Beyond Blood Glucose and Blood Pressure Control in Type 2 Diabetes: Alternative Management Strategies to Prevent the Development and Progression of CKD

Abstract

Chronic kidney disease associated with Type 2 diabetes is linked to significant increase in morbidity, reduced quality of life, and early death. Current guidelines recommend targets for the management of hyperglycemia, hypertension, and dyslipidemia but there remains a residual risk of chronic kidney disease progression and adverse cardiovascular outcomes in patients with Type 2 diabetes. The 2022 consensus report from the American Diabetes Association and Kidney Disease: Improving Global Outcomes support the use of sodium–glucose co-transporter 2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists to improve kidney and cardiovascular outcomes. Coordination between those working in the primary care setting and those in endocrinology and nephrology clinics may optimize the prevention of chronic kidney disease progression in patients with Type 2 diabetes. Nurse practitioners, physician assistants, and primary care physicians play an important role in making timely patient referrals to kidney specialists. This article explores the use of novel therapies capable of reducing the risk of cardiovascular disease and chronic kidney disease progression beyond what can be achieved with control of blood glucose, blood pressure, and lipid levels. It also discusses the importance of monitoring at-risk patients to facilitate early diagnosis and initiation of effective kidney-protective therapy.

Figure 1.

(Press play for video abstract) Multidisciplinary care model for identification of patients with T2D and CKD at high risk of CV and kidney events. ^aDiscontinuation of ACE/ARB for minimal increases in serum of creatinine in absence of volume depletion should be avoided. Adapted from the American Diabetes Association Standards of Medical Care in Diabetes 2022 ⁵ and Addendum. 11. Chronic Kidney Disease and Risk Management: Standards of Medical Care in Diabetes-2022. ⁶

Introduction

Controlling blood glucose, blood pressure, and lipid levels is seen as the backbone of care for patients with Type 2 diabetes (T2D).^1–4 However, the treatment of chronic kidney disease (CKD) in T2D is changing with the emergence of new drug classes, such as sodium–glucose co-transporter 2 (SGLT2) inhibitors and nonsteroidal mineralocorticoid receptor antagonists (MRAs), that significantly reduce the risk of cardiovascular disease (CVD) and renal complications. Updates to 2022 American Diabetes Association (ADA) guidelines^5,6 now support looking beyond blood glucose and blood pressure control in the treatment of T2D and concomitant CKD, as does the 2022 consensus report from the ADA and Kidney Disease: Improving Global Outcomes (KDIGO). ⁷ As such, primary care clinicians are expected to make informed decisions when managing these patients. Nurse practitioners, physician assistants, and primary care physicians all serve vital roles in ensuring timely CKD diagnosis, appropriate treatment selection, and management of therapies. In addition, they also empower patients with T2D to feel confident in self-management. ⁸

Diabetic kidney disease (DKD) develops in approximately 40% of patients with T2D and is the primary cause of CKD worldwide. ⁴ CKD in patients with T2D is associated with elevated medical costs, increased risk of other comorbidities, and high mortality rates. ⁹ DKD is defined as a continual reduction in estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² and/or the existence of albuminuria (urine albumin:creatinine ratio [UACR] ≥30 mg/g). These 2 measurements are taken at least 3 months apart in a patient with diabetes. ¹⁰ DKD is initially characterized by glomerular hyperfiltration and albuminuria, and progresses to declining glomerular filtration rate and lastly, end-stage renal disease (ESRD).^4,11

Guidance from the ADA ⁵ and KDIGO ¹² specifically for patients with T2D advise adopting a multifactorial approach to reduce the risk of cardiovascular (CV) complications and CKD progression in patients with T2D.^7,12 Historically, this has been achieved through controlling hyperglycemia and blood pressure. ¹ Blocking the renin–angiotensin–aldosterone system (RAAS) to control blood pressure and using SGLT2 inhibitors for renoprotection has shown promise in the treatment of T2D and CKD.^2,3

This article will discuss the risk factors in T2D associated with the development and progression of CKD. It will explore current management of patients with T2D, including the use of RAAS and SGLT2 inhibitors, and highlight novel treatment recommendations, such as nonsteroidal MRAs. It will also discuss how nurse practitioners, physician assistants, and primary care physicians can ensure that a referral of a patient diagnosed with CKD in T2D is appropriate and timely.

Current Management of Patients With CKD and T2D

Optimal management of CKD associated with diabetes can be complex. It involves multidisciplinary teams of clinicians in primary care, endocrinology, and other specialties including nephrology and cardiology (Figure 1). ⁷ Day-to-day management of patients with T2D has largely focused on controlling blood glucose, blood pressure, and lipids^13–15 to effectively lessen the risk of T2D-related CV and CKD complications.^1,4,5,16,17

Controlling blood glucose is a well-recognized approach for preventing CKD and microvascular risk in patients with T2D. ¹⁸ Recommendations on first-line therapy for patients with T2D from the ADA include lifestyle changes and metformin administration^7,19,20 to lower the risk of CKD. Large prospective randomized trials demonstrated that blood glucose optimization attempting to achieve normoglycemia delayed the development and advancement of albuminuria and reduced eGFR in patients with T2D.^5,21,22

Maintaining blood pressure and lipid control is also important for the prevention of CKD in patients with T2D. ²³ The RENAAL study and IDNT trial demonstrated how angiotensin receptor blockers (ARBs) could delay the onset of CKD in patients with T2D. For both investigations, the primary endpoint was a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death, ²⁴ and additionally a serum creatinine of ≥6.0 mg/dl. ²⁵ Unfortunately, 43.5% (RENAAL) and 32.6% (IDNT) of participants taking an ARB reached one of the aforementioned primary endpoints.^24–26 Furthermore, ARBs did not significantly reduce the risk of CV death, myocardial infarction, hospitalization for heart failure, or stroke in RENAAL. ²⁴

Though treatment strategies have become progressively better at controlling blood glucose and blood pressure, a residual risk of CKD and associated CV comorbidities remains even when these factors are within optimal ranges.^1,11 The KDIGO guidelines recommend angiotensin-converting enzyme (ACE) inhibitors and ARBs to reduce blood pressure in patients with T2D and CKD, but caution against combining these 2 classes of agents to avoid acute kidney injury or hyperkalemia.^12,27,28 Lipid-lowering treatments have been shown to reduce CVD risk in patients with T2D and CKD; ²³ hence, 2022 guidance from the ADA and KDIGO encourages statin treatment for all patients with T2D aged between 40 and 75 years without atherosclerotic cardiovascular disease.^5,7 For patients with T2D and DKD with an eGFR ≥ 20 mL/min/1.73 m² and UACR ≥ 200 mg/g, the 2022 ADA guidelines recommend prescribing an SGLT2 inhibitor to reduce the risk of CKD progression, CV events, or both. ⁶ In addition, 2022 recommendations from the ADA and KDIGO consensus statement, ⁷ and guidelines from both ADA ⁵ and Association of Clinical Endocrinologists (AACE) ²⁹ recommend that patients with CKD and diabetes at increased risk for CV events or CKD progression should be on a nonsteroidal MRA with proven cardiorenal benefit, to reduce CKD progression or CV event risk; currently, finerenone is the only nonsteroidal MRA with proven clinical kidney and CV benefits. ⁷

Additional Therapies for Patients With CKD and T2D

SGLT2 Inhibitors

Despite achieving optimal glycemic and blood pressure control, there is still a high risk of CKD progressing to ESRD in many patients with T2D on standard treatment regimens. ³⁰ There remains a need for additional therapies targeting renal protection and eGFR preservation. SGLT2 inhibitors reduce proximal renal tubular glucose and sodium reabsorption. ³⁰ Large phase 3 trials showed that patients with T2D treated with SGLT2 inhibitors had lower rates of mortality, ³¹ lower rates of CV death and hospitalization for heart failure, ³² and lower rates of CV events compared with those on placebo. ³³

The CREDENCE ³⁴ and DAPA-CKD ³⁵ trials investigated the effects of SGLT2 inhibitors in patients already on an ACE inhibitor or an ARB (referred to as the standard of care [SoC]). ³⁴ Results from CREDENCE showed that canagliflozin and SoC reduced the risk of several renal endpoints in patients with T2D and CKD compared with placebo plus SoC. ³⁴ After a median follow-up of 2.6 years, a residual risk of CV events was present in 12.5% of patients receiving SGLT2 inhibitor plus SoC. ³⁴ In DAPA-CKD, ³⁵ dapagliflozin with SoC significantly reduced the risk of progressive CKD or renal/CV death in patients with CKD (with or without T2D). Patients receiving the drug also exhibited an attenuation of progressive eGFR loss compared with patients receiving placebo. However, a risk of 6.6% remained for the composite CV endpoint (hospitalization for heart failure or CV-related death). ³⁵

EMPEROR-Reduced was a heart failure trial with a high proportion of patients with CKD and T2D. Results showed that empagliflozin reduced eGFR decline in a mixed population of patients with heart failure and CKD irrespective of the presence of T2D, but this finding was based only on secondary outcomes. ³⁶ The EMPA-KIDNEY trial was stopped early due to positive kidney benefits.^37,38 The trial data are due in late 2022 and will provide additional information regarding the use of SGLT2 inhibitors in patients with CKD, with or without T2D.^30,37,38

MRAs

Classical steroidal MRAs have demonstrated cardioprotective and nephroprotective properties through their ability to reduce albuminuria and blood pressure.^39,40 However, due to the lack of phase 3 studies, neither eplerenone nor spironolactone have a label in the CKD indication. Mineralocorticoid receptor overactivation has a role in T2D and CKD through inflammation and fibrosis, which contribute to CV and renal dysfunction.^41–44 Meta-analyses have suggested that steroidal MRAs can reduce urinary protein and albumin excretion in patients with CKD, but these patients may develop hyperkalemia as a consequence. ⁴⁵ However, the selective nonsteroidal MRA, finerenone, was reported to reduce UACR in patients with CKD already on RAAS inhibitor treatment. This effect was observed without notable impact on serum potassium levels when compared with the steroidal MRA, spironolactone.^46,47 In addition, finerenone demonstrated potent anti-inflammatory and anti-fibrotic effects in preclinical models.^48–50

The FIDELIO-DKD ⁵¹ and FIGARO-DKD ⁵² trials investigated the efficacy and safety of finerenone on kidney failure and CV outcomes from early to advanced CKD in patients with T2D. ⁵¹ In patients with T2D and CKD whose HbA_1c and blood pressure levels were well maintained, the FIDELIO-DKD trial demonstrated that finerenone treatment decreased the risk of CKD progression and CV events compared with placebo. ⁵¹ Filippatos et al ⁵³ reported that in patients with CKD and T2D, finerenone reduced the risk of new-onset atrial fibrillation or flutter (AFF); the risk of kidney or CV events was also lowered, irrespective of history of AFF at baseline. As mentioned previously, despite the cardioprotective and nephroprotective properties of classical steroidal MRAs, patients with both T2D and CKD treated with these MRAs may be at risk of developing hyperkalemia.^39,40 Results from phase 2 trials show that finerenone is associated with a lower incidence of hyperkalemia-related adverse events compared with steroidal MRAs.^46,47 It is also currently the only agent with the indication for renoprotection making it a viable therapeutic approach for reducing CKD progression or CV events in high-risk patients with T2D and CKD. ⁵

Monitoring Recommendations for Patients With T2D

Besides glycemic control, ⁶ optimal diabetes management for patients with T2D involves regular screening for additional risk factors (eg, UACR, hypertension, dyslipidemia, obesity, and lifestyle factors such as diet, smoking, and physical activity).^2,3,6,11 A typical presentation of CKD in patients with T2D includes longstanding diabetes, retinopathy, progressive loss of eGFR, ¹¹ and albuminuria without hematuria. ¹¹ Both UACR and eGFR should be closely monitored in these patients to ensure timely diagnosis of CKD and prevention of CKD progression.^5,11,54

It is also important for primary care clinicians to note that UACR is now used as the quality metric of choice recommended by professional diabetes societies to monitor CKD development and progression. As of 2021, the ADA^5,55 and AACE guidelines^5,56,57 recommend an annual spot measurement of UACR and eGFR in all patients with T2D regardless of treatment as part of a screening process for CKD.^5,55 Patients with T2D and UACR ≥ 300 mg/g and/or an eGFR of 30 to 60 mL/min/1.73 m² should be monitored twice annually.^5,55 Clinicians should consider initiating an SGLT2 inhibitor in patients with T2D and DKD (eGFR ≥ 20 mL/min/1.73 m² and UACR ≥ 200 mg/g) to reduce the risk of kidney disease progression and CV events. ⁶ The 2022 ADA guidelines also recommend a ≥ 30% reduction in urinary albumin in patients with CKD who have ≥300 mg/g albuminuria to slow CKD progression as this is considered by the Division of Cardiology and Nephrology of the US Food and Drug Administration ⁵ to be a valid surrogate for renal benefit. ⁵⁸ Clinical trials with ACE inhibitors or ARB therapy in T2D have demonstrated an association between a 30% reduction in albuminuria from baseline and improved cardiorenal outcome. This has led some to believe that therapies should be titrated to maximize reduction in UACR, but this remains to be determined. ⁵⁹ Primary care clinicians should also consider administering finerenone to patients with T2D and CKD treated with maximum tolerated doses of ACE inhibitors or ARBs to improve CV outcomes and reduce the risk of CKD progression. ⁶

Timely Diagnosis of CKD Requires Effective Multidisciplinary Management

A recent qualitative study examining unmet needs in the management of patients with T2D and CKD in the primary care setting found that early and accurate identification of patients at risk of developing CKD could improve patient outcomes. ⁶⁰ Detecting and managing early CKD in patients with T2D may require collaboration across different practice settings involving nurse practitioners, physician assistants, primary care physicians, and endocrinologists, before a patient is referred to a kidney specialist for advanced renal assistance. ⁸

To meet targets in the 2019 Executive Order on Advancing American Kidney Health, primary care clinicians were encouraged to consider early consultation with a kidney specialist. The 2022 ADA guidelines recommend referring patients to Nephrology in 3 major scenarios: (1) when there is uncertainty about the etiology of kidney disease; (2) when there is rapid progression of kidney decline; ⁵ and, (3) for issues difficult to manage such as anemia, secondary hyperparathyroidism, and significant increases in UACR despite good blood pressure control. The 2022 ADA guidelines and KDIGO CKD Working Group recommend that patients with advanced kidney disease (eGFR < 30 mL/min/1.73 m²) also be referred to a kidney specialist.^61,62

The ADA notes that, despite recommendations for early referral, there are additional factors that influence the decision for primary care clinicians to refer patients, which may not always make early referrals feasible. ⁶³ Study results from an US academic healthcare system found that only 45.4% of patients actively visiting their primary care clinicians are referred to a nephrologist, but the study did not specify whether patients who were referred had an eGFR < 30 mL/min/1.73 m². ⁶² A qualitative study by Greer et al ⁶⁴ identified key barriers to appropriate nephrology referral of patients with CKD: lack of timely and adequate information exchange between nephrologists and primary care clinicians; limited access to nephrologists; lack of clarity regarding clinical roles and responsibilities; challenging working relationships with nephrologists; and, lack of trust between patients and nephrologists. ⁶³ These findings highlight the multifactorial approach required to enhance cohesion among primary care clinicians, endocrinologists, and nephrologists to improve clinical outcomes for patients with T2D and CKD.

Conclusions

Advances in therapy for patients with T2D have substantially improved glycemic and blood pressure control with associated reductions in diabetes-related complications. Despite this, many patients still develop CKD and are at high risk of all-cause mortality and CV mortality. Additional effort is required to identify patients at risk, and provide kidney-protective therapy beyond what can be achieved with blood pressure and blood glucose control. The prevention of CKD progression in patients with T2D may benefit from multidisciplinary collaboration between clinicians in primary care settings and those in endocrinology and nephrology clinics. Early diagnosis of CKD can be achieved through identification of associated risk factors and the implementation of eGFR and UACR screening protocols, as outlined in the ADA and AACE guidelines. Optimization of treatment algorithms, for example, by including SGLT2 inhibitors and nonsteroidal MRAs, will also improve outcomes in patients with T2D.