Clinical implications and guidelines for CKD in type 2 diabetes

ABSTRACT

Background

Chronic kidney disease (CKD) is a complication of type 2 diabetes (T2D) with high morbidity and mortality. The prevalence of CKD in T2D is increasing due to rising numbers of persons with T2D. Multiple clinical trials have been conducted testing novel therapies to reduce the progression of CKD, cardiovascular morbidity, in particular hospitalization for heart failure, and mortality. Results of these clinical trials have informed guidelines for the management of CKD in T2D.

Methods

The epidemiology of CKD in T2D and the process of guideline writing, including data gathering, grading and consensus development, were reviewed. Recent guidelines for the management of CKD in T2D that include recent renal outcome clinical trials are reported, along with supporting evidence.

Results

All current guidelines recommend annual screening for CKD, control of blood pressure and glucose, although the target levels and background therapy recommendations vary. Renin–angiotensin system (RAS) inhibition is uniformly recommended. Sodium-glucose cotransporter-2 (SGLT2) inhibition with proven agents is recommended by all guidelines, with minor variations in suggested estimated glomerular filtration rate and albuminuria levels. Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist with renal outcome data, is recommended by the most recent guideline available.

Conclusions

Current guidelines continue to recommend screening for CKD, blood pressure control using RAS inhibition as first-line therapy, and glucose control. SGLT2 inhibition and finerenone are recent additions to current guidelines to improve CKD outcomes in T2D, based on robust clinical trial data.

Graphical Abstract

chronic kidney disease, diabetes, diabetic kidney disease, diabetic nephropathy, guidelines

INTRODUCTION

Chronic kidney disease (CKD) affects approximately one out of nine people globally or approximately 800 million people, and the prevalence has been increasing with serious and important implications for public health and society due to increasing disease burden, complications leading to cardiovascular (CV) morbidity—particularly related to heart failure—and excess mortality, as well as costs related to the management of kidney failure [1]. CKD is an increasingly common cause of death. Diabetes is the leading cause of CKD followed by hypertension and glomerular diseases. The global increase in diabetes from more than 537 million people currently to 780 million by 2045 means more people are at risk for diabetes-related complications including CKD, which affects 30%–40% of people with diabetes [2]. Population-based data from the USA demonstrated a 28% reduction in risk for kidney failure in diabetes from 1990 to 2010, but due to the increased population at risk, the number of patients referred for the management of kidney failure increased from ∼17,000 to 50,000 during this period [3]. These data reflect a need for better prevention and treatment of CKD in diabetes [4].

After many years where renin–angiotensin system (RAS) blockade was the only therapy with renal protection, we now have sodium-glucose cotransporter-2 inhibitors (SGLT2i) which reduce progression of CKD in addition to cardiovascular disease (CVD) events, in particular heart failure hospitalization, in people with CKD with and without diabetes [5, 6]. In addition, blocking mineralocorticoid receptor overactivation with a nonsteroidal mineralocorticoid receptor antagonist (MRA) demonstrated benefit in type 2 diabetes (T2D) and CKD, where two large studies of finerenone demonstrated reduced progression of CKD and of CVD (particularly heart failure hospitalization) [7, 8]. These studies provide new and promising opportunities for reducing the burden of CKD for patients and society, but screening for CKD and use of proven therapies is critical for successful implementation of the new trial data into clinical practice. Recent data from the USA demonstrated that only 55% of persons with T2D are screened for albuminuria [9], and although RAS blockade became standard of care in 2001 surveys still demonstrate that implementation of RAS blockade is far from optimal [10]. In order to improve screening and implementation of the new therapeutic options, national and international scientific societies and organizations have issued guidelines to clarify recommendations and support optimal screening and treatment of CKD. Here we compare some of the recent guidelines with national or international impact.

MATERIALS AND METHODS

The process of guideline development and the status of current guidelines for the management of CKD in T2D was reviewed. Guidelines and treatment recommendations come in many different forms and thus, the process to develop a guideline also differs widely. Usually, the intention is to develop an evidence-based guidance for healthcare professionals, where evidence is searched for and analyzed in a systematic way to collect and condense the available relevant information. The Cochrane network has developed a handbook for this [11]. Typically, a working group of persons with relevant expertise is gathered and commissioned with the task of developing a guideline for a specific area and, if relevant, a cross-disciplinary group potentially including patients and or relatives may be included. An evidence review team may coordinate the methodological and analytical processes of guideline development, including literature searching, data extraction, critical appraisal, evidence synthesis and meta-analysis, grading the quality of the evidence per outcome, and grading the quality of the evidence for recommendations. The development of the guideline may follow the standards of GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) [12].

To structure the literature search, clinically relevant questions are formulated (e.g. Do RAS inhibitors improve clinically relevant outcomes and reduce clinically relevant harms in patients with diabetes and CKD?) [13], and the evidence review team performs the search and evaluates the literature. An often-applied method to structure the search questions is PICOM, referring to Population, Intervention, Comparator Outcomes and Methods. For the question above, the population could be “people with diabetes and CKD,” the intervention “angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB),” the comparator “placebo or standard of care,” the outcomes could include “mortality, kidney failure, major adverse cardiovascular events,” and the methods “randomized controlled trials or systematic reviews of trials.” Once relevant studies have been identified, they are evaluated for limitations in design and conduct in a critical appraisal process looking at, for example, the randomization and blinding procedures. Then data are extracted and pooled to provide summary statistics. The consistency or heterogeneity of the finding is assessed. As there is a tendency for positive findings to be reported more often than neutral findings, it is important to try to avoid publication bias and, for example, look for unpublished data. Sub-analyses can provide insight into the consistency of the findings, and sensitivity analyses may provide information on robustness of the findings. The underlying evidence is graded with respect to quality of the evidence and a recommendation can be issued. After balancing benefits and risks, the strength of the recommendation can be graded. Costs for implementation and savings from prevented or delayed events may also be evaluated. Finally, the conclusion may be reported according to AGREE II [14]. As an alternative to this thorough but time-consuming process, the working group may develop a local guideline based on international guidelines, or systematic reviews with adaptation of recommendations to local needs and conditions.

RESULTS

Diagnosis and definition of diabetic kidney disease or CKD in diabetes

The diagnosis of CKD was proposed by the 2002 KDOQI writing group and confirmed by the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) working group [15, 16]. The diagnosis and classification of CKD are based on demonstration of reduced kidney function, estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² or kidney damage that is present for at least 3 months. The finding of a urine albumin to creatinine ratio (UACR) of >30 mg/g represents kidney damage, while higher levels of UACR >300 mg/g, predict more rapid decline of kidney function [17]. The combination of these biomarkers provides a classification system with risk stratification for progression to end-stage kidney disease [17].

Diabetic kidney disease (DKD) is a clinical diagnosis based on the findings of reduced eGFR (<60 mL/min/1.73 m²) or elevated albuminuria (UACR ≥30 mg/g) in an individual with either type 1 diabetes (T1D) or T2D in the absence of other causes of kidney disease, notwithstanding the limitations and variability of the tests including higher UACR in marked hyperglycemia, fever, or infection irrespective of altered renal function [18]. In recent guidelines, the terms DKD and CKD in diabetes or diabetes and CKD are used interchangeably, with a trend toward use of the CKD terminology [17, 19]. The American Diabetes Association (ADA) 2022 Standards of Care recommend annual screening for CKD in diabetes with measurements of eGFR and UACR, and verification of the first abnormal test within 3 to 6 months. More frequent testing is indicated if kidney function is reduced, declines rapidly or if albuminuria increases rapidly [19]. The 2020 KDIGO guideline does not cover screening or diagnosis of CKD in diabetes, but focuses on management [17]. Despite recommendations, UACR is underutilized in the real-world leading to unrecognized DKD risk [18].

Blood pressure

Blood pressure (BP) management is central for preventing CKD and reducing progression, and all guidelines agree on this issue. Recommended BP measurement method and BP targets, however, differ somewhat between guidelines. The ADA and KDIGO BP guidelines are similar, with regards to recommended drugs for treatment, correct BP measurement, and individual BP targets [19, 20]. The ADA 2022 guidelines mention a BP target of <140/90 mmHg, but lower targets (<130/80 mmHg) should be considered to reduce CVD and CKD progression when UACR is ≥300 mg/g [19]. The European Society of Cardiology (ESC) 2019 guidelines state the target in persons with diabetes should be 130 mmHg systolic BP (SBP), and less (<130 but >120 mmHg) if tolerated, with a goal of 130–139 mmHg in people >65 years [21]. The KDIGO 2021 BP guideline recommends a target SBP of <120 mmHg using office BP, based mostly on the Systolic Blood Pressure Intervention Trial (SPRINT) study conducted in people without diabetes, acknowledging the limitation for this target in persons with diabetes and CKD [20]. In general, the guidelines advocate choosing individual BP targets that balance anticipated benefits (higher benefit in higher risk-profile patients) and risks of drug side effects. There is wide consensus on the use of ACEi or ARBs as first-line therapy, both in persons with diabetes and CKD as well as in non-diabetic CKD. This is based on studies in patients with elevated albuminuria that demonstrated decreased risk of CKD progression. The KDIGO BP guidelines recommend MRA in refractory hypertension [20]. In addition, KDIGO/ADA recommend first-line therapies are acceptable including dihydropyridine calcium channel blockers and thiazide-like diuretics for patients with hypertension who do not have albuminuria [17, 22].

Glycemic targets

Assessing glycemic control by hemoglobin A_1c (HbA_1c) is recommended in persons with diabetes and CKD twice yearly if at glycemic goal and four times per year if not at goal (Table 1) [17, 23]. HbA_1c has reduced accuracy in advanced CKD (G4-5) and dialysis according to the KDIGO 2020 guidelines [17]. Further, the following CKD conditions bias HbA_1c measurements: bias towards higher HbA_1c in metabolic acidosis (overestimation of mean glucose) or bias towards a lower HbA_1c (underestimation of mean glucose) when anemia is present or when transfusions, iron replacement or erythropoiesis-stimulating agents are used due to more rapid red blood cell turnover and shorter survival. With these limitations, the KDIGO 2020 guideline advises using glucose management indicator (GMI) from a continuous glucose monitor (CGM) as an alternative to HbA_1c, particularly in patients with discordance between blood glucose values including those with advanced CKD [17]. The KDIGO 2020 guidelines recommend HbA_1c target <6.5 or 7.0% to prevent complications, while patients with multiple comorbidities or high risk for hypoglycemia can aim for HbA_1c <7.5 or 8.0% [17]. This is in agreement with the ADA 2022 guidelines which advises using HbA_1c or GMI twice annually or quarterly [23]. The recommended HbA_1c goal is <7% for nonpregnant patients without significant hypoglycemia while less stringent goals can be used (<8%) for those with limited life-expectancy or at higher risks for harm [23]. Further, CGM metrics such as time in range (70–180 mg/dL) >70%, below range <4%, and <1% of time <54 mg/dL can be used [23]. The ESC 2019 guidelines advise targeting a HbA_1c <7.0% to prevent microvascular complications with individualized targets based on patient-specific factors [21]. Finally, the Japanese Clinical Practice Guidelines 2019 suggests aiming for a HbA_1c <6.0% if trying to achieve normal glycemia, <7.0% to prevent complications and <8.0% if intensifying therapy is difficult [24]. Despite variations on HbA_1c goals, all guidelines recommend individualized glycemic targets.

Table 1:

Summary of guidelines for diabetes management in CKD.

Guideline	Albuminuria testing	Blood pressure	ACEi or ARB	Glycemic control	SGLT2i	GLP-1 RA	Metformin	Finerenone
KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease	Yearly screening with urine albumin excretion and eGFR	Diabetes, hypertension, albuminuria: ACEi or ARB (1B) Refractory hypertension: Mineralocorticoid receptor antagonists	Recommend ACEi/ARB in patients with diabetes, hypertension and albuminuria. Titrate to highest tolerated dose (1B) May be considered in patients with diabetes, albuminuria and normal blood pressure	Recommend individualized HbA1c target ranging from <6.5% to <8.0% in patients with diabetes and CKD not treated with dialysis (1C): Prevention of complications is goal: HbA1c <6.5%–7.0% Multiple comorbidities, high risk for hypoglycemia: HbA1c <7.5%–8.0% *GMI from CGM can be used to judge glycemic control for patients whose HbA1c is discordant with blood glucose or clinical symptoms	Recommend treating patients with T2D, CKD, and eGFR ≥30 mL/min/1.73 m2 with SGLT2i (1A) or add to other antihyperglycemic medications if glycemic targets are not met or meeting glycemic target but can safely attain lower target *Prioritize SGLT2i with documented kidney or CV benefits and take eGFR into account	Patients with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT2i or unable to tolerate: recommend long-acting GLP-1 RA (1B)	Glycemic management for T2D and CKD should include lifestyle therapy, first-line treatment with metformin and a SGLT2i and additional drug therapy as needed for glycemic control First line for T2D, CKD and eGFR ≥30 mL/min/1.73 m2(1B)	NA
American Diabetes Association Standards of Medical Care in Diabetes 2022	T1D duration of ≥5 years and all T2D: at least annual urinary albumin (spot UACR) and eGFR (B) Diabetes and urinary albumin ≥300 mg/g creatinine and/or eGFR 30–60 mL/min/1.73 m2: monitor twice annually (B)	All diabetes: <140/90 mmHg *Lower targets (<130/80 mmHg) should be considered based on individual anticipated risks/benefits (UACR ≥300 mg/g creatinine)	Strongly recommended in nonpregnant adults with diabetes, hypertension and UACR ≥300 mg/g creatinine and/or eGFR <60 mL/min/1.73 m2(A) Recommended in modestly elevated albuminuria (30–299 mg/g creatinine) (B)	Nonpregnant adults: HbA1c <7.0% (A) CGM goal in nonpregnant adults: time in range >70%, below range <4%, <1% below 54 mg/dL (B) Limited life-expectancy or higher risk of harm with treatment: HbA1c <8.0% (B)	T2D and CKD: consider SGLT2i for CV risk reduction if eGFR ≥25 mL/min/1.73 m2 or ≥300 mg/g creatinine (A) T2D and DKD: use SGLT2i for eGFR ≥25 mL/min/1.73 m2 or ≥300 mg/g creatinine to reduce CKD progression and CV events (A)	T2D with established or indicators of CVD, HF or CKD: GLP-1 RA and/or SGLT2i with CVD benefit for glycemic control and CV risk reduction independent of HbA1c considering patient-specific factors (A)	First-line therapy depends on comorbidities, patient-centered factors and management needs, and generally includes metformin and comprehensive lifestyle modification (A) *Metformin may be initial treatment of glycemic control, including those with early CKD	CKD subjects at high risk for CV events or CKD progression or unable to tolerate SGLT2i: use nonsteroidal MRA (finerenone) to reduce CKD progression and CV events (A)
European Society of Cardiology Guidelines 2019 on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the European Association for the Study of Diabetes	Screen annually for kidney disease by eGFR and UACR (IA)	Target SBP 130 mmHg and <130 mmHg if tolerated, but not <120 mmHg. In older people (>65 years), SBP goal is to range 130–139 mmHg (IA) Target DBP to <80 mmHg, but not <70 mmHg (IC)	ACEi or ARBs indicated in patients with DM and CAD to reduce risk of CV events (IA) ACEi/ARB recommended to treat hypertension in patients with DM, particularly with proteinuria, microalbuminuria or LVH (IA)	HbA1c target <7.0% to prevent microvascular complications (1A) HbA1c target <7.0% to prevent macrovascular complications (IIa, C) HbA1c targets are individualized according to duration of DM, comorbidities, age (1C)	SGLT2i (empagliflozin, canagliflozin, or dapagliflozin) is associated with lower risk of renal endpoints and recommended if eGFR 30–90 mL/min/1.73 m2(IA) SGLT2i are recommended to reduce progression of DKD (IA) Empagliflozin, canagliflozin, dapagliflozin recommended in T2D and CVD or at very high/high CV risk to reduce CV events (IA) Empagliflozin recommended in T2D and CVD to reduce risk of death (IB)	GLP-1 RA liraglutide and semaglutide is associated with lower risk of renal endpoints and should be considered for DM if eGFR >30 mL/min/1.73 m2(IIa,B) liraglutide, semaglutide, or dulaglutide recommended in patients with T2D and CVD or at very high/high CV risk to reduce CV events (IA) Liraglutide recommended in patients with T2D and CVD or at very high/high CV risk to reduce the risk of death (IA)	Consider in overweight patients with T2D without CVD at moderate CV risk (IIa,C)	NA
Japanese Clinical Practice Guideline for Diabetes 2019	Measurement of urinary albumin useful in early diagnosis of diabetic nephropathy (Grade A)	Target blood pressure of <130/80 mmHg in patients with diabetes and hypertension to prevent complications (Grade B)	ACEi/ARB recommended first line for blood pressure control in patients with diabetic nephropathy (Grade A) Patients with microalbuminuria or proteinuria: ACEi/ARB should be priority (Grade B)	HbA1c <6.0%: Target when aiming for normal glycemia HbA1c <7.0%: Target when aiming to prevent complications HbA1c <8.0%: Target when intensification of therapy considered difficult	Empagliflozin and canagliflozin significantly reduces risk of macroangiopathy in patients at high risk of CV events	Liraglutide and dulaglutide significantly suppress onset of macroangiopathy in patients with high risk of CV events	Evidence suggests usefulness in reducing macroangiopathy in T2D	NA

ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker; CAD, coronary artery disease; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; DBP, diastolic blood pressure; DKD, diabetic kidney disease; DM, diabetes; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucose-like peptide-1 receptor agonist; GMI, glucose management indicator; HbA1c, hemoglobin A1c; HF, heart failure; LVH, left ventricular hypertrophy; NA, not available; SBP, systolic blood pressure; SGLT2i, sodium-glucose Cotransporter-2 inhibitor; T1D, type 1 diabetes; T2D, type 2 diabetes; UACR, urine albumin-to-creatinine ratio.

SGLT2 inhibitors

Across all guidelines in this overview, the use of SGLT2 inhibition is recommended for CKD in T2D. This is not surprising following the initial secondary outcomes with empagliflozin in the EMPA-REG OUTCOME study, and with canagliflozin in the CANVAS program [25, 26]. In addition, the secondary renal outcome in the DECLARE-TIMI study with dapagliflozin also showed promise [27]. It was not until the CREDENCE study in 2019, a randomized clinical trial (RCT) in persons with T2D and albuminuria (>300 mg/g and <5000 mg/g) randomized to canagliflozin or placebo, that the effect of SGLT2i on a primary kidney composite outcome was demonstrated [5]. This was soon followed by the DAPA-CKD study, demonstrating the effect of dapagliflozin on a composite kidney outcome in persons with or without T2D, with albuminuria of at least 200 mg/g and eGFR between 25 and 75 mL/min/1.73 m² [6]. Lending even more support to the treatment paradigm are secondary analyses of heart failure studies with empagliflozin (EMPEROR-REDUCED, EMPEROR-PRESERVED) and dapagliflozin (DAPA-HF) [28–30].

Who should be offered therapy with SGLT2i for treatment of CKD? Current guidelines focus on preventing progression of CKD and reducing CV events and propose similar recommendations, but with differing thresholds and cutoffs for eGFR, the latter dependent on when the guidelines were published. The KDIGO 2020 guideline recommends SGLT2i for patients with T2D, CKD and eGFR ≥30 mL/min/1.73 m² with no threshold for albuminuria [17]. In addition, it adds to “prioritize SGLT2i with documented kidney or CV benefits” and it is “reasonable to continue when eGFR <30 mL/min/1.73 m² unless not tolerated or kidney replacement therapy is initiated.” The ADA 2022 Standards of Care recommends using SGLT2i in persons with T2D with eGFR ≥25 mL/min/1.73 m² or albuminuria ≥300 mg/g regardless of background therapy or HbA_1c [19]. The ESC guidelines from 2019 recommend the use of empagliflozin, dapagliflozin or canagliflozin in persons with T2D with eGFR 30–90 mL/min/1.73 m² with no mention of albuminuria [21]. Japanese Clinical Practice Guidelines from 2019 acknowledge that empagliflozin or canagliflozin can reduce the risk of macroangiopathy, but provide no specific recommendations regarding CKD [24].

In summary, most current guidelines agree with the recommendation to use SGLT2i in CKD (grade 1A where reported) with minor differences in eGFR thresholds, but with substantial variation regarding albuminuria levels (if any). Most guidelines also mention that SGLT2i can be continued up to the initiation of renal replacement therapy or kidney transplantation. From a glycemic therapy, SGLT2i have evolved into organ-protective therapy with several indications and a solid evidence base.

Metformin and glucagon-like peptide-1 receptor agonists

Metformin has been the first-line therapy in guidelines for the treatment of T2D for many years. The KDIGO 2020 guidelines recommend “glycemic management for patients with T2D and CKD should include lifestyle therapy, first-line treatment with metformin and a SGLT2i, and additional drug therapy as needed for glycemic control” [17]. Similarly, metformin can be initial therapy according to the ADA 2022 guidelines for glycemic control in early CKD [19]. The ESC 2019 guidelines recommends metformin can be utilized by “overweight patients with T2D without CVD and at moderate CV risk” [21]. Common to all guidelines, metformin remains an important early treatment option for T2D.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have benefits in improving CV outcomes in RCTs. The KDIGO 2020 guidelines recommend a long-acting GLP-1 RA for patients with T2D and CKD unable to reach glycemic targets with or unable to tolerate metformin and a SGLT2i [17]. In the ADA 2022 guidelines, patients with T2D and at risk for or with atherosclerotic cardiovascular disease (ASCVD), heart failure or CKD should receive a GLP-1 RA or SGLT2i with CV benefit for glycemic control and CV risk reduction regardless of HbA_1c [31]. For nonalbuminuric CKD, a GLP-1 RA with proven CV benefit can be used to reduce CV risk. Further, for CKD subjects with albuminuria ≥200 mg/g, the ADA guidelines recommend GLP-1 RA if SGLT2i is unable to be used [31]. Finally, the ESC 2019 guidelines recommends the use of liraglutide and semaglutide for T2D when eGFR >30 mL/min/1.73 m² due to the association with a “lower risk of renal endpoints” [21]. In summary, GLP-1 RA are an important adjunctive therapy for patients with T2D and CKD in all guidelines, though dedicated renal outcome trials have not been completed.

MRA

More than 60 years ago, the steroidal MRA spironolactone was developed, but large outcome studies have been limited to heart failure patients. In relation to CKD there are no hard outcome studies, as concern for hyperkalemia has been a limiting factor. Some guidelines have recommended low-dose steroidal MRA for treatment-resistant hypertension (as 4th line treatment), but usually also with warnings on use in people with impaired kidney function because of concern for hyperkalemia and decline in kidney function [17, 22]. There are a number of studies investigating kidney protective effects of spironolactone in doses 25–50 mg/day in combination with ACEis or ARBs showing reduction in albuminuria in patients with T1D [32] or T2D [33, 34], with moderately increased albuminuria [35], severely increased albuminuria or nephrotic-range albuminuria (>2500 mg/24 h) [36]. In a meta-analysis of 16 studies of MRA added to usual antidiabetic/renoprotective/antihypertensive treatment with a duration of 2–18 months demonstrated on average a significant reduction in end-of-treatment 24-h urinary albumin/protein excretion (mean difference = –61; 95% confidence interval –97 to –26 mg; P = .0006), with the major concern being a more than five-fold increased risk for hyperkalemia, particularly in those with impaired renal function [37]. In another meta-analyses of MRA, including patients with diabetic and nondiabetic CKD, similar results were found with a 39% reduction in albuminuria/proteinuria [38]. As there are no outcome studies with steroidal MRAs and kidney protection, they are not recommended for CKD protection.

Recently, new nonsteroidal MRAs were developed with the intention of preserving beneficial effects on progression of kidney and CV disease, but with less risk for hyperkalemia. This includes agents such as esaxerenone, KBP-5074 and finerenone [39–42]. Finerenone has been studied the most [43, 44]. Finerenone was tested in patients with T2D and CKD in the FIGARO-DKD (FInerenone in reducing cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease) and FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) studies [45, 46]. The FIDELITY analysis combined the two studies and demonstrated 14% reduction in the composite CV endpoint of time to CV death, non-fatal MI, non-fatal stroke or hospitalization for heart failure, and a 23% reduction in the composite kidney endpoint of time to kidney failure, sustained ≥57% decrease in eGFR from baseline or renal death [47]. Finerenone is approved for use in T2D with CKD in 2021 in the USA and in 2022 in Europe by the EMA as well as in other countries. One of the first guidelines to include finerenone was the ADA guideline from 2022 recommending finerenone to reduce CKD progression and CVD events in people with CKD and at risk for progression [19]. Then the updated KDIGO guideline for management of diabetes in patients with CKD suggested a nonsteroidal MRA with proven kidney or CV benefit for patients with T2D, an eGFR ≥25 mL/min/1.73 m², normal serum potassium concentration and albuminuria (≥30 mg/g) despite maximally tolerated dose of RAS inhibitor [48]. Although finerenone is associated with less risk for hyperkalemia compared with spironolactone, there is an increased risk for hyperkalemia compared with placebo, and 1.7% of patients treated with finerenone in the FIDELITY analysis stopped treatment because of hyperkalemia compared with 0.6% in the placebo group. Thus, it is recommended to monitor potassium after 4 weeks and at regular intervals. Interestingly, the effect of finerenone seems to be the same with or without an SGLT2i, so maybe the benefits are additive and at the same time the risk for hyperkalemia is reduced (hazard ratio 0.45) [49].

DISCUSSION

Guidelines are developed through a deliberative process whereby compelling data are translated into treatment recommendations in a graded fashion, allowing practitioners to easily understand the strength of the evidence. Guidelines addressing management of CKD have been updated to reflect new data from RCT with hard renal and CV outcomes. Notwithstanding variation between guidelines, all recommend that BP and glucose control are achieved, RAS blockade be utilized, and SGLT2i be employed for renal and cardiac benefits. Use of metformin and GLP-1 RA are reasonable choices for glycemic control and additional CV protection. The nonsteroidal MRA finerenone is recommended in the ADA 2022 guideline for renal and CV protection.

What is not fully clear from guidelines spanning several medical specialties is who should be responsible for implementation. Is it the endocrinologist, the nephrologist or the general practitioner? In the opinion of these authors, guidelines that follow a solid evidence base and address therapies available to all medical healthcare providers should be implemented regardless of specialty. Coordination and communication between healthcare sectors is necessary to reduce barriers to use of recommended, life-saving treatments. Although initial payment for medication may be a barrier for implementation, multiple analyses demonstrated long-term cost-savings due to the delay or prevention of dialysis [50].

FUNDING

The American Heart Association Career Develop award number is 855967.

AUTHORS’ CONTRIBUTIONS

All of the authors contributed to writing this manuscript and revising it, and all have given approval of the final version. J.B.M. and P.R. agree to be accountable for all aspects of the work, including originality and integrity.

DATA AVAILABILITY STATEMENT

No new data were generated or analyzed in support of this research.

CONFLICT OF INTEREST STATEMENT

P.R. receive consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi and Bayer as honoraria to the Steno Diabetes Center. J.B.M. has grant funding from Novo Nordisk, Dexcom, Medtronic, Beta Bionics and JDRF grant funding to Washington University. J.B.M. receives consulting fees for Bayer, Boehringer Ingelheim, Mannkind, Novo Nordisk, Lilly, Provention Bio, Salix, Metavant and Dexcom. J.B.M. receives honoraria from Boehringer Ingelheim, Janssen and Medscape. J.B.M. participates on the data safety monitoring/advisory board from NIH, Jaeb Center and Bayer. J.B.M. received travel funding from ADA and Endocrine Society. F.P. has grant funding from Novo Nordisk, AstraZeneca and Boehringer Ingelheim paid to the institution. F.P. receives consulting fees from AstraZeneca, Bayer, Amgen, Boehringer Ingelheim and Novo Nordisk. F.P. receives honoraria from AstraZeneca, Sanofi, Novo Nordisk and Boehringer Ingelheim. R.M.Z. receives research support from the American Heart Association Career Development Award, and support from the Division of Physician Scientists at Washington University funded by the Burroughs Wellcome fund. R.M.Z. is a sub-investigator for the Bayer CONFIDENCE study.