“In spite of the accumulating evidence of their efficacy, established treatments for maintaining renal function remain woefully underutilized. Clinicians and health care systems must be encouraged to make use of these treatments.”1
The above was written in an editorial by Thomas Hostetter1 that accompanied three landmark nephrology trials published in 2001.2–4 The studies will be well-known to nephrologists and demonstrated that angiotensin-receptor blockers (ARBs) had anti-proteinuric effects and/or slowed the decline of kidney function in patients with diabetic kidney disease. These trials added weight to the evidence that supported the use of both angiotensin-converting enzyme inhibitors (ACEi) or ARBs in diabetic kidney disease and chronic kidney disease (CKD), particularly in patients with proteinuria.5 The evidence-base supporting the use of these drugs for patients with heart failure and cardiovascular diseases is unquestioned, and given the inter-related nature of the heart and the kidneys, the hope and optimism around these drugs was understandable. Dr Hostetter, however, was right to be cautious in his appraisal of the impact these medications might have on outcomes for patients with CKD, not because of the quality or compelling nature of the trial data, but because of the difficulties overcoming clinical and systems-related inertia to achieve effective implementation of the drugs. His predictions have proved cogent.
ACEi/ARB use
Despite overwhelming evidence and innumerable local, regional, national and international guidelines, the prescription of ACEi/ARB therapies for patients with CKD have remained (to use Dr Hostetter’s word) ‘woeful’. North American data showed that between 1999 and 2014 the use of ACEi/ARB therapy in patients with CKD rose from 25.5% between 1999 and 2002 to 40.1% between 2011 and 2014, with their use being the exception unless patients had additional diseases, such as diabetes mellitus or cardiac disease.6 These findings are consistent with National Health and Nutrition Examination Survey data, which suggested that only 39% of patients in North America with hypertension and proteinuria who were eligible for ACEi/ARB therapy were on those therapies.7 In the UK, prescribing patterns for ACEi/ARB therapies may not be much better, with discontinuation of these drugs particularly common for patients with CKD and heart failure – the two patient groups with (arguably) the most to gain from these therapies.8 Worryingly, the ‘better care better value’ policy aimed at improving ACEi/ARB prescription had little to no impact on prescribing practices.9 This represents a collective failing to mobilise knowledge to support implementation of these drugs for patients in whom they will have major benefit. Consider too that these data are from countries who spend more on health per capita than most, and in completely different systems. Simply injecting more money, it seems, is unlikely to lead to improvements.
The next generation
Nearly a quarter of a century later and the nephrology community are (quite rightly) animated about new classes of medications capable of modifying disease trajectory and improving cardiovascular outcomes for patients with CKD. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the exemplar medication in that regard,10 but glucagon-like peptide 1 (GLP1) receptor agonists11 and non-steroidal mineralocorticoid-receptor antagonists (MRAs),12 have also been shown to be efficacious and safe for patients with diabetic kidney disease. Commentators are, again, making bold predictions about the impact these medications, particularly SGLT2 inhibitors, will have on the progression of CKD and patient outcomes, and if they are implemented as they were in the clinical trials then they are right, the impact will be enormous. It seems unlikely, however, that they will be, and that is a problem. Apart from there being no good reason to think prescribing inertia relating to these drugs will be any different to how it was (is) for ACEi/ARB therapies, it was crucial to the design of the definitive SGLT2 inhibitor trials (CREDENCE, DAPA-CKD and EMPA-Kidney) that patients were already treated with maximally tolerated doses of renin–angiotensin–aldosterone inhibition.
To implement these drugs as they were in the clinical trials, therefore, first requires us to dramatically improve prescription of ACEi/ARB therapies – something we have singularly failed to do at scale over the last 20 years. While patients are still likely to derive benefit from SGLT2 inhibitor therapies if prescribed for patients not on maximally titrated ACEi/ARB therapy, we cannot expect to see the same clinical outcomes when you consider what is known about the effectiveness of ACEi/ARB therapies in CKD. Without specific work and consideration, we run the risk of being similarly ineffectual in attempts to get SGLT2 inhibitors prescribed for patients with CKD, repeating the mistakes and missed opportunities of the past.
Learning lessons
So what to do? We must look at why implementation of ACEi/ARB therapies has failed. First, the requirement for monitoring of renal function at initiation and with dose adjustments, prescriber concerns about worsening renal function, hyperkalaemia and the incorrect, but often established dogma, that ACEi/ARB therapies are nephrotoxic have all led to prescriber caution. Second, in many healthcare systems, specialists routinely recommend to primary care physicians to start, monitor and up-titrate these medications, rather than prescribing them directly. Primary-care physicians are, quite reasonably, not assuaged of the literature in the same way as secondary-care colleagues and, coupled with fears around perceived risks of ACEi/ARBs in CKD, it is little wonder prescriptions are low. Indeed, models of true shared-care between primary and secondary care are scarce, which limits the effectiveness of specialist advice and recommendations. While the side-effect profile of SGLT2 inhibitors and monitoring requirements are different to ACEi/ARB therapies, they exist, and will likely lead to a similar reluctance to prescribing with the desire to avoid doing harm, particularly from clinicians less familiar with the evidence and true risks. This is crucial, as primary-care physicians are going to be responsible for the prescription of SGLT2 inhibitors for many patients and will be pivotal in the successful implementation treatments for CKD, both new and old.
We need a cultural shift in the way these therapies are viewed by clinicians and in the way they are presented to patients. ACEi/ARB therapies and SGLT2 inhibitors should be thought of as ‘disease modifying therapies’ and not just for CKD. Both classes of drug are known to be of great benefit for patients with cardiovascular diseases, including heart failure and improving metabolic control in type 2 diabetes mellitus,13 so a wide spectrum of clinicians and patients have a vested interest in getting the implementation of these drugs right. The repositioning of ACEi/ARBs and SGLT2 inhibitors as ‘disease modifying therapies’ is perhaps the rebrand that is needed to permeate collective clinical and public consciousness regarding the importance of these medications for the spectrum of cardiovascular-renal-metabolic (CVRM) conditions.
One would be forgiven for thinking we are being nihilistic, but actually nothing could be further from the truth. There is a tremendous opportunity following the publication of this remarkable series of trials to improve outcomes for patients with CKD and cardiovascular diseases for a generation, but it would be naïve to think these studies alone will result in successful implementation. To really improve pharmacotherapy for patients with CVRM conditions we need a different approach to address the problems in our healthcare systems that separate specialists in secondary care from patients in primary care. This will be complex, but will require two sets of actions:
- Proper engagement and systems working between secondary-care CVRM physicians and primary-care colleagues to support, educate and operationalise medication optimisation and monitoring.
- Empowerment and education of patients to challenge care givers to be optimising their therapies.
This body of work needs tackling now and we must learn from history – compelling clinical trial data does not automatically translate into improved patient outcomes in the real-world. The ACEi/ARB CKD story is a cautionary tale in this regard, but learning from mistakes of the past is our most powerful weapon to improve the future and we must learn these lessons quickly.
Conflicts of interest
None declared.
Funding
None.
References
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