Evidence for Novel Pharmacotherapies in Diabetic Kidney Disease

Abstract

Chronic kidney disease, defined as abnormal kidney function for more than 3 months, affects roughly 15% of the US, and approximately 40% of people with chronic kidney disease have type 2 diabetes. In the last decade, pharmacotherapies have been approved that may reduce chronic kidney disease progression and its complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) are recommended for diabetic kidney disease as they may reduce chronic kidney disease progression and cardiovascular events. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are recommended for those with diabetic kidney disease who have not achieved glycemic targets with metformin and SGLT2Is. Finerenone (a nonsteroidal mineralocorticoid receptor antagonist [MRA]) may reduce chronic kidney disease progression and cardiovascular events. This chapter will review the evidence for these pharmacotherapies for diabetic kidney disease.

1. Introduction

Chronic kidney disease (CKD) is defined as the presence of an abnormality in kidney structure or function persisting for more than 3 months [1]. This includes one or more of the following: (1) estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m²; (2) urine albumin ≥30 mg per 24 h or urine albumin-to-creatinine ratio (UACR) ≥30 mg/g; (3) abnormalities in urine sediment, histology, or imaging suggestive of kidney damage; (4) renal tubular disorders; or (5) history of kidney transplantation [2]. Stages of CKD are based on UACR and eGFR and predict risk of progression to end-stage kidney disease (ESKD), defined as the requirement for renal replacement with chronic dialysis or kidney transplantation.

The prevalence of CKD in people with diabetes is approximately 20%, while it is 10% in those with prediabetes [1]. Because it is the leading cause of CKD, optimal screening and treatment of diabetes is essential in preventing CKD progression. This includes screening for proteinuria, optimizing glucose levels, and reducing cardiovascular morbidity and mortality [3].

Pharmacotherapy is a mainstay in the treatment of CKD for controlling blood pressure, glucose levels, and preventing CKD progression. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) demonstrated benefit for diabetic nephropathy decades ago. In 1993, The Collaborative Study Group Captopril Trial showed that in participants with insulin-dependent diabetes and proteinuria, captopril reduced the risk of serum creatinine doubling by 48%, and the composite risk of death, dialysis, and transplantation by 50% [4]. In 2001, The Irbesartan Diabetic Nephropathy Trial (IDNT) showed that irbesartan reduced disease progression in participants with diabetic nephropathy (32.6% vs. 39.0%; RR 0.8; p = 0.02), independent of its antihypertensive effects [5]. In 2001, The Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study showed that losartan reduced progression to ESKD (19.6% vs. 25.5%; relative risk (RR) 0.72; p = 0.002) and serum creatinine doubling (21.6% vs. 26.0%; RR 0.75; p = 0.006) in participants with diabetic nephropathy [5].

Aside from ACEI/ARBs for CKD treatment, novel pharmacotherapies include sodium-glucose cotransporter-2 inhibitors (SGLT2Is), glucagon-like peptide 1 receptor agonists (GLP-1 RAs), and finerenone. SGLT2Is are recommended for diabetic kidney disease to prevent CKD progression and cardiovascular events [6]. GLP-1 RAs are recommended for those with diabetic kidney disease who have not achieved glycemic targets with metformin and SGLT2Is [7]. Finerenone (a nonsteroidal mineralocorticoid receptor antagonist [MRA]) has been shown to reduce CKD progression and cardiovascular events [8].

2. Evidence

2.1 Sodium-glucose Cotransporter-2 Inhibitors

SGLT2Is reduce renal tubular glucose reabsorption, lowering blood glucose without stimulating insulin release. Several trials (CANVAS, CREDENCE, DAPA-CKD) have shown that SGLT2Is may reduce CKD progression (Table 1). The proposed mechanisms are: (1) reduction of glomerular hyperfiltration via increased delivery of sodium to the macula densa and afferent arteriolar constriction, which lowers intraglomerular pressure and reduces albuminuria, (2) reduction of tubular workload due to decreased SGLT2 co-transporter activity, and (3) reduced renal inflammation due to reduced albuminuria, tubular cell glucose, and induction of inflammatory cytokines and fibrotic mediators [9].

	CANVAS	CREDENCE	DAPA-CKD
Study Design	Double-blind RCT	Double-blind RCT	Double-blind RCT
Participants	10,142	4401	4304
Inclusion Criteria	DM2, high CV risk	DM2, albuminuria	CKD, albuminuria, with or without DM2
Exclusion Criteria	DM1, DKA history	DM1, dialysis, transplant, non-DM kidney disease	DM1, PCKD, lupus nephritis, vasculitis, transplant history
Baseline Therapy	Antihyperglycemic agents or no therapy	ACEI/ARB therapy	Maximum ACEI/ARB therapy
Intervention	Canagliflozin (300 mg daily vs.100 mg daily) vs. placebo	Canagliflozin (100 mg daily) vs. placebo	Dapagliflozin (10 mg daily) vs. placebo
Outcomes	CV mortality, nonfatal MI, or nonfatal stroke: 26.9 vs. 31.5 participants per 1000 pt-yrs; HR 0.86; 95% CI 0.75–0.97	ESKD, Cr doubling, or renal/CV mortality: 43.2 vs. 61.2 events per 1000 pt-yrs; HR 0.70; 95% CI 0.59–0.82	Reduction in eGFR >50%, new ESKD, or renal/CV mortality: 9.2% vs. 14.5%; HR 0.61; 95% CI 0.51–0.72
	Albuminuria increase >30%: 89.4 vs. 128.7 participants per 1000 pt-yrs; HR 0.73; 95% CI 0.67–0.79	Cr doubling: 20.7 vs. 33.8 events per 1000 pt-yrs; HR 0.60; 95% CI 0.48–0.76	Reduction in eGFR >50%: 5.2% vs. 9.3%; HR 0–53; 95% CI 0.42–0.67
	Reduction in eGFR>40%, renal replacement or renal death: 5.5 vs. 9.0 participants per 1000 pt-yrs; HR 0.60; 95% CI 0.47–0.77	ESKD: 20.4 vs. 29.4 events per 1000 pt-yrs; HR 0.68; 95% CI 0.54–0.86	New ESKD: 5.1% vs. 7.5%; HR 0.64; 95% CI 0.50–0.82
Adverse Events	Mycotic genital infection, amputation risk (both higher in canagliflozin group)	Mycotic genital infection, DKA (higher in canagliflozin group).	Volume depletion (higher in dapagliflozin group)
Limitations	Few patients with baseline CKD	Statin use not controlled	Trial stopped early due to benefits; underpowering of less common endpoints

Table 1.

Clinical trials involving SGLT2Is.

Abbreviations: SGLT2Is—sodium-glucose cotransporter-2 inhibitors; CANVAS—CANagliflozin cardioVascular Assessment Study; CREDENCE—Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-CKD—Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; RCT—randomized controlled trial; DM2—type 2 diabetes mellitus; CV—cardiovascular; CKD—chronic kidney disease; DKA—diabetic ketoacidosis; DM1—type 1 diabetes mellitus; PCKD—polycystic kidney disease; ACEI—angiotensin converting enzyme inhibitor; ARB—angiotensin receptor blocker; mg—milligrams; MI—myocardial infarction; pt-yrs—patient-years; HR—hazard ratio; CI—confidence interval; eGFR—estimated glomerular filtration rate; ESKD—end-stage kidney disease; Cr—creatinine.

2.1.1 CANVAS

The CANagliflozin cardioVascular Assessment Study (CANVAS) involved two multicenter, randomized, placebo-controlled trials with 10,142 participants in 30 countries [10]. It was an intention-to-treat analysis that enrolled participants from 2009 to 2013 and followed participants for a median of 126 weeks, and it included those with type 2 diabetes with hemoglobin A1C (HbA1C) between 7% and 10.5% not currently on antihyperglycemic therapy. Progression of albuminuria, defined as >30% increase in UACR, and progression of CKD, defined as >40% reduction in eGFR, were lower in the canagliflozin group (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.67–0.79; and HR 0.60; 95% CI 0.47–0.77, respectively). Canagliflozin lowered the primary cardiovascular outcome, which included cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (HR 0.86, 95% CI 0.75–0.97) [10]. Significant adverse events included: risk of amputation, genital infections, and osmotic diuresis.

CANVAS has been criticized for having too few participants with baseline CKD, and so these results may not be generalizable to the population with CKD. Overall, these were novel results because previous medications such as insulin, sulfonylureas, and dipeptidyl peptidase-4 (DPP-4) inhibitors had not been associated with improvements in cardiovascular outcomes or survival. This study was the first to show that SLGT2Is may reduce kidney disease progression.

2.1.2 CREDENCE

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was a prospective, double-blind randomized controlled trial with 4401 participants across 690 sites in 34 countries [11]. It was an intention-to-treat analysis that enrolled participants from 2014 to 2017, and followed them for a median of 2.6 years. The study included 4401 participants with type 2 diabetes (HbA1C 6.5–12.0%) and CKD stage G2-G3/A3 (baseline eGFR 30 to <90 mL/min/1.73m² and UACR>300 to 5000 mg/24 h) taking ACEI or ARB therapy. Those randomized to canagliflozin had a lower risk of developing the primary composite kidney outcome of doubling of serum creatinine, ESKD, or death from a kidney or cardiovascular cause, compared with those randomized to placebo (HR 0.70; 95% CI 0.59–0.82; p < 0.01). Significant adverse events included genital mycotic infection and diabetic ketoacidosis. A criticism of this study was that statin use was not universal in this trial and could have confounding effects since statins have been shown to prevent cardiovascular events [12].

2.1.3 DAPA-CKD

The Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial was a multicenter, double-blind, randomized placebo controlled trial with 4304 participants enrolled from 2017 to 2018 in 450 sites from 20 countries [13]. It was an intention-to-treat analysis with a mean follow-up of 2.4 years. Participants had eGFR between 25 and 75 mL/min/1.73 m², UACR between 200 and 5000 mg/g, and were already on maximum ACEI/ARB therapy. This study found reduced primary outcome of eGFR decline >50%, new ESKD, or kidney or CVD mortality in the dapagliflozin group (9.2% vs. 14.5%, HR 0.61, 95% CI 0.51–0.72). A subgroup analysis revealed that in participants without diabetes, dapagliflozin reduced the primary outcome (HR 0.50; CI 0.35–0.72).

2.1.4 EMPA-KIDNEY

The EMPAgliflozin Once Daily to Assess Cardiorenal Outcome in Patients with Chronic KIDNEY Disease (EMPA-KIDNEY) trial was designed to investigate the effect of empagliflozin on kidney outcomes and cardiovascular death in people with CKD [14]. It began in 2019 and is estimated to be completed near the end of 2022. This trial will shed light on whether SGLT2Is benefit people with proteinuria regardless of diabetes status.

2.2 Glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) stimulate glucose-dependent insulin secretion. They are thought of as a “satiety peptide” that promotes release of insulin when glucose is elevated, while also decreasing prandial glucagon and delaying gastric emptying. GLP-1 RAs have the added benefit of promoting weight loss. Because they have shown to improve cardiovascular outcomes in the LEADER and REWIND trials among others, the American Diabetes Association (ADA) recommends GLP-1 RAs in people with type 2 diabetes with cardiovascular disease (Table 2) [7]. However, in a meta-analysis, GLP-1 RAs did not significantly decrease the risk of kidney events (RR 0.86 [0.72–1.03]) [15]. There has not been substantial evidence to date that GLP-1 agonists slow CKD progression, as there has not been a published GLP-1 RA trial with primary endpoint of kidney events. Existing data on kidney outcomes have been provided by cardiovascular outcomes trials.

	LEADER	REWIND
Study design	Double-blind RCT	Double-blind RCT
Participants	9340	9901
Inclusion Criteria	DM2	DM2, CV risk factors
Exclusion Criteria	DM1, previous use of GLP-1 RA, ESKD, prior transplant	eGFR<15 ml/min/1.73 m^2, life expectancy<1 yr, severe hypoglycemia in previous yr
Baseline Therapy	Antihyperglycemic agents or no therapy	Antihyperglycemic agents or no therapy
Intervention	Liraglutide (1.8 mg daily) vs. placebo	Dulaglutide (1.5 mg daily) vs. placebo
Outcomes	Nonfatal MI, nonfatal stroke, or CV mortality: 13.0% vs. 14.9%; HR 0.87; 95% CI 0.78–0.97	Nonfatal MI, nonfatal stroke, or CV mortality: 12.0% vs. 13.4%; HR 0.88; 95% CI 0.79–0.99
	All-cause mortality: 8.3% vs. 9.6%; HR 0.78; 95% CI 0.74–0.97	New albuminuria>300 mg/g, reduction in eGFR>30%, or need for renal replacement: 17.1% vs. 19.6%; HR 0.85; 95% CI 0.77–0.93
	New or persistent albuminuria, Cr doubling, CRRT need, or renal death: 5.7% vs. 7.2%; HR 0.78; 95% CI 0.67–0.92
Adverse Events	Severe hypoglycemia (higher in placebo group), acute gallstone disease (higher in liraglutide group)	GI adverse events (higher in dulaglutide group)
Limitations	Unequal statin use between groups	>25% participants were not taking study drug at last visit

Table 2.

Clinical trials involving GLP-1 RAs.

Abbreviations: GLP-1 RAs—Glucagon-like peptide-1 receptor agonists; LEADER—Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; REWIND—Researching Cardiovascular Outcomes with a Weekly Incretin in Diabetes; RCT—randomized controlled trial; DM2—type 2 diabetes mellitus; CV—cardiovascular; DM1—type 1 diabetes mellitus; ESKD—end-stage kidney disease; eGFR—estimated glomerular filtration rate; yr.—year; mg—milligrams; MI—myocardial infarction; HR—hazard ratio; CI—confidence interval; Cr—creatinine; CRRT—continuous renal replacement therapy; mg/g—milligrams per gram; GI—gastrointestinal.

2.2.1 LEADER

In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide was found to reduce cardiovascular events compared to placebo in participants with diabetes at risk for cardiovascular disease [16]. This study was a multicenter, randomized, controlled trial that evaluated 9340 participants with type 2 diabetes at 410 sites in 32 countries. Participants had diabetes and cardiovascular diseases, including peripheral vascular disease, CKD, symptomatic congestive heart failure, or hypertension with left ventricular hypertrophy, among others. This intention-to-treat analysis enrolled participants from 2010 to 2012 and followed them up for a median of 3.8 years. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality. Those who received liraglutide had a lower primary outcome compared to placebo (13.0% vs. 14.9%, HR 0.87, 95% CI 0.78–0.97). Those in the liraglutide group also had lower all-cause mortality (8.2% vs. 9.6%, HR 0.78, 95% CI 0.74–0.97, p = 0.02), and a lower rate of the kidney composite endpoint of new or persistent UACR>300 mg/g, doubling of serum creatinine and eGFR<45 ml/min/1.73m², need for continuous renal replacement therapy, or death due to kidney disease (5.7% vs. 7.2%, HR 0.78, 95% CI 0.67–0.92, p = 0.003).

2.2.2 REWIND

The Researching Cardiovascular Outcomes with a Weekly Incretin in Diabetes (REWIND) trial was a multicenter randomized, double-blind controlled trial spanning 371 sites in 24 countries [17, 18]. It examined participants with type 2 diabetes, cardiovascular risk factors, and eGFR>15. The primary composite outcome included non-fatal MI, non-fatal stroke, or death from cardiovascular causes. Compared to placebo, those in the dulaglutide group had fewer primary outcome events (12.0% vs. 13.4%, HR 0.88, 95% CI 0.79–0.99; p = 0.026). However, all-cause mortality was not significantly different between the groups (10.8% vs. 12.0%, HR 0.90, 95% CI 0.80–1.01; p = 0.067).

The kidney outcome evaluated was a composite of new albuminuria>300 mg/g, decline in eGFR 30% or more from baseline, or need for renal replacement therapy. Fewer in the dulaglutide group exhibited the composite kidney outcome (17.1% vs. 19.6%; HR 0.85; 95% CI 0.77–0.93; p = 0.0004). The most prominent effect was reduction of albuminuria (HR 0.77; 95% CI 0.68–0.87; p < 0.0001).

2.2.3 FLOW

The Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease (FLOW) trial was the first kidney outcome trial involving GLP-1 RAs, and it sought to determine the effects of semaglutide on kidney outcomes in people with type 2 diabetes [19, 20]. It began in 2019 and is estimated to be completed in 2024.

2.3 Finerenone

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist. It has been studied recently in two trials (FIDELIO-DKD and FIGARO-DKD) to determine its effect on cardiovascular and kidney outcomes (Table 3). Its proposed mechanism is through decreased mineralocorticoid receptor activation, and subsequent reduction in inflammation, fibrosis, and reactive oxygen species [21].

	FIDELIO-DKD	FIGARO-DKD
Study Design	Double-blind RCT	Double-blind RCT
Participants	5734	7437
Inclusion Criteria	DM2, CKD	DM2, CKD, albuminuria
Exclusion Criteria	Non-diabetic kidney disease, already on MRA, kidney transplant	Symptomatic chronic HFrEF, non-diabetic kidney disease, already on MRA, UACR>5000 mg/g
Baseline Therapy	Maximum ACEI/ARB therapy	Maximum ACEI/ARB therapy
Intervention	Finerenone (20 mg daily) vs. placebo	Finerenone (20 mg daily) vs. placebo
Outcomes	Reduction in eGFR > 40%, kidney failure, or death from kidney causes: 17.8 vs. 21.1%; HR 0.82; 95% CI 0.73–0.93	CV death, nonfatal MI, nonfatal stroke, or heart failure hospitalization: 12.4% vs. 14.2%; HR 0.87; 95% CI 0.76–0.98
	CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization: 13.0% vs. 14.8%; HR 0.86; 95% CI 0.75–0.99	Reduction in eGFR>40%, kidney failure, or death from kidney causes: 9.5% vs. 10.8%; HR 0.87; 95% CI 0.76–1.01
Adverse Events	Hyperkalemia (higher in finerenone group)	Hyperkalemia (higher in finerenone group)
Limitations	Most patients had advanced CKD; only 4.7% Black patients	Only 3.5% Black patients

Table 3.

Clinical trials involving Finerenone.

Abbreviations: FIDELIO-DKD—FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease; FIGARO-DKD—Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease; RCT—randomized controlled trial; DM2—type 2 diabetes mellitus; CKD—chronic kidney disease; MRA—mineralocorticoid receptor antagonist; HFrEF—heart failure with reduced ejection fraction; UACR—urine albumin-creatinine ratio; mg/g—milligrams per gram; ACEI—angiotensin converting enzyme inhibitor; ARB—angiotensin receptor blocker; mg—milligrams; eGFR—estimated glomerular filtration rate; HR—hazard ratio; CI—confidence interval; CV—cardiovascular; MI—myocardial infarction; CKD—chronic kidney disease.

2.3.1 FIDELIO-DKD

The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) trial was a double-blinded randomized trial that showed in participants with CKD and type 2 diabetes, finerenone may lower risk of CKD progression and cardiovascular events [22]. The primary outcome was a composite of a sustained decrease of >40% in eGFR from baseline over a period of >4 weeks, or death from kidney causes. The secondary outcome event was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The primary and secondary outcomes occurred less in the finerenone group (17.8% vs. 21.1%; HR 0.82; 95% CI 0.73–0.93 for the primary outcome; 13.0% vs. 14.8%; HR 0.86; 95% CI 0.75–0.99 for the secondary outcome). Hyperkalemia-related trial discontinuation was higher in the finerenone group vs. placebo (2.3% and 0.9%, respectively).

Finerenone may also reduce new-onset atrial fibrillation/flutter in people with CKD and type 2 diabetes [23]. In this study, new onset atrial fibrillation was lower in the finerenone group compared to placebo (3.2% vs. 4.5%, p = 0.016).

2.3.2 FIGARO-DKD

The Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD) trial was a double-blind randomized trial that finerenone may reduce new onset heart failure and heart failure hospitalization rate among people with CKD and type 2 diabetes [8]. In this study of 7437 participants, 3686 were given finerenone, while there were 3666 in the placebo group. The primary outcome was a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or heart failure hospitalization. This primary outcome event occurred in 12.4% in the finerenone group, and in 14.2% of the placebo group (HR 0.87; 95% CI 0.76–0.98).

Most of the benefit of finerenone was found to be from heart failure hospitalization (HR 0.71). The secondary outcome was a composite of kidney failure, defined as a sustained decrease in eGFR from baseline of at least 40%, or death from kidney causes. This event occurred in 9.5% of the finerenone group and 10.8% of the placebo group (HR 0.87; 95% CI 0.76–1.01). Of note, hyperkalemia-related discontinuation of the trial regimen was higher in the finerenone group (1.2% vs. 0.4%).

3. Discussion

3.1 Summary of kidney outcomes

In people with type 2 diabetes, canagliflozin may reduce albuminuria progression, and the composite outcome of doubling of serum creatinine, ESKD, or kidney or cardiovascular mortality [10, 11]. In people with CKD, dapagliflozin may reduce the composite outcome of eGFR decline >50%, new ESKD, or kidney or CVD mortality, independent of diabetes status [13]. In people with diabetes at risk for cardiovascular disease, liraglutide may reduce all-cause mortality, and the composite outcome of new or persistent albuminuria, doubling of serum creatinine and eGFR<45 ml/min/1.73 m², need for continuous renal replacement therapy, or death due to kidney disease [16]. In people with diabetes and cardiovascular risk factors, dulaglutide may reduce the composite outcome of new albuminuria > 300 mg/g, decline in eGFR 30% or more from baseline, or need for renal replacement therapy [18]. In people with CKD and type 2 diabetes, finerenone may lower the composite outcome of sustained decrease of at least 40% in the eGFR, or death from kidney causes [8, 22].

3.2 Comparison of newer therapies to established therapies

It is important to note that the reduction in kidney events was higher in general for ACEI/ARBs compared to SGLT2Is or finerenone, although these therapies have not been directly compared [5, 10, 11, 22]. In the SGLT2I and finerenone trials, participants were also on ACEI/ARB therapies. Thus ACEI/ARB are still first line for treatment of kidney disease with albuminuria. Studies have not compared SGLT2Is to finerenone. The effects of combined SGLT2I and finerenone therapy on kidney outcomes are unknown. Both SGLT2Is and finerenone cause adverse events, which must also be considered along with their benefits [24].

3.3 Approach to therapy along the continuum of diabetic kidney disease

All people with CKD should follow lifestyle modifications (increased exercise, low sodium diet, protein restriction, and reduced dietary acid loads) to manage blood pressure and glucose levels, and to reduce cardiovascular risk (Figure 1).

Figure 1.

DKD treatment continuum. This illustrates therapeutic approaches that may reduce DKD progression, and the associated eGFRs for which they have been studied. Listed underneath each drug class are the benefits and side effects. Abbreviations: DKD—diabetic kidney disease; eGFR—estimated glomerular filtration rate; CKD—chronic kidney disease; ACEI—angiotensin converting enzyme inhibitor; ARB—angiotensin receptor blocker; CV—cardiovascular; GFR—glomerular filtration rate; SGLT2Is—sodium-glucose cotransporter-2 inhibitors; DKA—diabetic ketoacidosis; GLP-1 RAs—glucagon-like peptide-1 receptor agonists; GI—gastrointestinal.

*SGLT2Is may be continued for eGFR < 30 mL/min/1.73 m² given that they were initiated when eGFR > 30 mL/min/1.73 m², and they may be continued until a person is on dialysis.

ACEI/ARB therapy is recommended for treatment in people with CKD (diabetic or non-diabetic), with urine albumin excretion>30 mg/day. They can also be used as initial pharmacotherapy to treat hypertension. These medications should be held in the setting of acute kidney injury and should be discontinued if associated with hyperkalemia that cannot be controlled with dietary restriction or potassium binders [24].

SGLT2Is should be initiated in people with type 2 diabetes and CKD with eGFR≥30 mL/min/1.73 m². They have not been studied in people with eGFR <30 ml/min/1.73 m², thus they should not be initiated in people with CKD stages 4–5. Studies have shown that if they are started when eGFR is above 30 mL/min/1.73 m², they can be continued until the individual is on dialysis and then stopped [25, 26]. However, they likely have benefit in people with eGFR<30 mL/min/1.73 m² based on a pooled analysis of phase 3 randomized controlled trials [27]. Dapagliflozin may benefit people who have albuminuria who do not have diabetes [13]. The DAPA-CKD study excluded patients with type 1 diabetes and specific kidney conditions including polycystic kidney disease, lupus nephritis, vasculitis, and history of organ transplantation [13]. Therefore, outcomes of SGLT2Is in these specific populations are unknown. SGLT2Is should be used with caution in people with a prior lower extremity amputation or threat of amputation. Adverse effects include polyuria, hyperkalemia, a higher risk for genital mycotic infections, diabetic ketoacidosis, bony fractures, and the need for lower limb amputations.

GLP-1 RAs may be used in people with type 2 diabetes and diabetic kidney disease, after metformin and SGLT2Is have not shown improved glycemic control. Studies have shown that liraglutide and dulaglutide improved kidney outcomes, although most of the trials involving GLP-agonists focused on improved cardiovascular outcomes as the primary endpoint. In REWIND, dulaglutide was studied in people with eGFR>15 mL/min/1.73 m², thus it may be used for Stage 4 CKD. Adverse effects include diarrhea, nausea, headache, and hypoglycemia.

Finerenone may be used in people with type 2 diabetes and diabetic kidney disease, with eGFR≥25 mL/min/1.73 m². It has not been studied among people with eGFR<25 mL/min/1.73 m². The risk of hyperkalemia may be higher among people on concurrent finerenone and ACEI/ARB therapy [28]. Caution is advised among people with hepatic impairment and those taking strong CYP3A4 inhibitors, because finerenone is a sensitive CPY3A4 substrate and its effects may be increased through CYP3A4 inhibition [29].

3.4 Approaches to develop therapeutics for CKD progression

The rising global burden of CKD requires comprehensive educational campaigns, screening for early CKD, and novel therapeutics to mitigate progression to ESKD and the need for dialysis [30]. Coordination between scientists, policymakers, physicians, pharmaceutical companies, insurance companies, governments, and other key players is paramount in advancing therapies from bench to bedside. The relationship between CVD and CKD is complex—it is known that CVD is a common complication in people with CKD, yet there are limited evidence and therapies to prevent CVD in people with CKD [31]. Blood pressure control, statin use, and renin-angiotensin-aldosterone axis blockade have improved cardiovascular outcomes, however excess mortality remains in people with CKD compared with the general population [3]. There is also an increasing incidence of CKD resulting from unknown causes in certain “hotspots” that exacerbates this problem [32].

Pollock et al. outlined four major goals towards establishing and validating novel therapeutic targets to reduce CKD progression [33]. The first goal is to improve identification of therapeutic targets. This requires use of biomarkers, −omics data, and cross-disciplinary research to identify pathophysiologic mechanisms. For example, what we learn about the physiological mechanism of kidney fibrosis may be useful in informing drug mechanistic approaches to prevent fibrosis leading to CKD. Acute kidney injury (AKI) is associated with CKD development, and understanding the multifactorial relationship between the two is crucial [34].

The second goal is to enhance preclinical and early clinical development. This requires improving clinical networks for CKD populations to facilitate trial recruitment, developing infrastructure to study human tissue to better understand CKD progression, improving collaboration between academic research scientists and the biotechnology company researchers, and rewarding academic career development when involved with industry to develop therapeutics.

The third goal is to increase availability of novel therapeutic approaches. This entails evaluating opportunities for repurposing drugs to find treatments for CKD and its complications, as well as improving access to costly drugs and biologics in low- and middle-income countries.

The fourth goal—encouraging investment in CKD therapeutics—is crucial to the overall global mission to reduce CKD progression. This includes marketing economic opportunity and developing business cases, lobbying for funding from governments and industry, and documenting differences in CKD treatment practice patterns and the therapeutic needs of different countries. Therapeutics in development for CKD include those mentioned in this article as well as drugs that reduce inflammation and mitigate oxidative injury [35].

4. Conclusion

ACEI/ARBs have been the mainstay for preventing CKD progression for the last several decades [36]. SGLT2Is and finerenone are newer therapies that may prevent disease progression in those with diabetic kidney disease, while GLP-1 RAs are useful in preventing cardiovascular disease in those with diabetes and cardiovascular risk factors. GLP-1 RAs have shown promise in preventing kidney outcomes through primary cardiovascular outcomes trials, but they have not directly been tested for kidney outcomes as a primary endpoint.

As the global burden of CKD rises, it is essential to improve the therapeutic development process from all perspectives, including academic research and industry. The scientific process of advancing basic and clinical biological research to identify therapeutic targets is just as critical as creating avenues for investment in CKD research, global collaboration in implementing clinical trials and information sharing, and improving access to costly drugs. To arrive at a comprehensive solution for CKD, many more advances in the basic science and genetics of kidney disease are essential. The increasing need to serve people with CKD will hopefully engender an era of evidence-based therapeutics that will revolutionize CKD care such that reaching ESKD will be a rarity.

Conflicts of interest and sources of funding

No conflicts of interest or funding sources are reported.