A newly approved therapy offers the first new option in years to prevent hyperkalemia.
The prevalence of diabetes, whether type 1 or type 2, continues to increase at a rapid pace worldwide. According to the American Diabetes Association, the worldwide prevalence of diabetes in 2010 was estimated at 6.4%, affecting 285 million individuals. That percentage is projected to increase by 2030 to 7.7%, affecting 439 million individuals across the world.1 Diabetes can bring with it other health complications, which can drastically impact everyday life. Hypertension, heart disease, and kidney failure are the more common serious comorbidities. The good news is that with all these disease states, including diabetes, there are a number of efficacious drug regimens that can keep patients healthy and slow disease progression.
Management of diabetic renal disease, referred to as diabetic nephropathy, plays a critical role in increasing the survival rate of patients in this demographic. Diabetic nephropathy is defined as diabetes with the presence of microalbuminuria, which can increase risk of death due to heart disease.2 Studies suggest that 30% of patients with type 1 diabetes are affected by kidney disease, while 20% with type 2 diabetes are affected.2 When it comes to kidney disease, with or without diabetes, it is extremely important to keep any comorbidities under control; this requires monitoring blood pressure cardiac output, and glycemic levels. One of the problems when managing these disease states are adverse events caused by the medications that help keep both the kidneys and heart healthy and under less stress.
Hyperkalemia is a condition that is more common in patients who have kidney disease or heart disease, and it is confounded when diabetes becomes a part of the mix. Hyperkalemia is defined as an increase in serum potassium levels in the blood—a very serious, life-threatening complication. Normal potassium levels in a healthy adult range from 3.5 mmol/L to 5.0 mmol/L. Serious increase in potassium levels, defined as >6.5 mmol/L, can lead to arrhythmias, cardiac arrest, and death within hours of the event. To understand more about hyperkalemia, it is important to understand the underlying pathophysiology that causes hyperkalemia.
As mentioned before, blood pressure control is extremely important in maintaining kidney and heart health. Both disease states require medication to keep blood pressure in the desired range, no greater than 140/90 mm Hg. Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, and aldosterone receptor antagonists are all drug classes that are used in both heart failure and chronic kidney disease (CKD) to keep blood pressure under control and decrease the amount of stress placed on the heart and kidneys. All of these drug classes work on the renin-angiotensin-aldosterone (RAAS) system. In short, both angiotensin II and aldosterone play important roles in the reabsorption of sodium and chlorine, water retention, and the excretion of potassium in the kidneys. When these hormones are blocked—a function of ARBs and ACE inhibitors—the reabsorption of water and other electrolytes is reduced, which then decreases blood pressure, consequently relieving the stress on the heart and kidneys. However, a complication of inhibiting the RAAS system is an unwanted increase in serum potassium levels since potassium is no longer excreted as effectively, especially with decreased kidney function, which is common in diabetic renal disease.
It is extremely important to monitor potassium levels in patients in this demographic due to the fact that elevated potassium levels drastically increases their risk for mortality. When patients are in the later stages of kidney disease (stages 3 and 4), they are at increased risk for hyperkalemia due to the worsening of their kidney function, but also due to the medications they must take to manage their primary diseases. Although these patients must remain on inhibitors of the RAAS system in order to decrease kidney and heart complications, they also need close monitoring of their potassium levels, as they are at a higher risk for hyperkalemia. In these cases, physicians will advise patients to consume low-potassium diets, which means avoiding foods like beans, legumes, green leafy vegetables, potatoes and some dairy products. Physicians may also prescribe medications to lower serum potassium levels. For years, there has been only 1 FDA-approved medication for the indication of chronic hyperkalemia: Kayexelate (sodium polystyrene sulfonate).
Kayexelate works by binding potassium in the gut in exchange for sodium which prevents its absorption and causes potassium to be excreted in the feces. The drug is shown to be effective in CKD and heart failure patients who must remain on the medications that inhibit the RAAS system; however, a number of side effects associated with the drug have created barriers to prescribing Kayexelate. In 2011, the FDA issued a black box warning for Kayexelate, advising patients on the increased risk of developing colonic necrosis and gastrointestinal adverse events including bleeding, ischemic colitis, and possible perforation.3 For patients who require chronic hyperkalemia management but have only one therapeutic option, this can be an issue. For patients at risk of serious side effects that can lead to mortality, there are no other options. The physician must decide between risk versus benefit and prescribe not only Kayexelate but also the medications that affect the RAAS system. Fortunately, recent research has addressed this unmet medical need, and there are new drugs on the horizon that look promising for the concurrent use of RAAS system—blocking drugs and chronic hyperkalemic management.
A therapy developed by the pharmaceutical company Relypsa, called patiromer, is an oral solution that works like Kayexelate in that it binds potassium in the gut to avoid absorption and excrete it in the feces. However, instead of the sodium/potassium exchange seen in Kayexelate, patiromer modulates calcium/potassium exchange, which is believed to reduce some of the adverse events associated with Kayexelate. The FDA approved patiromer, to be marketed as Veltassa, on October 21, 2015.4 Patiromer has demonstrated both efficacy and safety in preventing hyperkalemia events in patients with heart failure and kidney disease who were also on spironolactone therapy.5 Another study evaluating the efficacy of patiromer found that 76% of patients with hyperkalemia were normalized following just 4 weeks of treatment. For all levels of severity, the mean potassium level was less than 5.5 mmol/L in just 2 days. In the same study, the incidence of recurrent hyperkalemia was significantly higher in the placebo group versus the patiromer group (60% vs 15%).6
With the apparent success in proving efficacy of the new drug, there is also the question of safety. The main adverse events reported regardless of dose were worsening of CKD (9.2%), hypomagnesemia (8.6), worsening of hypertension (7.9%), constipation (4.6%), and diarrhea (2.7%). The main adverse event related to the actual drug was gastrointestinal issues, mainly constipation and diarrhea, neither of which were reasons for patients to withdrawal from the trial or discontinue therapy.5
This could drastically change how physicians approach the treatment of patients with CKD, heart failure, and diabetes who are at a higher risk of hyperkalemia. The FDA’s approval of patiromer doubles the available options for long-term treatment of hyperkalemia. It also has the capability of decreasing cost by reducing hospitalizations and mortality due to hyperkalemia. Patiromer will allow patients to remain on important medications that keep their heart and kidneys healthy, which will prevent disease progression while decreasing their risks for hyperkalemia. Whereas hyperkalemia is only a symptom or indication of other serious chronic conditions, it is just as important to monitor and prevent occurrence due to the severity and drastic increase in mortality risks, especially for patients who have comorbidities like kidney disease, diabetes, and heart failure. The promise of patiromer could significantly alter the treatment paradigm for these patients. They will not only remain controlled on their heart and kidney medications, but they also will have less concern about potassium levels increasing the chances or cardiac arrest or death. The result will be lower hospitalization costs and increased patient survival and health. Ms Drewniany is a doctor of pharmacy candidate at Temple University, Philadelphia, Pennsylvania. References
1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diab Res Clin Pract. 2010; 87(1):4-14.
2. Eboh C, Chowdhury T. Management of diabetic renal disease. Ann Transl Med. 2015;3(11):154.
3. FDA website. Safety: kayexalate. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm. Published January 2011. Accessed August 7, 2015.
4. Caffrey MK. FDA approves drug to treat hyperkalemia. American Journal of Managed Care website. http://www.ajmc.com/newsroom/fda-approves-drug-to-treat-hyperkalemia. Published October 21, 2015. Accessed October 26, 2015.
5. Bakris GL, Pitt B, Weir M, et al. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease. JAMA. 2015;314(2):151-161.
6. Weir M, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221.