Barriers to Care: New Medications and CKD

Chronic kidney disease (CKD) is estimated to affect >800 million individuals worldwide, with more than 80% residing in low and middle-income countries.^1,2 The leading causes of CKD are diabetes and hypertension, both of which continue to rise in prevalence. At the current trajectory, CKD is forecast to see a 100%-fold increase in years of life lost between 2016 and 2040, rising to the fifth most common cause of death.³ There is no cure for CKD, and those who progress to kidney failure either die or require costly resource-intensive kidney replacement therapies, including dialysis and kidney transplant, which most people cannot access.⁴ This makes it crucial to slow the progression of CKD.

Over the past decade, the landscape of therapeutic agents in CKD has dramatically evolved with new proven and potential therapies that delay and prevent kidney failure. Sodium glucose cotransporter 2 (SGLT2) inhibitors improve kidney outcomes and reduce the risk of cardiovascular events in people with CKD in addition to standard-of-care, with similar effects found with selective mineralocorticoid receptor antagonists and suggested for glucagon like peptide-1 receptor antagonists (GLP-1 RA) in people with CKD and type 2 diabetes mellitus. Unfortunately, the use of these therapies has been slow, reminiscent of the patterns previously seen with renin-angiotensin system inhibitor use. Despite being a foundation of CKD management and strongly recommended in clinical guidelines based on high quality evidence, renin-angiotensin system blockers remain underutilized,^5,6 with similar trends observed for SGLT2 inhibitor and GLP-1 RA therapy in diabetes. In a study of almost 15,000 patients with diabetes across 37 countries, 10.8% were on an SGLT2 inhibitor or GLP-1 RA at baseline, which rose to just 16.1% overall after 3 years of follow-up, and 17.1% in those with CKD.⁷ There is a myriad of potential reasons for this suboptimal care stemming from gaps across systemic, provider, and patient-related levels (Figure 1), as well as specific regional challenges.

Figure 1.

Requirements for full utilization of proven therapies in chronic kidney disease. CKD, chronic kidney disease.

The World Kidney Day theme for 2024 is “Kidney Health for All – Advancing equitable access to care and optimal medication practice.” The first step toward generating change and shifting the narrative toward equitable healthcare in CKD is to identify the key barriers and promote awareness about the urgency for action at each level to ensure new effective medications reach those who need them (Figure 2).

Figure 2.

Potential solutions for the barriers to care in utilizing new medications in chronic kidney disease. CKD, chronic kidney disease.

Barriers to Utilization of New Medications in CKD

System Barriers

Accessibility and affordability of new medications is crucial and especially so in low and middle-income countries, where the risk of kidney failure is the greatest. For example, 94% of communities in high-income countries were found to have access to four antihypertensive classes compared to just 13% in low-income countries.⁸ The data on the availability of newer medications in CKD are sparse; however, these gaps are likely similar or perhaps even greater. SGLT2 inhibitors were added to the World Health Organization Essential Medicines List in 2021 to encourage their inclusion in national formularies and negotiations about cost reductions. Modeling demonstrates the cost-effectiveness of treating patients with CKD with dapagliflozin, an SGLT2 inhibitor, because of its potential to prevent kidney failure, reduce kidney replacement therapy requirements, and lower incidence of hospitalization for heart failure with a post hoc analysis of the DAPA-CKD trial⁹ estimating that the annual net financial benefit of treating all non-diabetic patients with CKD in the USA with dapagliflozin could be as high as $21 billionS1 (Supplementary References). Despite this, SGLT2 inhibitors are not available or subsidized for many eligible patients with CKD globally. The challenges are greater for GLP-1 RA which are more expensive, with inaccessibility further exacerbated by shortages from increased demand for off-label indications, thus again depriving the already disadvantaged. The engagement of policymakers and governments is essential to bridge this gap.

The uptake of new medications and reduction in costs are influenced by national drug regulatory body approval (e.g., from the US Food and Drug Administration) and inclusion in clinical practice guidelines. Updates in the international CKD guidelines tend to span up to 10 years; for example despite overwhelming evidence for the benefits of SGLT2 inhibitors, their inclusion in the non-diabetic CKD guidelines lagged by over 3 years. Similarly, finerenone, a mineralocorticoid receptor antagonist approved for use in diabetic kidney disease, is not included in the latest 2020 guidelines. As more research is generated in CKD, rapid incorporation of this new evidence into guidelines most likely requires the use of living guidelines and wide implementation of these guidelines.

The vast majority of people with CKD have earlier stages of the disease with the provision of care for this population group predominantly led by primary care physicians, which adds to provider-related barriers discussed below. For optimal impact, education on implementing guidelines and prescribing therapies in CKD should be specifically directed at the primary care level. This is further compounded by the inadequate ratio of nephrologists to the escalating number of people with CKD worldwide.S2 The reasons for this shortage vary by region and include inadequate healthcare infrastructure and medical training, waning interest in the field among trainees, and lower renumeration rates compared to other specialties.S2

Provider Barriers

The effective delivery of new medications relies on health professionals diagnosing CKD early, identifying those at risk of kidney failure, being up-to-date with the latest evidence, correctly prescribing therapies to eligible patients, and ensuring regular follow-up. Each step presents unique challenges and cumulatively contributes toward the underutilization of effective drugs. Insufficient awareness of CKD among primary healthcare providers and nonnephrology specialists has been recognized globally.S3 A recent international study found the prevalence of undiagnosed stage 3 CKD was between 61.6% and 95.5% but did not capture data from low and middle-income countries where the rates are likely to be higher.S4 This delay in diagnosis results in missed opportunities for the implementation of kidney protective therapy in early stages of CKD before progression to kidney failure.

Clinical inertia is a well-recognized phenomenon, which contributes to incongruencies between eligible patients with CKD and those who ultimately receive them and can be a greater barrier than cost to the uptake of new medications.S5 For example, in Australia, a high income country with universal healthcare, the uptake of SGLT2 inhibitors remained poor (4%–14%) among eligible patients with CKD between 2020 and 2021 despite the accessibility and subsidized cost,S6 suggesting that clinical inertia is a likely contributor. Lower rates of SGLT2 inhibitors and GLP-1 RA were also found in people treated by primary care physicians compared to other specialists.⁷ The roots of clinical inertia are multifactorial and include limited knowledge and siloed specialties with limited interdisciplinary collaboration. Although recent years have seen a faster pace of change in CKD medications, guidelines and education have failed to follow suit. Based on estimates from primary care data in Australia, even a modest increase in SGLT2 inhibitor use has the potential to prevent 437 patients from reaching kidney failure annually.S6 Raising awareness and improving education in primary care is imperative, where most patients with early stages of CKD are treated, offering the greatest potential to alleviate the burden of disease at a population-level.

Education alone is inadequate, and any individual intervention is unlikely to overcome the challenges with clinical inertia alone. In cardiovascular disease and type 2 diabetes mellitus, where analogous patterns in the underutilization of new evidence-based medications have been identified, a multifaceted suite of interventions was found to increase the prescription of these drugs by over 4-fold compared to usual care.S7 These interventions included the identification of local barriers to care, multidisciplinary coordination of care between different medical specialists (cardiologists, endocrinologists, and primary care clinicians), delivery of clinician education, audits, and feedback of the rates of prescribed therapies, and providing educational materials for patients. The efficacy of a similar constellation of strategies in CKD should be explored.

Patient Barriers

The diagnosis and management of CKD has proven challenging because of its insidious nature, and low awareness. Patients may be asymptomatic for years until they reach advanced disease, thereby limiting their insight into the implications of early diagnosis, regular monitoring, and attending routine medical care. For this reason, CKD has been labeled as a “silent killer.” New medications improve long-term kidney and cardiovascular outcomes by preventing disease progression, and so may not yield immediate tangible effects for patients while adding to pill burden. This combination risks fostering complacency and treatment nonadherence or discontinuation.

Proposed measures such as educational and self-management interventions to improve health literacy are based on low level evidence.S8 Effective medication adherence methods for patients with CKD are poorly understood and remain a research priority. Patient-led research and engaging patients in decision-making is crucial to identify effective healthcare models, address treatment gaps, and ultimately empower patients to actively improve their own health.

Out-of-pocket costs are another significant barrier and particularly affect disadvantaged communities and low and middle-income countries.S9 This issue arises from the high cost of the medications themselves, inadequate subsidization, lack of health insurance, and attending specialist appointments. The downstream effect of such systemic issues on individual patients can be overwhelming and discourage the use of these medications.

Conclusion

The paradigm of CKD management is changing, and it is exciting to be in an era where new medications are being developed to slow the progression of CKD. Global resources are insufficient to match the rising kidney replacement therapy requirements, making it crucial to use new medications to delay kidney failure targeted at earlier stages of CKD in order to maximize their benefits. Overcoming systemic, provider, and patient barriers requires a holistic approach that considers public health, economic, and patient-centered outcomes. Too many people are dying prematurely from kidney failure and associated cardiovascular disease worldwide, and the widespread equitable utilization of these medications has the potential to drastically improve kidney health for all.

Disclosure

DK declared no competing interests. SK has received honoraria from steering committee roles from Chinook and Dimerix. VP has received honoraria for steering committee roles, scientific presentations and/or advisory board attendance from Abbvie, Amgen, Astra Zeneca, Bayer, Baxter, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pharmalink, Pfizer, Reata, Travere, Relypsa, Roche, Sanofi, Servier, and Tricida.

Supplementary Material

Supplemental References.