Overcoming barriers to implementing new guideline-directed therapies for chronic kidney disease

ABSTRACT

For the first time in many years, guideline-directed drug therapies have emerged that offer substantial cardiorenal benefits, improved quality of life and longevity in patients with chronic kidney disease (CKD) and type 2 diabetes. These treatment options include sodium-glucose cotransporter-2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists. However, despite compelling evidence from multiple clinical trials, their uptake has been slow in routine clinical practice, reminiscent of the historical evolution of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use. The delay in implementation of these evidence-based therapies highlights the many challenges to optimal CKD care, including: (i) clinical inertia; (ii) low CKD awareness; (iii) suboptimal kidney disease education among patients and providers; (iv) lack of patient and community engagement; (v) multimorbidity and polypharmacy; (vi) challenges in the primary care setting; (vii) fragmented CKD care; (viii) disparities in underserved populations; (ix) lack of public policy focused on health equity; and (x) high drug prices. These barriers to optimal cardiorenal outcomes can be ameliorated by a multifaceted approach, using the Chronic Care Model framework, to include patient and provider education, patient self-management programs, shared decision making, electronic clinical decision support tools, quality improvement initiatives, clear practice guidelines, multidisciplinary and collaborative care, provider accountability, and robust health information technology. It is incumbent on the global kidney community to take on a multidimensional perspective of CKD care by addressing patient-, community-, provider-, healthcare system- and policy-level barriers.

INTRODUCTION

In recent years, a number of new drug therapies have emerged that represent a paradigm shift in the treatment of chronic kidney disease (CKD) and type 2 diabetes (T2D). These include sodium-glucose cotransporter-2 inhibitors (SGLT2i), nonsteroidal mineralocorticoid receptor antagonists (MRA) and glucagon-like peptide-1 receptor agonists (GLP1-RA). In 2020, the US Food and Drug Administration designated the SGLT2i, dapagliflozin, as a breakthrough therapy for the treatment of patients with CKD, with or without T2D—an unprecedented moment in the history of nephrology given that no prior breakthrough designation has been granted for a potential kidney disease therapy [1].

The emergence of these highly effective therapies led to the Kidney Disease: Improving Global Outcomes (KDIGO) 2020 Clinical Practice Guideline for Diabetes Management in CKD [2]. Both metformin and SGLT2i are preferred medications for patients with T2D, CKD and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (Fig. 1). For those who have not achieved individualized glycemic targets despite use of metformin and SGLT2i, or who are unable to use those medications, a long-acting GLP1-RA is recommended. Further, the American Diabetes Association recently updated its recommendation that for patients with T2D and CKD treated with maximum tolerated doses of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB), addition of the MRA, finerenone, should be considered to improve cardiovascular outcomes and reduce the risk of CKD progression [3–5].

Figure 1:

KDIGO 2020 treatment algorithm for selecting antihyperglycemic drugs for patients with type 2 diabetes and chronic kidney disease. KDIGO, Kidney Disease: Improving Global Outcomes; eGFR, estimated glomerular filtration rate; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium–glucose cotransporter-2; TZD, thiazolidinedione.

However, despite compelling evidence from multiple clinical trials on the benefits of these cardiorenal therapies and recommendations by international organizations [2, 3, 6–9], uptake has been slow. Based on the National Health and Nutrition Examination Survey (NHANES) data from 2017–20 [10], the overall prevalence of SGLT2i and GLP1-RA use was 5.8% and 4.4%, respectively, in adults with T2D and eGFR ≥30 mL/min/1.73 m2. SGLT2i and GLP1-RA were similarly underutilized (2.8% and 3.9%, respectively) in a large US cohort of more than 300 000 patients with T2D and cardiovascular disease (CVD) during 2018 [11]. In the UK, although use of SGLT2i and GLP1-RA in adults with T2D has increased, overall adoption remained low in 2019, with slightly less use in those with CVD despite this group being likely to gain the most benefit (SGLT2i: 9.8% and 13.8%; GLP1-RA: 4.3% and 4.9%) in those with and without CVD, respectively [12].

The barriers to implementation of these newer agents mirror the historical evolution of ACEi and ARB use. A large number of candidates for renin–angiotensin–system inhibition do not receive them, at least in part because of concern about hyperkalemia and initial decrease in eGFR [13]. ACEi/ARB use in patients with CKD in the US was 40% by 2014 but seemed to have plateaued after the early 2000s [14], and initiation of ACEi/ARB therapy within the first year after CKD diagnosis in patients with T2D was only about 17% [15]. However, ACEi/ARB use appears higher in Europe and Canada. The German Chronic Kidney Disease Study investigators reported that over 80% of their cohort received either an ACEi or ARB [16], and a Canadian registry study showed that among patients with CKD and T2D, ACEi/ARB use was 76% [17]. This global variation in practice patterns may be partly related to differences in healthcare systems and delivery.

BARRIERS AND STRATEGIES IN IMPLEMENTING NEW CARDIORENAL THERAPIES FOR CKD

The delay in implementation of newer guideline-directed cardiorenal therapies highlights the many challenges to optimal care in patients with CKD and T2D [18, 19]. Overcoming these barriers will likely require a combination of patient-, community-, provider-, healthcare system- and public policy-level approaches (Fig. 2).

Figure 2:

Barriers and strategies in implementing new cardiorenal therapies for chronic kidney disease. HIT, health information technology; SDOH, social determinants of health.

Clinical inertia

Clinical inertia has been proposed as a key driver limiting initiation of SGLT2i, nonsteroidal MRA and GLP1-RA in eligible patients with cardiorenal risk [20, 21]. Phillips et al. [22] first highlighted this concept to indicate a “failure of health care providers to initiate or intensify therapy when indicated.” Maintaining the status quo—recognition of the problem, but failure to act—is common in management of patients with asymptomatic chronic illness. Clinical inertia related to the management of diabetes, hypertension and lipid disorders may contribute to up to 80% of cardiovascular events [23]. It is therefore a leading cause of potentially preventable adverse events, disability, death and excess medical care costs. Its causes are multidimensional [20, 22, 23]. Provider factors include: (i) clinicians overrate the quality of the care they already deliver and underestimate the number of patients in need of intensified pharmacotherapy; (ii) providers make “soft excuses” or rationalizations to avoid advancing therapy (perceptions about patient nonadherence, and fear of drug side effects despite substantial benefits outweighing risks); and (iii) lack of knowledge, experience and training with the new therapies. Patient factors include unawareness of the need to intensify therapy, denial or overly optimistic views of their health risks, and avoidance of increased expenses and side effects associated with more intensive therapy. Health system factors include limited ability to capture real-time data to monitor the quality of care and identify patients in need of more intensive care, lack of active outreach to patients in need of care and failure to implement decision support strategies. Overcoming clinical inertia requires a multipronged approach to address the patient, provider and system-level factors. These include educational programs for both patients and providers with clear practice guidelines, patient empowerment through self-management programs, development of quality measures and active feedback to providers, care delivery through multidisciplinary teams and effective use of information systems [20, 24]. These multifaceted measures would not only address the initial uptake of cardiorenal therapies but also the critical aspect of persistent medication use and long-term adherence.

Low CKD awareness

Although 15% of adults in the USA are estimated to have CKD, up to 90% do not know they have CKD, and even 40% of those with severe CKD do not know they have CKD [25]. Although the wording of the questions (e.g. “weak or failing kidneys,” “kidney problem,” “kidney disease”) may lead to widely different estimates of CKD awareness, a meta-analysis of 32 studies showed low awareness overall (19.2%), with most studies reporting <50% of individuals with CKD being aware of their condition [26]. Despite some evidence of benefits from patient awareness of CKD [27, 28], a growing number of studies have failed to demonstrate associations between baseline CKD awareness and healthy behaviors [e.g. avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs)], ACEi/ARB use, blood pressure (BP) control, glycemic control, or changes in eGFR and albuminuria [29–31]. Thus, robust trial data are needed to determine whether patient awareness of the early stages of CKD promotes uptake of guideline-based therapies and improves outcomes. Awareness alone may not be sufficient to improve self-management or chronic disease management. Awareness efforts should be integrated with other interventions such as patient and healthcare provider education about CKD, as there is evidence that provider awareness of patient CKD improves BP control [32]. In addition, public awareness campaigns are important in raising CKD awareness. In March 2020, the US Department of Health and Human Services launched a nationwide kidney risk awareness campaign in collaboration with the National Kidney Foundation and the American Society of Nephrology, responding to the Executive Order on the Advancing American Kidney Health (AAKH) initiative [33]. The importance of public CKD awareness is further underscored as a national objective of the Healthy People 2030 initiative [34].

Suboptimal kidney disease education among patients and providers

The large gaps in CKD awareness highlight the need for effective education about kidney disease. Patient education is associated with improved outcomes across the CKD spectrum and is uniformly supported by international guidelines and organizations [35]. However, more research is needed to assess the impact of patient education in the earlier stages of CKD on clinical outcomes [36]. Barriers to improving patient education are well documented, including low baseline understanding of CKD health risks, low health literacy [37] and numeracy [38], and limited educational materials at a literacy level suitable for at-risk populations [39]. Although lack of time is cited by physicians as a barrier to CKD education [40], many physicians feel inadequately prepared to explain kidney disease to their patients [41]. Further, patient education is time-consuming and the kidney disease education benefit for Medicare beneficiaries in the USA has been underutilized [42].

A growing number of diverse investigators are engaged in meeting the educational needs of the communities with the greatest burden of kidney disease [43]. Strategies that have been shown to make kidney disease education more effective focus on patients with progressive disease, not on all people who meet laboratory criteria for a CKD diagnosis. Specific approaches to improve CKD education include emphasis on self-management support, shared decision making about treatment options, engagement of the entire interdisciplinary team in kidney disease education [44], group-based educational programs and incorporating performance measures related to patient education in quality improvement efforts.

Lack of patient and community engagement

The World Health Organization (WHO) defines patient engagement as “the process of building the capacity of patients, families, carers, as well as health care providers, to facilitate and support the active involvement of patients in their own care, in order to enhance safety, quality and people-centredness of health care service delivery” [45]. Patient engagement can lead to better health outcomes and improvements in quality and patient safety, and help control healthcare costs [46]. A systematic review found that patient engagement can inform patient and provider education and policies, as well as enhance service delivery and governance [47]. Factors that influence engagement are related to patients (beliefs about patient's role, health literacy), organization (hospital policies and practices) and society (local and national regulations and policies) [46]. Practical steps to improve patient engagement include educating patients and providers, obtaining feedback from patients, and involving patients at organizational levels (e.g. patient advisory committees) [45]. Meaningful engagement begins with empowering patients in daily self-care. Self-management skills involve focusing on illness needs, activating resources and the process of living with a chronic illness [48]. Diabetes self-management education programs have been shown to be efficacious and cost-effective in enhancing self-management, with improvements in patients’ knowledge, skills and motivation leading to improved biomedical, behavioral and psychosocial outcomes [49]. The KDIGO guidelines recommend that a structured self-management educational program be implemented for people with CKD and T2D, taking into consideration the local context, culture and availability of resources [2]. Thus, patient engagement strategies should be broadened to the community level through outreach efforts, recognizing the importance of social networks such as patient-support groups.

Multimorbidity and polypharmacy

Even at early stages, CKD commonly occurs in the context of multiple comorbid conditions [50] and polypharmacy, generally defined as regular use of five or more medications daily [51]. In a large population-based cohort study of Canadian adults, nephrology patients had the highest mean number of comorbidities (4.2; 95% confidence interval 4.2–4.3) and highest mean number of prescribed medications (14.2; 95% confidence interval 14.2–1.43), compared with those seen by primary care physicians and 10 other subspecialists [52]. In a recent European study, the prevalence of polypharmacy was 62%–86% in patients with Stage 1–3b CKD (with a median medication number of eight per day), with concurrent diabetes mellitus as a significant risk factor for polypharmacy [16]. In CKD, polypharmacy is associated with poor adherence, adverse drug reactions/interactions, CKD progression, morbidity and mortality [53]. Care providers should focus on multidisciplinary management with an eye toward “de-prescribing” of unnecessary or problematic medications and ensuring that medications are appropriate based on their indications and risks/benefits. Potential targets include proton pump inhibitors, some oral hypoglycemic agents, NSAIDs, benzodiazepines, gabapentin/pregabalin, diuretics, some anti-hypertensives, and potassium binders [54–56]. One study showed that 58% of all drugs could be discontinued in a cohort of community-dwelling elderly patients, without significant adverse events or deaths attributable to discontinuation, and 88% of patients reported global improvement in health [57]. Although the sample size was small (n = 70), the study findings suggest that it is feasible to safely reduce polypharmacy with the added benefit of enhanced quality of life.

SGLT2i and GLP1-RA are attractive replacements for other antidiabetic agents that do not provide the same cardiorenal benefits. SGLT2i have diuretic, antihypertensive and anti-proteinuric effects, allowing simplification of medication regimens and de-prescribing of less desirable agents [54, 58]. In addition, this may be desirable because the beneficial effects of SGLT2i on renal outcomes may be blunted in the setting of polypharmacy [59]. Initiation of new cardiorenal agents to the medication regimen should be used as an opportunity to scrutinize and possibly deprescribe or dose adjust other medications. A polypill-based strategy (fixed-dose combination of medications) warrants investigation since it has the potential to improve adherence to therapy, lower costs and enhance safety profiles [60].

Challenges in the primary care setting

The majority of patients with CKD are managed in the primary care setting. Given that the global nephrology workforce is unable to meet the demands of the increasing CKD population, primary care providers play a crucial role in early intervention to prevent or delay CKD progression. However, primary care providers face multiple challenges [61–63], including: (i) lack of provider awareness and knowledge of CKD, risk assessment and guideline-directed interventions; (ii) complex patient characteristics; (iii) CKD not considered high priority versus competing health conditions; (iv) high work volume and insufficient time; (v) inadequate collaboration and poor access to nephrologists and other subspecialists; and (vi) difficulties with the process of specialist referral and lack of clear parameters for timely referral to nephrologists. The 2017 International Society of Nephrology Global Kidney Health Atlas survey reported that non-nephrologist physician-related factors (availability, access, knowledge and attitude) are some of the leading barriers to optimal kidney disease care [64]. These barriers can be ameliorated by concise and consistent practice guidelines that are transparent in the development process, actionable and patient-centered [65], automated CKD decision support tool integrated into the electronic health records (e.g. electronic alerts, lab decision support) [66] and team-based care (e.g. task shifting from physicians to allied healthcare professionals such as nurses and pharmacists) [67, 68].

Fragmented CKD care

The integration of evidence-based therapeutics in clinical practice is impacted by the fragmentation of the US healthcare delivery system [69, 70]. Siloed care can exacerbate clinical inertia in starting SGLT2i or GLP1-RA by nephrologists and cardiologists given the added responsibilities of managing diabetes. A more collaborative, team-based and integrated care approach may result in better outcomes, with the participation of physicians and nonphysician personnel (e.g. trained nurses and dieticians, pharmacists, healthcare assistants, community healthcare workers and peer supporters) [2]. Although data are lacking in patients with early CKD and T2D, a systematic review of 11 studies on patients with Stage 3–5 CKD (41% had diabetes) revealed that multidisciplinary care slows CKD progression and decreases mortality, the risk of kidney replacement therapy (KRT), the need for emergent dialysis and healthcare costs [71]. Multidisciplinary care is predicated on close communication and active collaboration as well as defined roles and responsibilities for each member of the CKD team. Care coordination is facilitated by an interoperable health information technology system, allowing patient data to be easily accessible across providers and multiple healthcare settings (inpatient and outpatient facilities, emergency departments, pharmacies, extended and long-term care facilities) [72].

Disparities in underserved populations

Disparities in cardiorenal health remain pervasive, with a higher burden of CVD [73], cardiovascular death [74] and advanced CKD [75, 76] being greatest in the Black population. However, Black patients are less likely to receive novel therapeutics than White patients [77, 78]. A recent analysis of commercially insured US patients with T2D showed that Black race, female sex and lower household incomes were associated with lower rates of SGLT2i use overall and among those with heart failure (HF), CVD and CKD [79]. As noted by the study investigators, the observed disparities may be even greater among those with traditional Medicare or Medicaid or those without private healthcare insurance [79]. While the SGLT2i trials are limited by small sample sizes of Black patients (∼5% or less) [80–82], subgroup analyses suggest that the positive impact of SGLT2i are also present among Black subjects. Taken together, these findings highlight racial inequities in access to evidence-based therapies. Major reasons for both the low and disparate use of evidence-based care are high costs driven by variations in health insurance affordability, medication coverage, provider access and other factors, such as trust of a health system that too often demonstrates an overriding interest in profit and prioritizing affluent members of society. It is imperative to overcome barriers such as these in order to deliver high quality and affordable healthcare to all patients.

Lack of public policy focused on health equity

The WHO has outlined three principles of global action to address health injustices: (i) improve living and working conditions; (ii) ensure equitable distribution of power, money and resources; and (iii) measure health inequity and educate healthcare workers and the wider society on how inequity in the social determinants of health (SDOH) lead to disparities [83]. These principles can help create a foundation for health equity, reduce avoidable risk factors for CKD and redirect resources towards CKD prevention and early intervention [84]. In the USA, the Centers for Medicare & Medicaid Service has committed to make health equity the first “pillar” of its strategic vision [85]. Five strategies have been proposed to advance health equity through payment and delivery system reform: (i) improve data collection on race/ethnicity and SDOH; (ii) monitor the impact of payment programs on health equity; (iii) shift from pay-for-performance approaches to invest-for-equity programs (e.g. providing greater resources to providers in underserved communities); (iv) ensure that under-resourced patients and health systems participate in value-based payment models that could improve quality and increase affordability; and (v) align payers (Medicare, Medicaid, commercial) to provide consistent incentives for providers and experiences for patients [86]. We remain cautiously optimistic that this strategic vision can become a reality.

High drug prices

High drug cost, low reimbursement rates and the financial burden of clinical monitoring and adjustments represent an important impediment to guideline-directed cardiorenal therapy, even in wealthy nations. Out-of-pocket costs for Medicare Part D beneficiaries in 2019 were at least $1000 annually for an SGLT2i and greater than $1500 for an GLP1-RA, and may not be affordable to many older or socially disadvantaged patients [87]. Given their renal and cardiac protective properties, the upstream costs of these agents should be weighed against the high downstream costs for patients with CKD and T2D. An analysis of claims data for adults with CKD and T2D showed that the estimated 4-month CKD management costs ranged from $7725 for Stage 1 to 2 disease to $11 879 for Stage 5 (without KRT). Acute event costs for CKD complications were $31 063 for HF, $21 087 for stroke and $21 016 for myocardial infarction in the first 4 months after the incident event [88]. A microsimulation model based on data from the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study showed that canagliflozin improved patient outcomes while reducing net costs from the National Health System perspective in the UK [89]. A Markov model of an US patient population with CKD, T2D and HF demonstrated that dapagliflozin has the potential to reduce cardiorenal disease prevalence by 8% and direct healthcare costs by 3.6% by 2030 [90]. A systematic review of cost-effectiveness studies demonstrated that newer antidiabetic medications (e.g. SGLT2i, GLP1-RA) were cost effective from both payer and societal perspectives, compared with insulin, thiazolidinediones and sulfonylureas [91]. Despite these favorable cost-effectiveness data, there are currently insufficient incentives for the pharmaceutical industry to lower drug prices. Recently, the American Society of Nephrology Diabetic Kidney Disease Collaborative (DKD-C) Task Force has called for healthcare systems, federal agencies, payers and pharmaceutical companies to align incentives, partner in new financial models, conduct further pharmacoeconomic studies, promote health policy for insurance coverage, and collaborate on value-based care defined as health outcomes achieved per dollar spent [92], in order to increase uptake of newer cardiorenal therapies [93].

CHRONIC CARE MODEL IN CKD

The fragmentation of the US healthcare delivery system is a fundamental barrier to optimal CKD care. It leads to poor patient experiences; lack of communication and coordination resulting in medical errors, waste and duplicative services; absence of peer accountability and quality improvement infrastructure; and ultimately poor overall quality and lower value of care [69].

The Chronic Care Model (CCM) is an evidence-based and widely implemented framework to improve chronic illness management [94, 95]. The CCM aims to improve patient outcomes by supporting an informed, activated patient and a prepared, proactive, multidisciplinary healthcare team. It has six essential components: a proactive delivery system design, self-management support, decision support tools, functional clinical information systems, community resources and effective policy, and quality-oriented healthcare organization. In practice, this promotes systems thinking and results in a “learning health system” where data and experience are utilized to improve patient safety, quality of care and workplace environment [96]. The CCM was the guiding principle for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Kidney Disease Education Program's (NKDEP) comprehensive educational efforts to foster a population health approach to CKD [97] (Fig. 3).

Figure 3:

The Chronic Care Model as the guiding principle for the National Kidney Disease Education Program's (NKDEP) comprehensive educational efforts to foster a population health approach to chronic kidney disease (CKD). CME, continuing medical education; GFR, glomerular filtration rate; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; PCP, primary care provider; UACR, urine albumin-creatinine ratio.

Population-based approaches to kidney disease prevention and management, inspired by the CCM, using existing infrastructure and with limited additional cost, have been shown to be effective. For instance, American Indians served by the Indian Health Service experienced a rapid rise in the prevalence of end-stage kidney disease (ESKD) in the 1970s and 1980s. In response, an interdisciplinary, primary care–based approach to implementing preventive therapies was initiated which, over the next two decades, led to a 54% reduction in incidence rates of diabetes-attributed ESKD [98]. This approach was based on the consistent implementation of simple measures by all members of the primary care team, in a system built on the principles of population health. These included routine screening for kidney disease using simple blood and urine tests, establishment of simple and easy-to-implement guidelines on management and monitoring of CKD and its complications, and the development of a suite of clinical tools and educational materials for patients and providers. This approach was promoted through continuing education activities for all healthcare professionals and paraprofessionals to enable them to feel comfortable and competent to manage patients with kidney disease and educate patients about CKD and their treatment choices [97]. These simple evidence-based interventions were highly effective in improving outcomes in a high-risk population with fewer than half the per capita healthcare resources available compared with the US civilian population.

CONCLUSIONS

For the first time in many years, there is emergence of guideline-directed drug therapies that offer substantial cardiorenal benefits, improved quality of life and longevity in patients with CKD and T2D. The multiple challenges of implementing these drug treatments in daily clinical practice will require a renewed focus on increasing CKD awareness, detection and early interventions. Restructuring of the current reimbursement systems is much needed to incentivize all stakeholders, including healthcare systems and clinicians, to prioritize CKD care and reduce progression to ESKD. Furthermore, barriers to optimal CKD care can be ameliorated by a multifaceted approach, using the CCM framework and providing open access to high value care for all.

FUNDING

G.Y. is supported in part by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK112008. K.C.N. is supported by NIH grants UL1TR000124 and P30AG021684.

DISCLAIMER

The views expressed in this review article are those of the authors and do not reflect the official policy of the Department of the Army/Navy/Air Force, the Department of Defense, or the United States government.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interests.