Management of the ‘wicked’ combination of heart failure and chronic kidney disease in the patient with diabetes

Abstract

Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.

1 INTRODUCTION

The increasing prevalence of type 2 diabetes (T2D) is a growing clinical burden worldwide.¹ Heart failure (HF) and chronic kidney disease (CKD) are common complications that often occur in individuals with T2D, and the presence of both HF and CKD significantly increases morbidity and mortality in this group.²

HF often presents as the first cardiovascular (CV) event in patients with T2D³ and affects more than 30% of such patients, making it a major cause of mortality in this population.⁴ Patients with established T2D have a 33% higher risk of hospitalization for heart failure (hHF) than individuals without diabetes.⁵ Patients with HF and prediabetes are also at a greater risk of all-cause mortality and cardiac events compared with those with normoglycaemia.⁶ Diabetic kidney disease (DKD) is observed in ~40% of patients with T2D, and is the leading cause of end-stage kidney disease (ESKD).^{7, 8} In 2021, the global prevalence of diabetes was more than 500 million individuals worldwide, and this number is expected to rise to more than 750 million in 2045.⁹ It is therefore essential to optimize treatment strategies for managing both HF and CKD to decrease global morbidity and mortality.¹⁰

Management of T2D has notably improved over the last two decades, largely by focusing on the optimization of blood glucose, blood pressure and lipid levels. Despite reaching treatment goals with current strategies, a residual risk for developing HF and CKD remains.¹¹ Cardiac and renal complications associated with T2D can arise together and co-exist as cardiorenal syndrome (CRS).¹² CRS describes the interplay between the heart and kidney and classifications of such syndromes arose based on initial organ damage or insult (heart or kidney), and whether the disorders were acute or chronic.¹² The CRS categories acknowledge that HF, whether acute or chronic, can lead to kidney damage with a reduced estimated glomerular filtration rate (eGFR). The opposite is also true, in that progressive kidney damage can lead to HF with congestion.¹³ The bidirectional interaction of HF and kidney disease can be seen from placebo groups of major CV outcomes trials such as DAPA-HF,¹⁴ EMPEROR-Reduced¹⁵ and EMPEROR-Preserved.¹⁶ These show the presence of CKD in participants with HF. In addition, patients with CKD typically also present with HF, such as in DAPA-CKD^17-19 and CREDENCE.²⁰ There was presence of HF in all participants, both with or without T2D.²¹ Notably, the major recent clinical trials did not use CRS categories as entry criteria, but did capture onset or progression of CKD. As such, future meta-analyses may add insights into this combined disorder.

The emergence of effective treatments such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists (MRAs) highlights the importance of targeting alternative pathways to improve cardiorenal outcomes in patients with T2D. Major diabetes and cardiology societies^22-25 are updating their guidelines by recommending these targeted approaches.²⁶ Here, we review the clinical rationale for initiating cardiorenal-protective therapy beyond the traditional risk factor-reduction strategies of hyperglycaemia, hypertension and dyslipidaemia in individuals with T2D and summarize the evidence for its benefit.

2 LITERATURE SEARCH STRATEGY

In preparation for this review, we searched the PubMed database for articles published until July 2022. We identified articles on the management of CKD and HF using the terms ‘chronic kidney disease’ and ‘HF’. Articles on clinical studies related to the management of CKD associated with T2D were identified using the terms ‘diabetes’, ‘kidney’, ‘management’, ‘treatment options’, ‘SGLT2 inhibitors’ and ‘MRAs’. We also reviewed the reference lists of articles identified in these searches for other relevant papers illustrating pathophysiology underlying HF and CKD in T2D.

3 THE PATHOPHYSIOLOGY UNDERLYING HF AND CKD IN T2D

The pathogenesis of HF and CKD in patients with T2D can be attributed to the disrupted metabolic pathways associated with hyperglycaemia, hypertension, inflammation and fibrosis.²⁷ As previously mentioned, a bidirectional interaction between the heart and the kidneys exists (Figure 1). In addition, the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) contribute to the stimulation of pathways associated with HF and CKD.²⁸

FIGURE 1

Pathophysiology underlying HF and CKD in patients with type 2 diabetes. CKD, chronic kidney disease; HF, heart failure; LV, left ventricle; RAAS, renin–angiotensin–aldosterone system; SNS, sympathetic nervous system

The aetiology of HF in patients with T2D can be explained through the cardiotoxic triad of diabetic cardiomyopathy, hypertension and coronary artery disease (CAD).¹ The term diabetic cardiomyopathy describes ventricular dysfunction in individuals without hypertension and CAD.²⁹ The term can also be used to describe myocardium dysfunction that is prevalent in patients with diabetes.³⁰ The presence of myocardial ischaemia is thought to induce changes in cardiac biochemistry. Impaired cardiac cells and tissues contribute to reduced cardiac function and are linked to abnormalities in electrophysiology.^{1, 31}

Cardiac ischaemia, whether attributable to large or small vessel disease, is responsible for pathophysiological changes in the myocardium.^{1, 32} This myocardial dysfunction, combined with hypertension, leads to fibrosis and dysregulated systolic function; the process is further aggravated by activation of the renin–angiotensin system (RAS) and the SNS. The result is a loss of cardiac myocytes and development of HF.^{1, 32} RAS and SNS activation causes disorganized compensatory cellular hypertrophy that is also known as ‘cardiac remodelling’.^{1, 32} A state of dysregulated gene expression lowers both diastolic and systolic ventricular function, and is thought to influence HF progression.^{1, 33} Reduced ventricular function may arise as a means to lessen the energy expenditure of the dysfunctional/weakened myocardium.^{1, 33}

Macrovascular cardiac impairments, such as myocardial infarction, are common in patients with T2D.³⁴ Vascular dysfunction may result from oxidative stress, which occurs when there is an imbalance of endogenous oxidants and antioxidants.³⁵ The presence of oxidative stress may accumulate from varying factors. This loss in redox homeostasis in reactive oxygen species (ROS) and reactive nitrogen species amounts to activation of the immune system and a proinflammatory and profibrotic environment. Although physiological levels of ROS are essential for proper cell function, overproduction of these molecules is known to stimulate both cardiac and renal dysfunction.^35-37 It is important to note that, in the kidney and vascular tissues, oxidative stress leads to hypertension, while hypertension also promotes oxidative stress.³⁷ Together, oxidative stress and inflammation are critical in CKD-related pathologies.³⁶ Furthermore, inflammation and oxidative stress contribute to the structural and functional diastolic dysfunction observed in HF with preserved ejection fraction (HFpEF).³⁸

Inflammation promotes fibrotic tissue production, impairing optimal myocyte contraction and resulting in suboptimal cardiac function.^{28, 39} Fibrosis is a crucial aspect of tissue repair and is regarded as a pathological phenomenon that is prevalent in chronic inflammatory diseases.⁴⁰ Overactive fibrosis can lead to the development of HF and CKD (Figure 1).⁴¹

In endothelial cells, mineralocorticoid receptor (MR) activation leads to higher levels of ROS, resulting in oxidative stress, which is associated with vascular inflammation.⁴² Based on evidence from animal models and from studies on primary hyperaldosteronism, aldosterone has been reported to cause left ventricular (LV) remodelling by inducing cardiomyocyte hypertrophy, chronic inflammation and extracellular matrix dysregulation.^{43, 44} The underlying mechanism involves: activation of extracellular signal-regulated kinases, c-Jun N-terminal protein kinases and protein kinase c-alpha⁴⁴; phosphorylation of both light- and heavy-chain myosin; and production of cardiotrophin-1, which can cause cardiomyocyte hypertrophy and increase the expression of myosin light chains.⁴⁵ Aldosterone also promotes inflammatory cytokine formation,⁴⁶ macrophage activation and macrophage proinflammatory factor production, while also increasing the expression of intercellular adhesion molecules on endothelial cells, which facilitate macrophage attachment to the endothelium. The ensuing fibrosis of the myocardium occurs when degradation of the extracellular matrix by metalloproteinases is exceeded by matrix production.⁴³ This leads to decreased contractility, non-compliant ventricles, as well as increased myocardial ischaemia. Fibrosis, in addition to LV hypertrophy, results in both systolic and diastolic dysfunction. The damage to the myocardium may also be exacerbated by a high-salt diet.⁴⁷

Hyperglycaemia disrupts intraglomerular pressure control and leads to intraglomerular hypertension in the kidneys, which has been shown to activate metabolic pathways that contribute to the accumulation of ROS⁴⁸; this, in turn, leads to mitochondrial dysfunction, as well as upregulation of pro-oxidant enzymes.⁴⁸ Abnormal glucose metabolism and dysregulated intracellular signalling also contribute to inflammation, fibrosis, and endothelial and epithelial injury, resulting in CKD.²⁷ Evidence suggests that MR overactivation promotes inflammation and fibrosis, as well as influencing the progression of CKD and cardiovascular disease (CVD).⁴⁹

4 THE IMPORTANCE OF MONITORING CARDIORENAL RISK IN PATIENTS WITH T2D, HF AND CKD

The co-existence of cardiorenal complications in patients with T2D is common; thus, it is important to conduct routine monitoring of T2D patients to assess their risk of developing HF and CKD.

For CKD screening, the American Diabetes Association (ADA) guidelines recommend an annual assessment of urinary albumin levels and eGFR in all patients with T2D, regardless of treatment.^{22, 50} Guidance from the 2023 ADA Standards of Care for CKD and risk management also advise that patients with established DKD should be monitored multiple times a year to guide therapy.⁵⁰ Monitoring serum potassium in patients taking diuretics is important to prevent cardiac arrythmias caused by hypokalaemia. Individuals receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) or MRAs should also have their medication dosages adjusted to diminish additional CKD-related risks.²²

The presence of LV hypertrophy is common in patients with T2D and is also a major CVD risk.⁵¹ Somaratne et al.⁵¹ reported that even echocardiograms are insufficient to detect LV hypertrophy, but are superior to N-terminal pro-B-type natriuretic peptide levels and electrocardiograms, and thus highlights the need for alternative tools to detect LV hypertrophy in patients with T2D. Meanwhile, the prevalence of LV hypertrophy, as measured by echocardiography, in asymptomatic patients with T2D is high,⁵¹ and routine screening for patients with T2D who are asymptomatic for CVD is not recommended at this time, provided atherosclerotic CVD risk factors are treated as per the 2023 ADA guidelines.⁵²

Hadjkacem et al.⁵³ reviewed the value of assessing masked arterial hypertension (HTN). Masked HTN (MHTN) is associated with CVD risk, a risk that is similar to that of permanent HTN and is common in patients with T2D. The results revealed that systematic screening for MHTN through 24-hour blood pressure monitoring in patients with T2D provided an insightful indication of CVD risk. This investigation emphasizes the need for screening tools to ensure optimal monitoring of cardiorenal risk to facilitate timely clinical intervention for patients with T2D.

The TOPCAT trial noted that more than one-third of participants with T2D and HFpEF had microvascular complications and a greater number of adverse outcomes than those without microvascular disease.^{38, 54} The report from the trial recommends that during routine screening of patients with T2D, physicians should also take note of structural and functional changes of the heart, eyes, kidneys and peripheral nerves to prevent further adverse outcomes. Therefore, routine monitoring of patients with T2D for early renal damage is not only a key component for delaying CKD progression through testing for eGFR and albuminuria, but also contributes to improved CVD risk stratification.⁵⁵

5 TREATMENTS SHOWN TO IMPROVE HF AND CKD IN PATIENTS WITH T2D

5.1 The role of SGLT2 inhibitors in the management of HF and for improving renal outcomes

SGLT2 inhibitors are able to improve cardiorenal outcomes through various mechanisms of action, including via reductions in blood pressure, arterial stiffness and endothelial dysfunction.¹⁴ A shift in bioenergetics may also explain the beneficial CVD outcomes from SGLT2 inhibitors.⁵⁶ Substituting ketone metabolism for fat consumption and glucose oxidation improves energy efficiency and reduces the workload placed on the myocardium.⁵⁶ Preclinical research has shown that the cardioprotective characteristics of dapagliflozin observed in diabetic cardiomyopathy may involve modulation of ion homeostasis as a way to reduce fibrosis and inflammation, and improve systolic function.⁵⁷ It is thought that SGLT2 inhibitors decrease inflammation and oxidative stress through activation of the nitric oxide–soluble guanylyl–protein kinase G pathway, contributing to attenuated diastolic stiffness of the left ventricle in HFpEF.⁵⁸

There are numerous renal benefits of SGLT2 inhibition including the positive effect on glomerular haemodynamics, which leads to long-term preservation of kidney function. SGLT2 inhibitors target mechanistic pathways that reduce intraglomerular pressure and the glomerular filtration rate.⁵⁹ Other modes of action that have been proposed are hypoxia reduction and activating transcription factors.⁵⁹ However, to better understand the mechanisms underlying the cardiorenal-protective properties of SGLT2 inhibitors, further investigation in humans is required.

CV outcomes trials such as DAPA-HF,¹⁴ CANVAS,^{60, 61} EMPEROR-REDUCED,¹⁵ EMPA-REG⁶² and EMPEROR-PRESERVED⁶³ show the cardioprotective and renoprotective benefits of SGLT2 inhibitor treatment in patients with T2D. Compared with placebo, SGLT2 inhibitors reduced the risk of hHF, as seen with dapagliflozin (DAPA-HF¹⁴; hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.65, 0.85; P < .001) and with canagliflozin (CANVAS Program⁶¹; HR: 0.67; 95% CI: 0.52, 0.87). Additionally, compared with placebo, empagliflozin treatment reduced the total numbers of hHF in patients in EMPEROR-Reduced (HR: 0.70; 95% CI: 0.58, 0.85; P < .001),¹⁵ in EMPA-REG (HR: 0.65; 95% CI: 0.50, 0.85; P = .002),⁶² in EMPEROR-PRESERVED (HR: 0.73; 95% CI: 0.61, 0.88; P < .001)⁶³ and in EMPA-KIDNEY (HR: 0.86; 95% CI: 0.78, 0.95; P = .003).⁶⁴

SGLT2 inhibitor trials with empagliflozin, dapagliflozin and canagliflozin also revealed significant relative reductions of primary renal outcomes.⁶⁵ In DAPA-CKD,¹⁷ dapagliflozin was shown to exhibit renoprotective benefits regardless of diabetes status, age, cause of CKD, baseline albuminuria (< 1000 vs. > 1000 mg/g) and eGFR (< 45 vs. > 45 mL/min/1.73m²).¹⁸ The HR for the composite outcome of a sustained decline in the eGFR of at least 50%, ESKD or death from renal causes, was 0.56 (95% CI: 0.45, 0.68; P < .001). Canagliflozin treatment was able to reduce the relative risk of composite of ESKD, doubling of creatinine levels or renal death by 34% (HR: 0.66; 95% CI: 0.53, 0.81; P < .001), as well as lowering the risk of ESKD by 32% (HR, 0.68; 95% CI, 0.54 to 0.86; P = .002).²⁰

The EMPA-KIDNEY trial now also provides evidence of renal protection in patients without T2D. Patients with CKD at risk of further disease progression in this trial experienced a lower risk of the composite outcome of worsening kidney disease (defined as ESKD, a sustained decrease in eGFR to < 10 mL/min/1.73m², a sustained decrease in eGFR of ≥ 40% from baseline, or death from renal causes) or CV-related death following empagliflozin treatment compared with placebo.⁶⁴

For patients with T2D, HF and CKD, treatment selection will need to be patient-specific and may depend on the CKD stage of the patient, as well as the presence of co-morbidities.²⁸ Adverse effects should be considered when administering treatment options. The use of SGLT2 inhibition has been associated with volume contraction because of osmotic diuresis. Although these effects may be mild and infrequent, they need to be monitored, particularly in elderly patients and patients utilizing diuretics.⁵⁸ Other clinical risks of SGLT2 inhibitors, such as euglycaemic diabetic ketoacidosis, have been noted, but were not observed in the CREDENCE^{20, 66} and DAPA-CKD trials.^{17, 18, 58} The 2022 ADA and Kidney Disease: Improving Global Outcomes (KDIGO) consensus statement recommends monitoring blood or urine ketones for managing diabetic ketoacidosis, as well as maintaining low-dose insulin in insulin-requiring patients.⁶⁷

SGLT2 inhibitor administration is also associated with an increased risk of hypoglycaemia.⁵⁸ This risk increases with higher doses in patients with T2D, CKD and HF who are also taking insulin or sulphonylureas, suggesting that careful dosage adjustments of antidiabetes therapy should be implemented when managing these patients,^{58, 67, 68} to avoid hypoglycaemia.³⁷

5.2 The role of MRAs in the reduction of CV and kidney outcomes

Fibrosis and inflammation are caused by overactivation of the MR.⁶⁹ Selectivity of MR antagonism varies between MRAs. Although it shows lower selectivity, the first-generation steroidal MRA spironolactone is more potent than the second-generation MRA eplerenone.⁶⁹ The non-steroidal MRA finerenone has been shown to inhibit detrimental gene activation independent of aldosterone inhibition,^70-72 whereas steroidal MRAs such as spironolactone and eplerenone show partial agonism on co-factor recruitment.⁷¹

Patients with T2D and HF exhibited clinical improvements following MRA treatment compared with non-MRA therapy, with lower all-cause mortality, CV mortality and hHF.⁷³ Treatment with steroidal or non-steroidal MRAs is also thought to positively impact individuals with HF with reduced ejection fraction (HFrEF) and those with HFpEF, as seen in the Randomised Aldactone Evaluation Study⁷⁴ and TOPCAT trial, respectively.^{38, 54}

The FIDELIO-DKD^{75, 76} and FIGARO-DKD⁷⁷ trials examined the efficacy and safety of the non-steroidal MRA finerenone on kidney and CV outcomes from early to advanced CKD in patients with T2D. Finerenone treatment resulted in a lower risk of CKD progression and CV events in patients with CKD and T2D compared with placebo.^{75, 76} It is worth noting that the patient populations in these trials had co-morbidities and were at a high risk of both kidney and CV events; nonetheless, HbA1c and blood pressure levels were sufficiently controlled. Filippatos et al.⁷⁶ reported that, in patients with CKD and T2D, finerenone lowered the risk of new-onset atrial fibrillation or flutter, as well as the risk of cardiorenal events. In FIDELITY,⁷⁸ the prespecified analysis of FIDELIO-DKD^{75, 76} and FIGARO-DKD,⁷⁷ finerenone treatment taken in addition to standard of care reduced the risk of clinically meaningful CV and kidney outcomes in patients with T2D over a broad spectrum of kidney function.⁷⁸

Finerenone was shown to be well tolerated by patients in the FIDELIO-DKD^{75, 76} and FIGARO-DKD⁷⁷ trials. However, the risk of adverse events should still be carefully considered when administering this drug. The FIDELIO-DKD trial, which evaluated the non-steroidal MRA finerenone in patients with CKD and T2D, found that hyperkalaemia resulted in a 2.3% discontinuation rate in the finerenone group compared with 0.9% in the placebo group.^{22, 76} Hyperkalaemia was reported in 18.3% of finerenone-treated patients compared with 9.0% of those receiving placebo.^{22, 76} No mortalities related to hyperkalaemia were observed. Similarly, in the FIGARO-DKD⁷⁷ trial and FIDELITY analysis,⁷⁸ the frequency of hyperkalaemia-related adverse events was higher in the finerenone-treated group compared with the placebo group, yet no hyperkalaemia-related adverse events were fatal.^{77, 78} To manage the risk of hyperkalaemia, it is recommended that serum potassium and eGFR are measured in all patients prior to initiation of finerenone treatment. Frequent monitoring of patients on concomitant medications is also encouraged. Prescribing information for finerenone advises against starting finerenone treatment if serum potassium is more than 5.0 mEq/L.⁷⁹

Historically, MRAs have been linked with an increased risk of hyperkalaemia.^{22, 80} Currently there is no therapeutic option for patients with T2D at risk of CVD and CKD that is not associated with a risk of hyperkalaemia. However, MRAs could offer benefit for this patient group when appropriate monitoring for hyperkalaemia is taken into consideration.

6 UPDATED GUIDELINE RECOMMENDATIONS FOR THE MANAGEMENT OF PATIENTS WITH T2D

Optimal management of T2D involves collaboration between multidisciplinary teams of clinicians, including primary care providers, endocrinologists, cardiologists and nephrologists.²⁵ The management of patients with T2D has historically focused on controlling risk factors such as elevated blood pressure and optimizing blood glucose and lipid levels to prevent CV disease and reduce the risk of DKD.⁷ Management recommendations for patients with T2D with HF and CKD are summarized in Tables 1 and 2.

TABLE 1. Management recommendations for patients with T2D and HF

Patients with T2D and HFrEF
Medication	Guidance	Source
β blocker	Treatment of individuals with HF with reduced ejection fraction should include a β blocker with proven cardiovascular outcomes benefit, unless otherwise contraindicated	10.46 ADA Standards of Care 2023^52

Patients with T2D and HFrEF or HFpEF
SGLT2 inhibitor	In patients with T2D and established HFpEF or HFrEF, an SGLT2 inhibitor with proven benefit in this patient population is recommended to reduce the risk of worsening HF and cardiovascular death Recommendation 10.42b was added to recommend treatment with an SGLT2 inhibitor in individuals with T2D and established HF with either preserved or reduced ejection fraction to improve symptoms, physical limitations and quality of life	10.42a and 10.42b from ADA Standards of Care 2023^52, 81 The discussion of evidence to support this new recommendation was included in the last paragraph of the section ‘Glucose-Lowering Therapies and Heart Failure’ (Erratum, summary of revisions)^81
Metformin	In patients with T2D with stable HF, metformin may be continued for glucose lowering if the estimated glomerular filtration rate remains > 30 mL/min/1.73m^2, but should be avoided in unstable or hospitalized individuals with HF	ADA Standards of Care 2023^52

• Abbreviations: ADA, American Diabetes Association; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes.

TABLE 2. Management recommendations for patients with T2D and CKD

Drug	ADA Standards of Care 2023^50	ADA and KDIGO consensus statement^67
Main therapies
Metformin	Metformin is contraindicated in patients with an eGFR < 30 mL/min/1.73m^2 While taking metformin, eGFR should be monitored The benefits and risks of continuing treatment should be reassessed when eGFR decreases to < 45 mL/min/1.73m^2 Metformin should not be initiated for patients with an eGFR < 45 mL/min/1.73m^2 Metformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in patients with eGFR 30-60 mL/min/1.73m^2	Metformin is recommended for patients with T2D, CKD and eGFR ≥ 30 mL/min/1.73m^2 The dose should be reduced to 1000 mg daily for patients with eGFR 30-44 mL/min/1.73m^2 and for some patients with eGFR 45-59 mL/min/1.73m^2 who are at high risk of lactic acidosis
RAS inhibitor at maximal tolerated dose	An ACE inhibitor or an ARB is not recommended for the primary prevention of CKD in people with diabetes who have normal blood pressure and a normal urine albumin: creatinine ratio	An ACE inhibitor or ARB is recommended for patients with T2D who have hypertension and albuminuria, titrated to the maximum antihypertensive or highest tolerated dose
SGLT2 inhibitor	Summary of revisions: 2023 ADA Standards of Care^81: recommended for patients with eGFR ≥ 20 mL/min/1.73m^2 and urinary albumin ≥ 200 mg/g creatinine to reduce CKD progression and CV events^81	An SGLT2 inhibitor with proven kidney or CV benefit is recommended for patients with T2D, CKD and eGFR ≥ 20 mL/min/1.73m^2 Once initiated, the SGLT2 inhibitor can be continued at lower levels of eGFR
Additional risk-based therapy^a
GLP-1 RA	For additional CV risk reduction, a GLP-1 RA can be considered if eGFR ≥ 25 mL/min/1.73m^2	GLP-1 RA with proven CV benefit is recommended for patients with T2D and CKD who do not meet their individualized glycaemic target with metformin and/or an SGLT2 inhibitor, or who are unable to use these drugs
Non-steroidal MRA	10.43: For people with T2D and CKD with albuminuria treated with maximum tolerated doses of ACE inhibitor or ARB, addition of finerenone is recommended to improve CV outcomes and reduce the risk of CKD progression^52, 81	A non-steroidal MRA with proven kidney and CV benefit is recommended for patients with T2D, eGFR ≥ 25 mL/min/1.73m^2, normal serum potassium concentration and albuminuria (ACR ≥ 30 mg/g) despite maximum tolerated dose of RAS inhibitor
Steroidal MRA	Summary of revisions in the 2023 ADA Standards of Care^81: MRAs are now recommended along with other medications for CV and kidney protection rather than as alternatives when other treatments have not been effective	Steroidal MRA is recommended if needed for resistant hypertension and if eGFR ≥ 45 mL/min/1.73m^2

• Abbreviations: ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ADA, American Diabetes Association; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide-1 receptor agonist; KDIGO, Kidney Disease: Improving Global Outcomes; MRA, mineralocorticoid receptor antagonist; RAS, renin–angiotensin system; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes.
• ^a Regular reassessment of glycaemia, albuminuria, blood pressure, CV disease risk and lipids is recommended.

Guidelines from the American Heart Association⁸² and ADA⁸³ recommend treating patients with diabetes using ACE inhibitors or ARBs,⁸⁴ MRAs and SGLT2 inhibitors.⁸³ The KDIGO guidelines advise reducing the risk of CV complications and CKD progression in patients with T2D by implementing a multifactorial approach.²⁵ However, despite guideline-recommended treatments such as metformin, many patients with well-controlled blood pressure and blood glucose progress to kidney disease and/or develop CV co-morbidities,^{85, 86} highlighting the complex nature of cardiorenal protection. The US Food and Drug Administration (FDA) has not only approved SGLT2 inhibitors for their antihyperglycaemic properties in the treatment of T2D, but also for the reduction of CV events.⁸⁷ The 2019 ADA/European Association for the Study of Diabetes consensus recommends using SGLT2 inhibitors in addition to metformin in people with diabetes and HF (especially HFrEF) to reduce hHF, major adverse CV events and CV death.^{68, 88} New guidance from the 2023 ADA Standards of Care recommends treatment with an SGLT2 inhibitor in individuals with T2D and established HF with either preserved or reduced ejection fraction to improve symptoms, physical limitations and quality of life. ADA recommendations specifically for people with HF are summarized and outlined in Table 1.⁸¹ The KDIGO guidelines suggest the use of ACE inhibitors or ARBs to reduce blood pressure in patients with T2D and CKD.²⁵ The ADA guidance recommends these agents as the preferred first-line therapy for blood pressure control in patients with diabetes, hypertension, an eGFR of less than 60 mL/min/1.73m² and a urine albumin: creatinine ratio of 300 mg/g or higher, because of their ability to prevent CKD progression.^{22, 50, 89-92} However, the recommendations do not support combining these treatments because of the risk of acute kidney injury or hyperkalaemia.^{25, 50, 93, 94} The 2022 ADA and KDIGO consensus statement recommends an ACE inhibitor or ARB for patients with T2D with hypertension and albuminuria, titrated to the maximum tolerated dose,⁶⁷ and this is supported by the 2023 ADA Standards of Care (Table 1).⁵⁰ To slow the progression of CKD in patients with T2D and CKD, the ADA recommends reducing urinary albumin of 300 mg/g or higher by 30% or more for patients with macroalbuminuria.^{22, 50} However, clinicians should be aware that some patients with T2D may experience ESKD in the absence of albuminuria.⁹⁵

Management recommendations for patients with T2D and CKD (Table 2) include the ADA Standards of Care guidance for SGLT2 inhibitor treatment for patients at high risk of CKD progression.^{22, 50} Empagliflozin⁸⁷ and dapagliflozin have been approved by the FDA for use in patients with T2D for their effects on kidney/HF outcomes. The 2022 KDIGO guidelines recommend treating patients with T2D and CKD, and an eGFR of less than 20 mL/min per 1.73m², with an SGLT2 inhibitor.⁶⁷ The consensus statement is also in favour of administering an SGLT2 inhibitor or glucagon-like peptide-1 receptor agonist to patients with T2D with either established atherosclerotic CVD or kidney disease, as part of a CV risk reduction protocol and glucose-lowering management.⁶⁷

Guidance from the 2022 American Association of Clinical Endocrinologists⁹⁶ recommends finerenone to reduce CKD progression and CV events in patients with CKD who are at an increased risk of CV events or CKD progression, and who are treated with maximum tolerated doses of ACE inhibitor or ARB.⁹⁶ The 2022 ADA and KDIGO consensus statement affirmed that a non-steroidal MRA with proven kidney and CV benefit is recommended for patients with T2D, an eGFR of 25 mL/min/1.73m² or higher, normal serum potassium concentration and albuminuria (ACR ≥ 30 mg/g) despite receiving the maximum tolerated dose of RAS inhibitor. The statement highlights that finerenone is currently the only non-steroidal MRA with evidence supporting its cardiorenal benefits.⁶⁷ New additions to the 2023 ADA standards of care for CVD and risk management include finerenone as treatment in individuals with T2D and CKD with albuminuria receiving the maximum tolerated doses of ACE inhibitor or ARB (Table 2).⁸¹

7 CONCLUSIONS

The increasing prevalence of T2D is an ongoing clinical burden worldwide, and the pathophysiology of T2D and its cardiorenal complications remain complex. Patients with T2D are at an increased risk of developing HF and CKD; therefore, identifying therapeutic solutions is a priority. There is now strong evidence favouring the use of SGLT2 inhibitors to improve CV and kidney outcomes, such as hHF and ESKD, in patients with T2D, with guidelines also recommending them as first-line treatment for patients with diabetes and a high risk of CV or kidney disease. Furthermore, finerenone is recommended for reducing the incidence of kidney outcomes in individuals with T2D and a wide range of kidney function. The mechanism of action of finerenone is distinct from other traditional MRAs, and it reduces CKD progression and the severity of CV events with a lower incidence of hypokalaemia in patients with T2D. Advances in treatment options have indeed shown promising results in improving clinical outcomes for patients with T2D, HF and CKD.

AUTHOR CONTRIBUTIONS

All the authors have made substantial contributions to the conception and design, or acquisition of data, or analysis and interpretation of data. All the authors were involved in drafting the manuscript or revising it critically for important intellectual content, giving final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content. Each author has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

ACKNOWLEDGEMENTS

Medical writing support, under the guidance of the authors, was provided by Ananya Das, PhD, 3 Stories High, London, UK, and medical writing support and article processing charges were funded by Bayer, in accordance with Good Publication Practice 2022 guidelines (Ann Intern Med 2022 [Epub 30 August 2022]; https://doi.org/10.7326/M22-1460).

FUNDING INFORMATION

Medical writing support and article processing charges were funded by Bayer, in accordance with Good Publication Practice 2022 guidelines (Ann Intern Med 2022 [Epub 30 August 2022]).

CONFLICT OF INTEREST STATEMENT

DSHB states no conflicts of interest. TJ has received speaker fees for Novo Nordisk, Bayer HealthCare Pharmaceuticals and Corcept Therapeutics, all unrelated to this work. JBM has received institutional grants from Medtronic, Novo Nordisk, Beta Bionics, JDRF and National Institutes of Health (NIH). She has received consulting fees from Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Gilead Sciences, Inc., Mannkind Corporation, Novo Nordisk, Salix, ProventionBio and Thermo Fisher. She has received honoraria from Bayer HealthCare Pharmaceuticals and Thermo Fisher. She has received support for attending meetings from Bayer HealthCare Pharmaceuticals and Thermo Fisher Endocrine Society, ADA, and participation on a Data Safety Monitoring Board or Advisory Board from NIH and Jaeb Center for Health Research, all unrelated to this work.

Open Research

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15181.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.