New Drugs to Treat Hyperkalemia

Q)I have heard talk about the development of new drugs to treat hyperkalemia. What is the status of these?

Hyperkalemia is a commonly seen electrolyte imbalance in clinical practice. Risks associated with moderate-to-­severe hyperkalemia include potentially ­fatal cardiac conduction abnormalities/­arrhythmias, making identification and management critical. An in-depth discussion of hyper­kalemia diagnosis can be found in our March 2017 CE/CME activity (2017;27[3]:40-49).

Risk factors for hyperkalemia include excess intake or supplementation of potassium, type 2 diabetes, liver cirrhosis, congestive heart failure (CHF), and chronic kidney disease (CKD). The kidneys excrete 90% to 95% of ingested potassium, and the gut excretes the rest. Normal kidneys take six to 12 hours to excrete an acute potassium load. As kidney function decreases, risk for hyperkalemia increases.¹ Hyperkalemia rates as high as 26% have been observed in patients with CKD stages 3 to 5 (glomerular filtration rate [GFR], < 60 mL/min).²

Renin-angiotensin-aldosterone system (RAAS) inhibitors—including ACE inhibitors (ACEis), angiotensin-receptor blockers, and aldosterone agonists—are associated with hyperkalemia. While RAAS therapy can play an important role in the management of CKD and cardiovascular disease (CVD), the development of hyperkalemia can necessitate a dose reduction or discontinuation of these medications, limiting their therapeutic benefit. Other medications that elevate risk for hyperkalemia include NSAIDs, heparin, cyclosporine, amiloride, triamterene, and nonselective ­ß-blockers.¹

Therapeutic options for nonurgent treatment of hyperkalemia are limited. In addition to reducing or discontinuing associated medications, strategies include use of diuretics (as appropriate), treatment of metabolic acidosis, and dietary restrictions (ie, limiting high-potassium foods).¹ Pharmacologically, there has been one (less than ideal) option—until recently.

Sodium polystyrene sulfonate (SPS), an ion-exchange resin approved in 1958, can be used to treat hyperkalemia.³ It comes in an enema and an oral form; the former has a faster onset, but the latter is more effective, with an onset of action of one to two hours and a duration of four to six hours.¹ However, each gram of SPS contains 100 g of sodium, and the typical dose of SPS is 15 g to 60 g.⁴ The resulting increase in sodium load can be a concern for patients with CHF, severe hypertension, or severe edema.⁵

Data from randomized controlled trials (RCTs) are limited; however, one double-blind RCT investigated the effect of SPS on 33 patients with CKD and mild-to-moderate hyperkalemia (potassium level, 5 mEq/L to 5.9 mEq/L). The researchers found that patients who took 30 g/d of SPS for seven days experienced a 73% reduction in serum potassium, compared with a 38% reduction in patients who took a placebo. Of note, more gastrointestinal issues were observed in the SPS group.⁶

Additionally, a retrospective chart review of 14 patients with CKD and heart disease found low-dose SPS to be safe and effective when used as a secondary measure for hyperkalemia prevention in those taking RAAS therapy.⁷ However, a systematic review found that SPS use with and without concurrent sorbitol may be associated with serious and fatal gastrointestinal injuries.⁸ In 2011, the FDA issued a black box warning regarding increased risk for intestinal necrosis when SPS is used with sorbitol.⁹ In 2015, the FDA recommended separating SPS from other oral medications by at least six hours, due to its potential to bind with other medications.¹⁰