receptor agonists address the metabolic derangements characteristic of type 2 diabetes. This strategy closely parallels the multidrug regimen commonly used in heart failure, where the ability of SGLT2 inhibitors to address different pathophysiological signaling pathways than the other drugs of “Fantastic Four of Cardiology” is well known [26, 27, 53, 54].

However, looking forward, the field is entering a phase of precision nephrology. Advances in imaging, digital health, and molecular profiling may soon allow more personalized therapeutic decisions, identifying patients most likely to benefit from specific agents or combinations. Meanwhile, novel therapies under investigation, including endothelin receptor antagonists [55], anti-inflammatory agents such as JAK/STAT inhibitors [56], and cell-based [57, 58] or extracellular vesicle therapies [59], offer new opportunities to further reduce residual risk.

Across regions, ACE inhibitors and ARBs remain relatively inexpensive and are broadly reimbursed, whereas SGLT2 inhibitors and nonsteroidal MRAs carry substantially higher costs, particularly in the USA. European health systems benefit from negotiated prices, resulting in lower annual expenditures, while Gulf Cooperation Council countries generally exhibit intermediate pricing. Reimbursement policies vary by drug class and region, with coverage often contingent on indication approval and, in some cases, prior authorization (Table 5).

Table 5.

Comparison of medication costs in the USA, Germany/Europe, and the Middle East

Drug class/example	Annual costs (USA)	Annual costs (Europe)	Annual costs (Gulf Cooperation Council)	Reimbursement notes
ACE inhibitors/ARBs (e.g., irbesartan 300 mg/d)	∼USD 1,060	∼EUR 100	∼USD 280	Broadly covered in all regions; usually fully reimbursed or subject to minimal copayment in public and private insurance systems
SGLT2 inhibitors (e.g., empagliflozin 10 mg/d, dapagliflozin 10 mg/d)	∼USD 6,000 (list prices); out of pocket often USD 0–50/month via insurance/assistance	EUR 750–950 (negotiated net price)	∼USD 570	Increasingly reimbursed for approved indications (T2D, CKD, HF); may require formulary inclusion or prior authorization
MRAs
Nonsteroidal MRA (finerenone 20 mg/d)	∼USD 9,900	∼EUR 800	∼USD 1,460	Coverage depends on national decisions and insurer policies; usually reimbursed for DKD with restrictions
Steroidal MRA (spironolactone 25 mg/d)	∼USD 240	∼EUR 80	∼USD 65	Widely available and fully reimbursed or associated with negligible copayment
GLP-1 receptor agonists (e.g., semaglutide 1 mg/week)	∼USD 4,100	EUR 3,500	∼USD 1,600	Coverage is heterogeneous; often restricted to approved indications with prior authorization; patient copayments can be substantial, particularly outside public insurance schemes

Pricing data were obtained from Amazon Pharmacy (USA), Kulud Pharmacy (Qatar/Gulf Cooperation Council), and the “Arznei aktuell” application (Germany/Europe); all sources accessed on 11 December 2025.

ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; SGLT2, sodium-glucose cotransporter 2; MRA, mineralocorticoid receptor antagonist; GLP-1, glucagon-like peptide-1.

In conclusion, therapeutic progress in DKD has been remarkable yet incomplete. The challenge now lies not only in discovering new drugs but also in implementing, individualizing, and equitably delivering the therapies we already have. Multidrug regimens that combine hemodynamic, metabolic, and anti-inflammatory strategies are likely to define the future standard of care, while precision approaches promise to further refine outcomes in this high-risk population.

Conflict of Interest Statement

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Sources

The authors declare that no financial support was received for the research and/or publication of this article.

Author Contributions

F.H.-S. and G.Y. contributed equally to this work and wrote the first draft of the manuscript. They conducted the literature search and identified relevant studies. Both authors were also substantially involved in the discussion and interpretation of the current literature. C.D. and J.J. critically reviewed the manuscript and provided intellectual input. B.Y. curated, extracted, and validated the data and played a leading role in data interpretation and discussion. He prepared the visualizations and was responsible for the overall supervision and final editing of the manuscript as the senior author.

Funding Statement

The authors declare that no financial support was received for the research and/or publication of this article.