title: Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial.
abstract: OBJECTIVE
  Hyperkalemia is a potentially life-threatening condition predominantly seen in patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both.
  
  
  OBJECTIVE
  To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia.
  
  
  METHODS
  Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment.
  
  
  METHODS
  Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower.
  
  
  METHODS
  The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks.
  
  
  RESULTS
  A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients.
  
  
  CONCLUSIONS
  Among patients with hyperkalemia and diabetic kidney disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier:NCT01371747.
authors.affiliation: ASH Comprehensive Hypertension Center, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Chicago Medicine, Chicago, Illinois.
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: University of Michigan, Ann Arbor.
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.affiliation: Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Weir
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston.
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
authors.affiliation: Relypsa, Redwood City, California.
authors.forename: Martha R
authors.initials: MR
authors.lastname: Mayo
authors.affiliation: Relypsa, Redwood City, California.
authors.forename: Dahlia
authors.initials: D
authors.lastname: Garza
authors.affiliation: Relypsa, Redwood City, California.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Stasiv
authors.affiliation: Relypsa, Redwood City, California.
authors.forename: Rezi
authors.initials: R
authors.lastname: Zawadzki
authors.affiliation: Relypsa, Redwood City, California.
authors.forename: Lance
authors.initials: L
authors.lastname: Berman
authors.affiliation: Division of Nephrology, Department of Medicine, University of Rochester, Rochester, New York.
authors.forename: David A
authors.initials: DA
authors.lastname: Bushinsky
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D003928:Diabetic Nephropathies / Q000150:complications*; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D011108:Polymers / Q000008:administration & dosage* / Q000009:adverse effects; D011188:Potassium / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011108:Polymers; C568789:patiromer; D011188:Potassium