Is clinical trial data showing positive progress for the treatment of diabetic kidney disease?

KEYWORDS:

• Diabetic kidney disease
• diabetic nephropathy
• diabetes mellitus
• renoprotection
• diabetic complications
• therapeutics

1. Introduction

Diabetic kidney disease (DKD) is a common complication of diabetes mellitus. The prevalence of DKD is reported to occur in 30% to 50% of all people living with diabetes [1–3]. DKD results in greater cardiovascular mortality, end-stage kidney disease (ESKD), and a poorer quality of life [4], leading to an increase in economic burden and in health-care utilization [5–7]. Preventing DKD and delaying the progression of chronic kidney disease is of paramount importance for the care of our patients.

The treatment of DKD has evolved over the last four decades. Data from clinical trials provide evidence that several classes of drugs can slow the progression of DKD, reduce hospitalizations from heart failure and lower cardiovascular mortality. We will also discuss novel therapeutic options for diabetic kidney disease, with a focus on drugs in phase 2 and 3 studies.

2. Current evidence and progress in DKD treatment

2.1. Intensive glycaemic control

Several landmark studies have shown that intensive glycemic control is beneficial in the treatment of DKD. In people with type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions (EDIC) study showed that early intensive glycemic control significantly reduced the risk of micro- and macroalbuminuria and reduced the progression of chronic kidney disease (CKD) [8–10]. This legacy effect was also demonstrated in people living with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) [11,12], with data 44 years from the original study being analyzed currently. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and the follow-up ADVANCE-ON study echoed this metabolic memory effect, as well as demonstrating a long-term reduction in ESKD risk, especially in patients with preserved kidney function and well-controlled hypertension [13,14].

The Veterans Affairs Diabetes Trial (VADT) showed that intensive glycemic control reduced the risk of albuminuria progression [15], but the follow-up VADT-F study reported that intensive glycemic control offered no protection on the risk of progression to ESKD [16]. This is likely because patients in the VADT study had a longer duration of preexisting diabetes, which leads to a greater degree of vascular damage probably as a result of the oxidative stress and inflammation due to chronic hyperglycemia. Although the Action to Control Cardiovascular Risk in Diabetes (ACCORD) [17] and the follow-up ACCORDION study [18,19] found no cardiovascular benefit with intensive glycemic control, a significant reduction in macroalbuminuria in patients with intensive glycemic control was observed in the post-hoc analysis [20]. However, a meta-analysis involving 28,065 participants across 7 trials found that intensive glycemic control reduced the risk of developing microalbuminuria and macroalbuminuria, but did not had a significant impact on preventing worsening renal function, ESKD, or death from renal causes [21]. This finding could be a result of the low incidence of these renal outcomes in the published studies.

2.2. Renin-angiotensin-aldosterone system (RAS) inhibitors

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have remained the mainstay of DKD management for the past three decades. They have been proven to reduce the progression of CKD [22,23] and effectiveness between the two drug classes is comparable [24]. Several meta-analyses have shown that the use of ACEi or ARB reduces the progression of albuminuria and CKD, but effects on reducing the progression to ESKD have not been as clearly demonstrated [25–27]. Studies have shown that continuing ACEi or ARB in patients with advanced CKD was associated with cardiovascular benefits without leading to an increase in ESKD risk [28,29]. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study demonstrated that a combination of ACEi and ARB should be avoided due to the increased risk of hyperkalemia and acute kidney injury, without affording additional cardiovascular or renal benefits [30]. These studies demonstrated that the benefits of the combination of ACEi and ARB on urinary albumin excretion seen in the CALM study [31] did not translate to benefits on renal function.

2.3. Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Originally developed as glucose-lowering agents, the cardiovascular outcome trials of SGLT2 inhibitors demonstrated that the use of SGLT2 inhibitors reduced the progression of albuminuria and slowed the trajectory of renal function decline. The primary renal outcome trials of SGLT2 inhibitors, namely the CREDENCE [32–34], DAPA-CKD [35–38] and EMPA-KIDNEY [39] trials have proven that the use of SGLT2 inhibitors in patients with DKD reduced albuminuria, retarded the worsening of renal function and attenuated the development of ESKD (Table 1). The renoprotective effects of SGLT2 inhibitors have also been confirmed in numerous real-world observational studies [40,41]. A retrospective cohort study found that the use of an SGLT2 inhibitor within the first two years of the diagnosis of diabetes significantly attenuated the legacy effect of poor glycemic control and the subsequent risk of cardiovascular diseases [42]. The mechanisms underlying the renoprotective effects of SGLT2 inhibitors are multifactorial, ranging from reducing glomerular hyperfiltration to attenuating inflammation and oxidative stress in the proximal tubular epithelial cells [43–46].

Table 1. Summary of primary renal outcome trials with an SGLT2 inhibitor.

Trial	CREDENCE [32–34]	DAPA-CKD [35–38]	EMPA-KIDNEY [39]
Drug, dose	Canagliflozin 100 mg daily	Dapagliflozin 10 mg daily	Empagliflozin 10 mg daily
Median follow-up, years	2.62	2.4	2.0
Proportion with diabetes, n (%)	4401 (100%)	2906 (67.5%)	3040 (46.0%)
Mean (SD) eGFR, ml/min/1.73 m^2	56.2 ± 18.2	43.1 ± 12.4	37.4 ± 14.4
Median (IQR) uACR, mg/g	927 (463–1833)	949 (477–1885)	329 (49–1069)
Composite renal outcome, HR (95% CI)	0.70 (0.59–0.82)	0.61 (0.51–0.72)	0.72 (0.64–0.82)
Worsening renal function, HR (95% CI)	0.60 (0.48–0.76)	0.53 (0.42–0.67)	0.71 (0.62–0.81)
Long term dialysis, HR (95% CI)	0.74 (0.55–1.00)	0.66 (0.48–0.90)	0.73 (0.59–0.89)
ESKD, HR (95% CI)	0.68 (0.54–0.86)	0.64 (0.50–0.82)	0.73 (0.59–0.89)
Death from cardiovascular causes, HR (95% CI)	0.78 (0.61–1.00)	0.81 (0.58–1.12)	0.84 (0.60–1.19)

SD=standard deviation; eGFR=estimated glomerular filtration; IQR=interquartile range; uACR=urine albumin:creatinine ratio; HR=Hazard ratio; CI=confidence interval; ESKD=end-stage kidney disease.

Sotagliflozin, a SGLT1/2 inhibitor, was found to significantly reduce heart failure hospitalizations and cardiovascular mortality in patients with type 2 diabetes who had been recently hospitalized (SOLOIST study) [47], and in patients with type 2 diabetes and CKD (SCORED study) [48]. In addition, a 34% reduction in fatal and non-fatal stroke was also observed in the SCORED study. A phase 3 study found that sotagliflozin significantly reduced the urinary albumin-to-creatinine ratio (uACR) by 30% in a dose-dependent manner and resulted in a slower but insignificant eGFR decline [49]. Post-hoc analysis of the inTandem trials found that sotagliflozin reduced the 5-year ESKD risk by 5% in patients with type 1 diabetes [50]. Results from a meta-analysis suggest that the renal benefits are similar when comparing SGLT1/2 versus SGLT2 inhibitors [51].

2.4. Glucagon-like peptide-1 receptor agonists (GLP-1RA)

GLP-1RAs are effective in improving glycemic control and providing weight reduction in people with type 2 diabetes. Results from numerous cardiovascular outcome trials have demonstrated the cardiovascular benefits of GLP-1RAs, including LEADER [52,53], SUSTAIN-6 [54,55], HARMONY [56], REWIND [57,58] and AMPLITUDE-O [59]. Two exendin-based GLP-1RAs, namely lixisenatide and exenatide, did not demonstrate cardiovascular benefits in the ELIXA [60,61] and EXSCEL [62,63] trials, respectively, although there was a difference in the recruitment and adherence from other GLP-1RA trials, which may have reduced the significance of their findings [64]. Several of these trials reported renal outcomes as secondary endpoints, and there is some evidence that GLP-1RAs reduce the progression of albuminuria, afford a modest reduction in estimated glomerular filtration rate (eGFR) decline and reduce ESKD risk (Table 2). In patients with advanced CKD (eGFR < 30 ml/min/1.73 m²) [67], GLP-1RAs have renal and cardiovascular protective effects, while patients with ESKD continue to reap the benefits of reduced mortality with the use of GLP-1RAs [68].

Table 2. Summary of secondary renal outcomes observed in GLP-1RA and dual GIP/GLP-1RA trials. Adapted from [64].

Trials	Drug	Median follow-up, years	Composite renal outcome, HR (95% CI)	Worsening renal function, HR (95% CI)	ESKD, HR (95% CI)	eGFR change	uACR change	New-onset macroalbuminuria, HR (95% CI)
ELIXA [60,61]	Lixisenatide	2.1	0.84 (0.68–1.02)	1.16 (0.74–1.83)	Rare	LSMD 0.34 (N.A.)	−10% (N.A.)	0.81 (0.66–0.99)
LEADER [52,53]	Liraglutide	3.8	0.78 (0.67–0.92)	0.89 (0.67–1.19)	0.87 (0.61–1.24)	1.02 (1.00–1.03)	0.83 (0.79–0.88)	0.74 (0.60–0.91)
SUSTAIN-6 [54,55]	Semaglutide, injectable	2.1	0.64 (0.46–0.88)	1.28 (0.64–2.58)	0.91 (0.40–2.07)	0.56 (−0.12–1.24)*	0.74 (0.67–0.81)	0.54 (0.37–0.77)
EXSCEL [62,63]	Exenatide ER	3.2	0.88 (0.76–1.01)	0.88 (0.74–1.05)	NR	LSMD 0.21 (−0.27–0.70)	−25.0% (−33.0–16.0)	0.87 (0.70–1.07)
REWIND [57,58]	Dulaglutide	5.4	0.85 (0.77–0.93)	0.70 (0.57–0.85)	0.75 (0.39–1.44)	LSMD 0.42 (−0.11–0.96)	LSMD 0.82 (0.78–0.86)	0.77 (0.68–0.87)
PIONEER-6 [55,65]	Semaglutide, oral	1.3	NR	NR	NR	0.56 (−0.12–1.24)*	NR	NR
AMPLITUDE-O [59]	Efpeglenatide	1.8	0.68 (0.57–0.79)	0.35 (0.10–1.27)	NR	LSMD 0.89 (0.27–1.51)	LSMD 0.79 (0.72–0.86)	0.68 (0.58–0.80)
SURPASS-4 [66]	Tirzepatide	1.6	0.58 (0.43–0.80)	NR	NR	Mean eGFR slope −1.6 ml/min/1.73 m^2	LSMD −6.8% (−14.1 to 1.1)	0.43 (0.27–0.71)

HR=hazard ratio; CI=confidence interval; LSMD=least-squares mean difference; eGFR=estimated glomerular filtration; uACR=urine albumin:creatinine ratio; ESKD=end-stage kidney disease.

*=pooled analysis of SUSTAIN-6 and PIONEER-6 studies.

Ongoing GLP-1RA studies with dedicated primary renal outcomes will assess the renoprotective effects of GLP-1RAs in a systematic manner. The effects of injectable semaglutide on renal outcomes in patients with type 2 diabetes, renal impairment, and albuminuria are currently being evaluated in the FLOW study (NCT03819153) [69]. The ongoing REMODEL trial (NCT04865770) will evaluate the effects of GLP-1RAs on inflammation and hypoxia-related pathways in DKD [70]. PRECIDENTD (NCT05390892) is an ongoing, large randomized open-label trial looking at the effects of a GLP-1RA, an SGLT2 inhibitor or a combination of both in primary and secondary prevention of cardiorenal events. The renal outcomes of oral semaglutide will also be addressed as part of the secondary outcomes of the SOUL study (NCT03914326) [71].

2.5. Mineralocorticoid receptor antagonists (MRA) – steroidal and nonsteroidal

The use of either ACEis or ARBs retard the progression of DKD, but aldosterone breakthrough is considered to be a factor that could lead to CKD progression. A Cochrane review published in 2020 showed that the addition of a steroidal MRA to standard RAS inhibition in patients who had mild-to-moderate CKD (stages 1 to 4) was associated with reduced albuminuria and improved eGFR [72]. Although the addition of MRAs such as spironolactone to standard RAS inhibition may confer additional renal protection, it is associated with a higher risk of hyperkalemia and anti-androgenic side effects [73,74]. The use of low-dose spironolactone at 12.5 mg daily has been shown to avoid the side effects of hyperkalemia, while still being effective at reducing albuminuria [75].

It has been suggested that nonsteroidal MRAs have less electrolyte and hormonal complications due to their greater selectivity for mineralocorticoid receptors [76]. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial showed that finerenone reduced albuminuria and slowed the decline in eGFR in patients with type 2 diabetes and CKD (Table 3) [77]. Finerenone was also found to reduce ESKD risk and a composite cardiovascular outcome of time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization from heart failure in the prespecified pooled analysis FIDELITY study [80], which included not only the FIDELIO-DKD study but also the FIGARO study [78]. The ESAX-DN trial demonstrated that esaxerenone reduced the progression of albuminuria and resulted in an albuminuria remission rate of 22% in the participants [79]. These positive findings have led to an increased use of nonsteroidal MRAs in the treatment of DKD, while steroidal MRAs such as spironolactone and eplerenone are not as often considered.

Table 3. Summary of renal outcomes observed in phase 3 trials of nonsteroidal MRAs.

Trial	Drug	Median follow-up, years	Composite renal outcome, HR (95% CI)	Worsening renal function, HR (95% CI)	ESKD, HR (95% CI)	eGFR change	uACR change	New-onset macroalbuminuria
FIDELIO-DKD [77]	Finerenone	2.6	0.82 (0.73–0.93)	0.81 (0.72–0.92)	0.87 (0.72–1.05)	LSMD 1.31	LSMD 0.7 (0.65 to 0.75) −31%	NR
FIGARO-DKD [78]	Finerenone	3.4	0.87 (0.76–1.01)	0.87 (0.75–1.00)	0.64 (0.41–0.995)	NR	LSMD 0.68 (0.65–0.70) −32%	NR
ESAX-DN [79]	Esaxerenone	1	22% of participants achieved remission of uACR (12%-25%)	NR	NR	LSMD 0.90 (0.88–0.93)	LSMD 0.38 (0.11–0.48) −58%	0.23 (0.11–0.48)

HR=hazard ratio; CI=confidence interval; LSMD=least-squares mean difference; eGFR=estimated glomerular filtration; uACR=urine albumin:creatinine ratio; ESKD=end-stage kidney disease.

For steroidal MRAs, the ongoing Aldosterone Blockade for Health Improvement Evaluation in End-Stage Renal Disease (ACHIEVE) trial (NCT03020303) seeks to evaluate if spironolactone reduces death or hospitalization from heart failure in ESKD. The ongoing Aldosterone Antagonist Chronic Hemodialysis Interventional Survival Trial (ALCHEMIST) (NCT01848639) will evaluate the cardiovascular outcomes of spironolactone use in patients on hemodialysis. More dedicated studies are needed to evaluate the renal outcomes of steroidal MRAs.

Several ongoing studies will provide more information on the renoprotective effects of nonsteroidal MRAs. The ongoing CONFIDENCE study (NCT05254002) is a phase 2 study which investigates if there is a synergistic effect in combining finerenone with the SGLT2 inhibitor empagliflozin to reduce albuminuria in patients with type 2 diabetes and CKD [81]. The novel nonsteroidal MRA ocedurenone (KBP-5074) is being tested for its safety and efficacy in treating uncontrolled hypertension in patients with stage 3b/4 CKD in the CLARION-CKD (NCT04968184) study. Balcinrenone (AZD9977), another novel nonsteroidal MRA, is being evaluated in the phase 2 MIRACLE study (NCT04595370) for its efficacy in albuminuria reduction and reducing CKD progression in patients with heart failure and established CKD.

3. Novel pathways and the future of DKD treatment

3.1. Glucose-related pathways

3.1.1. Incretin mimetics

The neuroendocrine cells of the gut secrete the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) after food ingestion. GLP-1 decreases the gastric emptying rate and glucagon secretion, while GIP reduces the secretion of gastric acid and increases the glucagon levels. Tirzepatide, a novel dual GIP/GLP-1 receptor agonist, has demonstrated superior results in improvement of glucose control and weight loss when compared to semaglutide in the SURPASS-2 study [82]. In addition, post-hoc analysis of the SURPASS-4 study found a 42% reduction in the renal composite outcome of >40% eGFR decline, ESKD, new-onset macroalbuminuria, or death from kidney failure in the participants who received tirzepatide, when compared to insulin glargine (Table 3) [66]. Tirzepatide was also found to reduce eGFR decline, new-onset macroalbuminuria, and led to a slight decrease in uACR as compared to insulin glargine. The ongoing phase 2 study of Tirzepatide in Participants With Overweight or Obesity and Chronic Kidney Disease With or Without Type 2 Diabetes (TREASURE-CKD, NCT05536804) will provide insights into the effects and mechanisms of tirzepatide in reducing CKD in obese patients with and without diabetes.

Retatrutide, a novel triple agonist of GIP, GLP-1, and glucagon receptors, demonstrated superior improvements in HbA1c by up to 2% and reduced body weight by almost 17% in patients with type 2 diabetes in a phase 2 study [83]. The activation of glucagon receptors, together with GIP and GLP-1 receptors, provides a synergistic effect in terms of energy expenditure. Triple agonism of GIP, GLP-1, and glucagon receptors may have a promising future for DKD treatment, as activation of glucagon receptors may reduce perirenal adiposity [84], improve renal blood flow and glomerular filtration [85], and may indirectly influence solute transport in the proximal renal tubules [86]. An ongoing phase 2b study investigating the renal effects of retatrutide in overweight or obese patients with CKD with or without type 2 diabetes (NCT05936151) will provide us with a deeper understanding of the changes to glomerular filtration, uACR and renal perfusion with the use of retatrutide.

3.2. Novel RAS inhibition

3.2.1. Aldosterone synthase inhibitor, neprilysin inhibitor, direct renin inhibitor

Aldosterone synthase inhibitors block aldosterone production by inhibiting CYP11B2. However, cortisol production may also be suppressed via inhibition of CYP11B1, as both enzymes have similar homology [87]. Baxdrostat, a novel aldosterone synthase inhibitor with a high selectivity for CYP11B2 [88], was found to be effective in the treatment of resistant hypertension in the phase 2 BrigHTN study [89]. In addition, braxdrostat led to a significant reduction in 24-hour urinary aldosterone levels and serum aldosterone, without significant changes to serum cortisol. Lowering aldosterone may confer renal and cardiovascular benefits due to reduced inflammation and fibrosis, but further studies are needed to confirm the renal effects of braxdrostat. Furthermore, whether there is an advantage of braxdrostat over conventional MRA inhibition remains to be ascertained.

An ongoing phase 2 study (NCT05182840) will test the efficacy and safety of combining a novel aldosterone synthase inhibitor, BI 690,517, with an SGLT2 inhibitor, for the treatment of CKD with or without diabetes [90]. Lorundrostat is another aldosterone synthase inhibitor that is undergoing phase 2 studies for the treatment of uncontrolled hypertension (NCT05769608, NCT05968430).

A neprilysin inhibitor blocks the degradation of natriuretic peptides, resulting in vasodilation, natriuresis, and diuresis. This leads to a reduction in blood pressure and aldosterone levels. Current evidence suggests that a neprilysin inhibitor may have renoprotective benefits. The UK HARP-III study, which randomized 414 participants with eGFR 20–60 ml/min/1.72 m² to sacubitril/valsartan, which is a combination of a neprilysin inhibitor and an ARB, or the ARB irbesartan alone, found that both medications have similar effects on albuminuria reduction and reducing eGFR decline [91]. However, sacubitril/valsartan further improved the mean systolic blood pressure by 5.4 mmHg and mean diastolic blood pressure by 2.1 mmHg. A post-hoc analysis of PARAGON-HF found that sacubitril/valsartan significantly decreased eGFR decline in patients with and without diabetes [92]. When compared with valsartan alone, sacubitril/valsartan reduced the renal composite outcome of >50% eGFR reduction, ESKD, or death due to renal cause by around 50% in patients with and without diabetes. A meta-analysis involving 6,217 participants across 6 trials found that compared with ACEi or ARBs, sacubitril/valsartan significantly reduced the risk of >50% eGFR decline by 48% [93]. Thus, neprilysin inhibitors hold promise in DKD treatment, but further studies with dedicated renal outcomes are required.

Aliskiren, the only FDA-approved direct renin inhibitor, blocks the RAS cascade by inhibiting the conversion of angiotensinogen to angiotensin I. However, the ALTITUDE study found that aliskiren significantly reduced albuminuria when used as an adjunct to conventional ACEi/ARB therapy, there was a higher risk of developing hyperkalemia and hypotension [94]. In addition, there was no difference in the secondary composite renal outcome of ESKD, death from renal failure, or dialysis rates in participants who received aliskiren compared to placebo. Nevertheless, newer and more selective direct renin inhibitors may have potential for future DKD treatment. A phase 2 study using a selective direct renin inhibitor, imarikiren (TAK-272), reported a 39% reduction in uACR, and the effect on albuminuria reduction was dose-dependent [95]. Although imarikiren led to a higher rate of albuminuria remission, a clear advantage over the ARB candesartan was not shown. Another novel renin inhibitor, SPH3127, is undergoing a phase 2 study to determine its safety and efficacy in reducing proteinuria in patients with DKD (NCT05593575).

3.3. Inflammatory pathways

3.3.1. Endothelin receptor antagonist, CB1R inverse agonists, Nrf2 activators, ASK1 inhibitor, IL-33 inhibitor

Inflammation and oxidative stress are considered key mediators of glomerulopathy, one of the hallmarks of diabetic kidney disease [96]. Several drugs targeting these pathways may hold the key to unlock a new treatment paradigm for DKD.

Endothelin receptor antagonists may reduce inflammation, increase vasodilation, and promote natriuresis. Although the first endothelin receptor antagonist, avosentan, significantly reduced uACR by more than 40% when added to standard ACEi/ARB therapy in patients with DKD, there was a significant increased risk of fluid overload and cardiac failure [97]. A subsequent and more selective endothelin receptor antagonist, atrasentan, was found to decrease the risk of serum creatinine doubling by 39% with a modest but insignificant reduction in ESKD risk in the phase 3 SONAR trial [98]. However, patients receiving atrasentan had a higher risk of developing cardiac failure. A post-hoc analysis of the SONAR trial reported that patients on atrasentan who were concomitantly treated with an SGLT2 inhibitor had a lower body weight compared to atrasentan alone, and it was postulated that the risk of fluid retention may be reduced when an endothelin receptor antagonist is combined with an SGLT2 inhibitor [99]. The anti-proteinuric effect of atrasentan will be further evaluated in the ongoing phase 2 AFFINITY study (NCT04573920). Another endothelin receptor antagonist, zibotentan, will be evaluated for its safety and efficacy in the ongoing phase 2 ZENITH-CKD trial (NCT04724837) and ZODIAC trial (NCT05570305) when combined with an SGLT2 inhibitor. SC0062, another novel endothelin receptor antagonist, is being studied for its efficacy and safety in a phase 2 trial involving patients with either DKD or IgA nephropathy (NCT05687890).

The cannabinoid-1 receptor (CB1R) is expressed in several organs, including the brain, as well as in podocytes and proximal tubular epithelial cells within the kidney [100,101]. In animal models, CB1R inverse agonists were reported to reduce albuminuria, improve eGFR, and reduce renal glucose reabsorption by decreasing inflammation and oxidative stress, as well as by blocking the downstream effects of angiotensin II [102,103]. The first CB1R inverse agonist, rimonabant, was approved for the treatment of obesity but subsequently withdrawn due to serious neuropsychiatric complications [104,105]. INV-202, a novel peripherally-acting CB1R inverse agonist which only minimally crosses the blood–brain barrier, was found to decrease glomerular injury, reduce renal fibrosis, and preserve podocyte function in mouse studies [103]. INV-202 is currently in a phase 2 study to test safety and efficacy in patients with DKD from either type 1 or type 2 diabetes (NCT05514548).

Nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts the oxidative stress resulting from DKD. In preclinical studies, Nrf2 activators were found to reduce albuminuria and increase eGFR by decreasing oxidative stress and attenuating renal fibrosis [106]. Bardoxolone, a Nrf2 activator, was initially reported to improve eGFR in patients with advanced CKD [107]. However, a subsequent trial found an increased risk of heart failure and worsening albuminuria in patients with type 2 diabetes and stage 4 CKD [108]. It remains to be seen if bardoxolone can slow the eGFR decline in patients with DKD, with the ongoing phase 3 AYAME trial (NCT03550443) potentially shedding more light on this issue [109]. Another novel NrF2 activator, CU01–1001, showed promising results with improvement of eGFR and reduced uACR in patients with DKD [110]. Currently, CU01–1001 is being evaluated for its anti-albuminuric effect in a phase 2 study (NCT05718375).

Inhibition of apoptosis signal-regulating kinase 1 (ASK1) results in a reduction in cytokine-induced cell death and renal fibrosis. Several preclinical studies have reported that ASK1 leads to oxidative stress-induced apoptosis of podocytes, mesangial cells, and tubular epithelial cells [111]. Therefore, ASK1 inhibitors were considered promising as a treatment for DKD. Although selonsertib, a selective inhibitor of ASK1, did not reach the primary end-point of slowing eGFR decline in a phase 2 study, an exploratory post-hoc analysis suggests that selonsertib could slow the progression of DKD [112]. The phase 2 MOSAIC trial (NCT04026165) seeks to answer if selonsertib can retard the progression of DKD in patients with moderate to advanced CKD.

Interleukin-33 (IL-33) is released due to cellular damage as a result of oxidative stress and hyperglycemia, and IL-33 inhibition have been shown to reduce albuminuria and glomerular damage in animal studies [113]. Tozorakimab, a potent human anti-IL-33 monoclonal antibody, inhibits IL-33 by blocking the advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signaling pathways [114]. The ongoing phase 2b FRONTIER-1 study (NCT04170543) will test the efficacy and safety of adding tozorakimab to conventional ACEi or ARB therapy in reducing inflammation and albuminuria in patients with type 2 diabetes and DKD.

3.4. Nutrition and metabolism

3.4.1. Ketoanalogue, probiotics

In patients with advanced CKD, low dietary protein may improve glomerular hyperfiltration, glomerular hypertension, and glomerulosclerosis by reducing inflammation and oxidative stress, as well as decreasing constriction of afferent arterioles [115]. Dietary protein restriction may slow the progression to ESKD; however, there is a risk of amino acid deficiency and sarcopenia from such a diet [116]. In patients with CKD without diabetes, supplementation of a low protein diet with ketoanalogues has been recommended to attenuate CKD progression and reduce the risk of dialysis initiation [117]. In patients who have DKD and are not on dialysis, a meta-analysis found that ketoanalogue supplementation of a low protein diet may ameliorate eGFR decline, reduce proteinuria by 1.41 g/day, and reduce serum urea levels [116]. However, most of the studies included were small and heterogenous, with ongoing trials evaluating the effects of ketoanalogue supplementation on eGFR decline (NCT05952544) and effectiveness in delaying dialysis initiation (NCT03415074) potentially providing greater insight into this form of treatment.

Dysbiosis of the gut microbiome has been linked to the progression of DKD due to increased gut permeability, leading to translocation of proinflammatory bacterial products and triggering an inflammatory response. A reduced level of short-chain fatty acids is the hallmark of gut microbiome dysbiosis, resulting in oxidative stress and damage to glomerular mesangial cells and podocytes [118]. It is postulated that altering the gut microbiome and reducing intestinal permeability may be useful in ameliorating the progression of DKD. Ongoing trials evaluating the effects of probiotics on albuminuria in patients with type 1 diabetes (NCT04635670) and on progression of DKD in type 2 diabetes (NCT05674981) may inform us on the importance of targeting the gut-kidney axis as an approach to retard DKD. However, more investigation is needed to explore the appropriate dose and duration of treatment in order to observe long-term outcomes.

3.5. Thromboxane synthase and thromboxane receptor inhibitor

Besides the activation of platelets, thromboxane A2 may mediate renal fibrosis in DKD. Mouse studies found that the urinary excretion of thromboxane B2, a more stable but inactive metabolite of thromboxane A2, correlates with the progression of nephropathy [119]. Infusion of a thromboxane A2 receptor antagonist in hypertensive mice demonstrated decreased proteinuria due to a reduction in renal inflammation and arteriolosclerosis [120]. The ongoing phase 2 study of SER150 (NCT04881123), a novel thromboxane synthase and thromboxane receptor inhibitor, may provide us with more clinical information on the efficacy of inhibiting the thromboxane pathway, including its effects on albuminuria and CKD progression (NCT04881123).

4. Expert opinion

Results from clinical trials in the past decades have shown remarkable progress in the pharmacological management of DKD. Building on the initial studies demonstrating the benefits of intensive glycemic control and RAS inhibition, there is strong evidence to support the renoprotective effects of SGLT2 inhibitors, and an increasing body of evidence supporting the use of GLP-1RAs and non-steroidal MRAs for the treatment of albuminuric DKD. However, more research is required to identify suitable treatment options for non-albuminuric DKD. Further studies are also needed to advance our knowledge and understanding of the renoprotective mechanisms conferred by the new therapeutic agents. It is also important to determine the suitability and efficacy of multiple interventions in prevention and retardation of diabetic kidney disease progression, as well as the ideal combination and sequence. The development of pharmacogenomics in diabetes will allow us to better understand the efficacy of the therapeutic options in different individuals, allowing us to provide personalized medicine care for our patients. Besides slowing the progression of DKD, more focus is also needed in the prevention and reversal of the condition. It is predicted that the numerous trials that are underway will provide us with new therapeutic options in DKD treatment, prevention and hopefully reversal over the years ahead.

Declaration of interest

M E Cooper has received honorarium from companies making anti-diabetic drugs including AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and Eli Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.