Journal of General Internal Medicine

, Volume 25, Issue 4, pp 326–333

Diabetes and Drug-Associated Hyperkalemia: Effect of Potassium Monitoring

  • Marsha A. Raebel
  • Colleen Ross
  • Stanley Xu
  • Douglas W. Roblin
  • Craig Cheetham
  • Christopher M. Blanchette
  • Gwyn Saylor
  • David H. Smith
Original Article



Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with hyperkalemia, but there is little evidence demonstrating patients who receive potassium monitoring have a lower rate of hyperkalemia.


To evaluate the association between potassium monitoring and serious hyperkalemia-associated adverse outcomes among patients with diabetes newly initiating RAAS inhibitor therapy.


Retrospective observational study.


Patients with diabetes without end-stage renal disease initiating RAAS inhibitor therapy between 2001 and 2006 at three integrated health care systems.


Potassium monitoring and first hyperkalemia-associated adverse event during the initial year of therapy. Hyperkalemia-associated adverse events included hospitalizations, emergency department visits or deaths within 24 h of hyperkalemia diagnosis and/or diagnostic potassium ≥6 mmol/l. Incidence rates were calculated in person-years (p-y). We used inverse probability propensity score weighting to adjust for differences between patients with and without monitoring; Poisson regression was used to obtain adjusted relative risks.


A total of 19,391 of 27,355 patients (71%) received potassium monitoring. Serious hyperkalemia-associated events occurred at an incidence rate of 10.2 per 1,000 p-y. Compared to patients without monitoring, adjusted relative risk of hyperkalemia-associated adverse events among all patients with monitoring was 0.50 (0.37, 0.66); in the subset of patients who also had chronic kidney disease (n = 2,176), adjusted relative risk was 0.29 (0.18, 0.46).


Patients prescribed RAAS inhibitors who have both diabetes and chronic kidney disease and receive potassium monitoring are less likely to experience a serious hyperkalemia-associated adverse event compared to similar patients who did not receive potassium monitoring. This evidence supports existing consensus-based guidelines.


hyperkalemia hyperpotassemia angiotensin-converting enzyme inhibitor ACEi angiotensin receptor blocker ARB spironolactone RAAS inhibitor 


  1. 1.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:1004–10.CrossRefPubMedGoogle Scholar
  3. 3.
    HOPE (Heart Outcomes Prevention Evaluation) Study Investigators. Effects of an angiotensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.CrossRefGoogle Scholar
  4. 4.
    Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–17.CrossRefPubMedGoogle Scholar
  5. 5.
    Chobanian AV, Bakris GI, Black HR, Cushman WC, Green LA, Izzo JL. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;39(suppl 1):S94–8.Google Scholar
  6. 6.
    Cohn JN, Tognoni G. for the Valsartan heart failure trial investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.CrossRefPubMedGoogle Scholar
  7. 7.
    McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.CrossRefPubMedGoogle Scholar
  9. 9.
    Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.CrossRefPubMedGoogle Scholar
  10. 10.
    Pfeffer MA. ACE inhibition in acute myocardial infarction. N Engl J Med. 1995;332:118–20.CrossRefPubMedGoogle Scholar
  11. 11.
    Pfeffer MA, Braunwald E, Moye LA. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement trial. N Engl J Med. 1992;327:669–77.PubMedCrossRefGoogle Scholar
  12. 12.
    Gruppo Italiano per lo Studio della Sopravvivenza nell'infart Miocardico. GISSI-3: effects of lisinopril and transfermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet. 1994;343:1115–22.Google Scholar
  13. 13.
    Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:2101–13.CrossRefPubMedGoogle Scholar
  14. 14.
    Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications. Kidney Int. 2005;67:799–812.CrossRefPubMedGoogle Scholar
  15. 15.
    The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldactone evaluation study [RALES]). Am J Cardiol. 1996;78:902–7.CrossRefGoogle Scholar
  16. 16.
    Palmer BF. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant. 2003;18:1973–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351:543–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Ahuja TS, Freeman D Jr, Mahnken JD, Agraharkar M, Siddiqui M, Memon A. Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors. Am J Nephrol. 2000;20:268–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Desai AS, Swedberg K, McMurray JJV, et al. Incidence and predictors of hyperkalemia in patients with heart failure: An analysis of the CHARM program. J Am Coll Cardiol. 2007;50:1959–66.CrossRefPubMedGoogle Scholar
  21. 21.
    Ramadan FH, Masoodi N, El-Solh AA. Clinical factors associated with hyperkalemia in patients with congestive heart failure. J Clin Pharm Therapeutics. 2005;30:233–9.CrossRefGoogle Scholar
  22. 22.
    Bakris G, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646–61.PubMedGoogle Scholar
  23. 23.
    Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685–93.CrossRefPubMedGoogle Scholar
  24. 24.
    Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med. 2001;110:438–41.CrossRefPubMedGoogle Scholar
  25. 25.
    Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin N Am. 2005;23:723–47.CrossRefGoogle Scholar
  26. 26.
    Berry C, McMurray J. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. Am J Med. 2001;111:587.PubMedGoogle Scholar
  27. 27.
    Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med. 2001;135:703–10.PubMedGoogle Scholar
  28. 28.
    Lloyd SJ, Mauro VF. Spironolactone in the treatment of congestive heart failure. Ann Pharmacother. 2000;34:1336–40.CrossRefPubMedGoogle Scholar
  29. 29.
    Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46:845–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235.CrossRefPubMedGoogle Scholar
  31. 31.
    de Denus S, Tardif J-C, White M, et al. Quantification of the risk and predictors of hyperkalemia in patients with left ventricular dysfunction: A retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. Am Heart J. 2006;152:705–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Stevens LA, Fares G, Fleming J, et al. Low rates of testing and diagnostic codes usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease. J Am Soc Nephrol. 2005;16:2439–48.CrossRefPubMedGoogle Scholar
  33. 33.
    Duru OK, Vargas RB, Kermah D, Nissenson AR, Norris KC. High prevalence of stage 3 chronic kidney disease in older adults despite normal serum creatinine. J Gen Intern Med. 2009;24:86–92.CrossRefPubMedGoogle Scholar
  34. 34.
    Miller WG. Reporting estimated GFR from serum creatinine: Recommendations from the laboratory working group of the National Kidney Diabetes Education Program. Oral presentation from the 2006 annual meeting of the American Association of Clinical Chemistry. 2006. Available from: Accessed Dec. 2009.
  35. 35.
    Winkelmayer WC, Schneeweiss S, Mogun H, Patrick AR, Avorn J, Solomon DH. Identification of Individuals with CKD from Medicare Claims Data: a validation study. Am J Kidney Dis. 2005;46:225–32.CrossRefPubMedGoogle Scholar
  36. 36.
    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–S266.CrossRefGoogle Scholar
  37. 37.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461–70.PubMedGoogle Scholar
  38. 38.
    Cockcroft Dw, Gault MH. Prediction o f creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Clark DO, Von Korff M, Saunders K, Baluch WM, Simon GE. A chronic disease score with empirically derived weights. Med Care. 1995;33:783–95.CrossRefPubMedGoogle Scholar
  40. 40.
    Raebel MA, McClure DL, Simon SR, et al. Laboratory monitoring of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in ambulatory patients. Pharmacoepidemiol Drug Saf. 2007;16:55–64.CrossRefPubMedGoogle Scholar
  41. 41.
    Raebel MA, McClure DL, Andrade SE, et al. Laboratory evaluation of potassium and creatinine among ambulatory patients prescribed spironolactone: are we monitoring for Hyperkalemia? Ann Pharmacother. 2007;41:193–200.CrossRefPubMedGoogle Scholar
  42. 42.
    Raebel MA, Lyons EE, Andrade SE, et al. Laboratory monitoring of high risk drugs at initiation of therapy in ambulatory care. J Gen Intern Med. 2005;20:1120–6.CrossRefPubMedGoogle Scholar
  43. 43.
    Rosenbaum PR, Rubin DB. The central role of propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.CrossRefGoogle Scholar
  44. 44.
    Robins JM, Herman MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiol. 2000;11:550–60.CrossRefGoogle Scholar
  45. 45.
    Rosenbaum PR. Model-Based Direct Adjustment. J Am Stat Assoc. 1987;82:387–94.CrossRefGoogle Scholar
  46. 46.
    Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149–56.CrossRefPubMedGoogle Scholar
  47. 47.
    Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value in Health. doi:10.1111/j.1524-4733.2009.00671.x.
  48. 48.
    Arruda J, Batlle D, Sehy J, Roseman M, Baronowski R, Kurtzman NA. Hyperkalemia and renal insufficiency: role of selective aldosterone deficiency and tubular unresponsiveness to aldosterone. Am J Nephrol. 1981;1:160–7.CrossRefPubMedGoogle Scholar
  49. 49.
    DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980;17:118–34.CrossRefPubMedGoogle Scholar
  50. 50.
    Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin N Am. 2005;23:723–47.CrossRefGoogle Scholar
  51. 51.
    Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ. Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med. 1997;30:612–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Kurata C, Uehara A, Sugi T, Yamazaki K. Syncope caused by nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors. Jpn Circ J. 1999;63:1002–3.CrossRefPubMedGoogle Scholar
  53. 53.
    Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289:1652–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Maddirala S, Khan A, Vincent A, Lau K. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on serum potassium levels and renal function in ambulatory outpatients: risk factors analysis. Am J Med Sci. 2008;336:330–5.CrossRefPubMedGoogle Scholar
  55. 55.
    Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med. 1998;158:26–32.CrossRefPubMedGoogle Scholar
  56. 56.
    Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46:845–9.CrossRefPubMedGoogle Scholar
  57. 57.
    NCQA. Annual monitoring for patients on persistent medications: new measure for HEDIS 2006. NCQA . 2006. Available from: Accessed December 2009.

Copyright information

© Society of General Internal Medicine 2010

Authors and Affiliations

  • Marsha A. Raebel
    • 1
    • 2
    • 3
  • Colleen Ross
    • 1
  • Stanley Xu
    • 1
  • Douglas W. Roblin
    • 3
    • 4
  • Craig Cheetham
    • 3
    • 5
  • Christopher M. Blanchette
    • 6
    • 7
    • 8
  • Gwyn Saylor
    • 1
  • David H. Smith
    • 3
    • 9
  1. 1.Kaiser Permanente Colorado Institute for Health ResearchDenverUSA
  2. 2.School of PharmacyUniversity of Colorado at DenverDenverUSA
  3. 3.HMO Research Network Center for Education and Research in Therapeutics (CERTs)BostonUSA
  4. 4.Kaiser Permanente Center for Health ResearchAtlantaUSA
  5. 5.Pharmacy Analytic ServicesKaiser Permanente Southern CaliforniaDowneyUSA
  6. 6.Lovelace Respiratory Research InstituteKannapolisUSA
  7. 7.School of PharmacyUniversity of North Carolina at Chapel HillChapel HillUSA
  8. 8.Salisbury VAMCSalisburyUSA
  9. 9.Kaiser Permanente Center for Health ResearchPortlandUSA

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