RASi Therapy, Elderly Patients and the Fight Against Diabetic Kidney Disease

Diabetes, both type 1 and type 2, is the leading cause of chronic kidney disease (CKD) as well as end-stage renal disease (ESRD, or kidney failure). Approximately 40% of American adults with diabetes have some degree of CKD and are at risk of progressing into kidney failure if left undiagnosed and undertreated.

In addition, diabetic kidney disease is infamous for being a disease multiplier, according to the National Institute of Diabetes and Digestive and Kidney Disease, with many of these patients having comorbidities that can increase their risk of mortality nearly 20 times. In fact, diabetic kidney disease carries one of the highest risk for cardiovascular diseases, such as stroke, heart failure or myocardial infarction.

With worldwide rates of diabetes continuing to climb, the prevalence of diabetic kidney disease is anticipated to increase in tandem, along with kidney failure. In an effort to make a dent in the fight against kidney disease, the US Federal Government recently issued an executive order that seeks to lower the number of new kidney failure cases by 25 percent by 2030.

To achieve this ambitious goal, the order includes a proposed change in the way Medicare providers are paid to incentivize the prevention of disease progression to kidney failure. Due to this, it becomes imperative that these patients are diagnosed and provided aggressive intervention as early as possible to prevent or delay the progression of the disease and associated comorbidities, such as hypertension.

However, with fewer than 10,000 practicing nephrologists and nephrology advanced practitioners combined, the burden of diagnosis and care of nearly 30 million Americans with diabetic and nondiabetic kidney disease will fall on the shoulders of primary care providers to prevent escalating rates of kidney failure or cardiovascular disease. Close monitoring of glomerular filtration rate (GFR) and blood pressure can help provide earlier diagnosis in these high-risk patients.

Once GFR is reduced to levels below 60 ml/min and/or high blood pressure or albuminuria above 300 mg is detected in patients with diabetes, guidelines typically recommend immediately prescribing renin-angiotensin system inhibitors (RASi), such as angiotensin receptor blockers (ARBs), or angiotensin-converting-enzyme (ACE) inhibitors. These therapeutics are indicated to slow the progression of diabetic kidney disease, as well as to reduce the risk of death from cardiovascular events.

These kidney-sparing and life-saving medications, though, are also among the most common causes of hyperkalemia, or high potassium levels in the blood. Often overlooked and recurrent, hyperkalemia impacts approximately three million Americans — with most of them reporting no symptoms. If left untreated, it can have potentially lethal consequences, including abnormal heart rhythms and sudden death.

Older patients are particularly predisposed to developing hyperkalemia due to the combination of age-associated reductions in kidney function, poorly controlled diabetes, heart failure and high blood pressure, which can either impact their bodies’ ability to eliminate excess potassium or cause too much potassium to be released into the bloodstream. Combined with RASi therapeutics, which inhibit potassium excretion by the kidneys, older patients with diabetic kidney disease are 50% more likely to develop hyperkalemia than the general population and should have their serum potassium levels closed monitored every two to four weeks.

Due to this significantly elevated risk, older patients with diabetic kidney disease can become challenging to treat for clinicians. If a patient experiences a hyperkalemic event (serum potassium level >5.0 mEq/L), which occurs in up to 30% of cases, then the clinician is faced with the difficult decision of reducing or discontinuing RASi therapy to bring potassium levels back down to a safer range (4.6 to 5.0 mEq/L). While studies have shown that discontinuing or reducing RASi therapy may reduce the immediate risk of hyperkalemia and lower potassium levels, it may also put patients at greater risk for progression or exacerbation of their underlying disease, leading to poorer clinical outcomes, increased hospitalizations and associated health care costs, as well as a higher death rate.

In 1958, the US Food and Drug Administration (FDA) approved a potassium-binding polymer, sodium polystyrene sulfonate (SPS), for the treatment of hyperkalemia in patients. However, newer non-absorbable potassium binders have recently emerged for the long-term treatment and management of adults with hyperkalemia to enable concurrent RASi therapy. These drugs bind with potassium, decreasing the amount available for absorption in the gastrointestinal tract, thereby enabling the use and continuation of RASi therapy in patients living with kidney disease. To date, real-world experiences and clinical trial data demonstrate that patients on potassium binders are able to significantly improve the likelihood they’ll remain on RAASi therapy.

More recently, a post-hoc subgroup analysis of the AMETHYST-DN study in diabetic kidney disease patients aged 75 years or older was reported at the American Diabetes Association 79th Scientific Sessions. The study, evaluating one of the potassium-binding polymers, patiromer, found that the medication significantly reduced and maintained serum potassium levels to ≤5.0 Eq/L in this difficult-to-manage patient population. More importantly, through the 52 weeks, the majority of these patients maintained RASi therapy. Since the subgroup consisted of only 60 patients, additional studies in older patients with diabetic kidney disease are needed to further evaluate the cardiorenal protective effects and safety of these therapies that can enable the continuation of RASi therapy.

With the elderly population in the United States estimated to double to 71 million by 2030, clinicians will begin caring for sicker patients living with age-related illnesses and multiple comorbidities, including diabetic kidney disease. Primary care physicians will be the first line of defense in quickly identifying them based on their patient history and lab results, as well as be able to start them early on life-saving RAASi therapies. To limit the risk of hyperkalemia in this vulnerable population, doctors should closely monitor potassium levels and prescribe a potassium binder when hyperkalemic events occur. Doing so will enable their older patients to continue to reap the cardiorenal protective benefits of RASi therapies, and will improve overall patient outcomes.

Disclaimer: Some of Dr. Bakris’ research has been supported by Relypsa, Inc.

Dr. Bakris is a tenured Professor of Medicine and Director of the Am. Heart Assoc. Comprehensive Hypertension Center at the University of Chicago Medicine. He has published over 800 peer-reviewed articles and book chapters in the areas of diabetic kidney disease, hypertension and progression of nephropathy. He is the Editor or Co-Editor of 21 books as well as the new 3rd edition of Hypertension: A Companion to Braunwald’s The Heart. Additionally, he is an Associate Editor of the International Textbook of Cardiology. He served on the Cardio-renal Advisory Board of the FDA and to CMS. He was a co-principal investigator on the NIH Clinical Research training grant for clinical research (K30) (1999-2004). He chaired the first National Kidney Foundation Consensus report on blood pressure and impact on renal disease progression (2000). He has also served on many national guideline committees.

This piece reflects his views, not necessarily those of the publication.

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