Olanzapine-Induced Diabetic Ketoacidosis

Olanzapine-Induced Diabetic Ketoacidosis Kelly R Ragucci and Brian J Wells

OBJECTIVE: To report the case of a patient taking olanzapine who developed diabetic ketoacidosis (DKA). CASE SUMMARY:

A 46-year-old African American woman with no previous history of diabetes mellitus was admitted to the hospital and subsequently diagnosed with DKA and acute pancreatitis. The patient had been taking olanzapine, valproic acid, carbamazepine, hydrochlorothiazide/triamterene, and conjugated estrogens prior to admission. Olanzapine was the last medication added to the regimen. In addition to clinicians treating the DKA with appropriate interventions, olanzapine (due to possible association with hyperglycemia and DKA) as well as valproic acid (due to possible association with pancreatitis) were discontinued from the medication regimen. The patient was discharged home and her most recent glycosylated hemoglobin and fasting glucose concentrations have been within the normal range.

DISCUSSION: Atypical antipsychotics, such as olanzapine, have been associated with hyperglycemia and possibly DKA. We believe that this occurred in our patient who had no previous history of diabetes mellitus. Possible mechanisms of action and potential confounding variables are discussed. CONCLUSIONS:

Clinicians should monitor blood glucose concentrations periodically in patients taking olanzapine, especially in those patients with risk factors for diabetes mellitus.

KEY WORDS: diabetic ketoacidosis, olanzapine.

Ann Pharmacother 2001;35:1556-8.

typical antipsychotics have been linked to hyperglycemia/new-onset diabetes and diabetic ketoacidosis (DKA).1-10 However, there are few reported cases of olanzapine-induced DKA,1,6-10 especially in patients with no prior history of hyperglycemia or diabetes mellitus. The following case and subsequent discussion illustrate the possibility of this adverse effect.

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CASE REPORT

A 46-year-old African American woman with a history of bipolar affective disorder also had a past history significant for hypertension and depression. The patient was admitted to the hospital in December 2000 with abdominal pain, dizziness, polyuria, and shortness of breath and was subsequently diagnosed with DKA (presence of serum ketones, anion gap 31 mEq/L, blood glucose 957 mg/dL, serum bicarbonate 11 mEq/L, pH 7.3). She had no history of diabetes mellitus or any laboratory evidence of diabetes or glucose intolerance; however, she did have a family history of diabetes mellitus. Her most recent fasting glucose concentration prior to admission was 83 mg/dL in July 2000. At the time of admission, the patient was taking valproic acid 750 mg/d, olanzapine 15 mg/d, carbamazepine extended-release 200 mg twice daily, hydrochlorothiazide/triamterene 25/37.5 mg/d, and conjugated estrogens 0.625 mg/d. She had been on valproic acid, carbamazepine, hydrochlorothiazide/triamterene, and conjugated estrogens since 1994; olanzapine was started in

Author information provided at the end of the text.

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late 1999. The woman was compliant with regard to taking her medications. In fact, carbamazepine and valproic acid concentrations were therapeutic at the time of admission, which further substantiated compliance. Other pertinent laboratory values at the time of admission include urinalysis, with positive ketones and glucose >1000 mg/dL, glycosylated hemoglobin (HbA1c) 11.7 mg/dL, blood alcohol level 0, amylase 373 U/L, lipase 1035 U/L, and liver function tests (LFTs)/triglycerides within normal limits. All other laboratory data were within normal limits. A computed tomography (CT) scan of the abdomen showed inflammation consistent with acute pancreatitis. During her hospital stay, the patient was treated appropriately with intravenous fluids and insulin. Subsequently, glucose concentrations slowly decreased and ketosis resolved. On day 2, lipase had decreased to 94 U/L and amylase decreased to 43 U/L. Olanzapine was discontinued on hospital day 3 due to its possible association with hyperglycemia and DKA. Risperidone 2 mg/d was started at this point. Valproic acid was also discontinued due to its possible association with pancreatitis. The patient was discharged home on metformin 500 mg twice daily, NPH/regular insulin 33/17 units every morning and 16/9 units every evening, carbamazepine extended-release 200 mg twice daily, risperidone 2 mg/d, hydrochlorothiazide/triamterene 25/37.5 mg/d, and conjugated estrogens 0.625 mg/d. Since the patient was discharged, her insulin requirements have been slowly decreasing and she has had no more hospitalizations or emergency department visits. The most current HbA1c (March 2001) was 5.8%, and fasting glucose concentrations have been within the normal range since she was discharged from the hospital. She has made minimal adjustments with regard to diet and exercise and has lost no weight. Bipolar disorder has been adequately controlled with carbamazepine and risperidone.

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Case Reports

Discussion Olanzapine is a commonly prescribed atypical antipsychotic medication that is highly effective for the treatment of schizophrenia, schizoaffective disorder, and other psychotic disorders.1 Olanzapine is structurally related to an older atypical antipsychotic agent, clozapine, which has been documented2-7 to have an association with hyperglycemia and DKA. It should be noted that other atypical antipsychotic agents, such as quetiapine and risperidone, have not been associated specifically with DKA. Although there are very few cases documented, olanzapine has been linked with new-onset diabetes mellitus and DKA.1,6-10 In these case reports, the time to developing hyperglycemia ranged from one week to 17 months after beginning the drug. Our patient had been taking olanzapine for approximately 14 months when this episode occurred. In the four cases in which patients taking olanzapine were diagnosed with DKA, three patients were taking 10 mg/d and one was taking 30 mg/d; three patients were also taking valproic acid, and all four were obese. Our patient had no significant weight gain/loss in the year prior to this hospitalization; however, she was obese, with a body mass index (BMI) of 39. Her BMI was 38 prior to beginning olanzapine in 1999. She had a family history significant for diabetes mellitus. The possible mechanisms that may account for atypical antipsychotic–induced hyperglycemia and DKA include primary damage to the pancreatic islet cells and/or sympathetic nervous system dysregulation, as well as a possible secondary phenomenon related to weight gain and insulin resistance.1,11,12 However, this is speculation and the underlying mechanism may be a combination of these factors. In fact, concomitant therapy (e.g., olanzapine with valproic acid) could also lead to or exacerbate hyperglycemia. Indeed, valproic acid itself has caused dramatic increases in weight as well as insulin resistance in women.13 However, our patient had been taking valproic acid for seven years, and this medication has not been found to cause DKA in and of itself. Our patient was also diagnosed with acute pancreatitis at the time of hospitalization. Most likely, this presentation, including the increased amylase and lipase concentrations, was a result of DKA; DKA alone can lead to transient increases in amylase and lipase.14-18 In fact, based on this information, it is difficult and may not be appropriate to diagnose acute pancreatitis during DKA with current routine clinical or laboratory procedures. Valproic acid, as well as estrogen and hydrochlorothiazide, have been associated with pancreatitis. However, it is unlikely that any of these medications indirectly led to DKA by causing pancreatitis because it is typically chronic pancreatitis that can lead to enough damage to result in diabetes mellitus and potentially DKA. It is important to note that our patient had no evidence of chronic pancreatitis, such as scarring shown on a CT scan. Use of the Naranjo probability scale19 indicated a possible relationship between DKA and the use of olanzapine in www.theannals.com

our patient. The only negative score on the probability scale related to the fact that alternative causes that could have caused the DKA could not definitively be excluded, since the patient had risk factors for diabetes mellitus. Since the discontinuation of olanzapine, the patient has improved, and fasting glucose concentrations are now within the normal range. She has had no more episodes of ketoacidosis, and insulin is slowly being discontinued. Her BMI remains 39. Although valproic acid was discontinued at the same time as olanzapine, valproic acid is unlikely to be the culprit since there is no evidence specifically linking it to DKA. The remainder of the medications, including carbamazepine, were continued throughout her hospital stay and discharge, and yet the DKA has resolved. Summary Hyperglycemia and, more specifically, DKA have been reported to occur with atypical antipsychotic medications such as olanzapine. While it is impossible to say with certainty that olanzapine was the definitive cause of our patient’s hyperglycemia and DKA, it may be prudent to consider periodic serum glucose monitoring in olanzapinetreated patients. This may be especially true for those with risk factors for diabetes mellitus. There are currently no recommendations with regard to glucose monitoring in patients who are on atypical antipsychotics; thus, the frequency of monitoring should be based on the individual patient and his/her other risk factors for diabetes mellitus. Appropriate controlled studies are necessary to fully determine whether a causal relationship exists between atypical antipsychotic therapy and the development of insulin resistance or glucose dysregulation. Kelly R Ragucci PharmD BCPS CDE, Assistant Professor, Departments of Pharmacy Practice and Family Medicine, Medical University of South Carolina, Charleston, SC Brian J Wells MD, Family Medicine Resident, University Family Medicine, Medical University of South Carolina Reprints: Kelly R Ragucci PharmD BCPS CDE, Medical University of South Carolina, 295 Calhoun St., PO Box 250192, Charleston, SC 29425-0001, FAX 843/792-0436, E-mail [email protected]

References 1. Goldstein LE, Sporn J, Brown S, Kim H, Finkelstein J, Gaffey GK, et al. New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment. Psychosomatics 1999;40:438-43. 2. Wehring H, Alexander B, Perry PJ. Diabetes mellitus associated with clozapine therapy. Pharmacotherapy 2000;20:844-7. 3. Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997;58:108-11. 4. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000;157:97581. 5. Maule S, Giannella R, Lanzio M, Villari V. Diabetic ketoacidosis with clozapine treatment. Diab Nutr Metab 1999;12:187-8. 6. Rigalleau V, Gatta B, Bonnaud S, Masson M, Bourgeois ML, Vergnot V, et al. Diabetes as a result of atypical antipsychotic drugs — a report of three cases. Diabet Med 2000;17:484-6. 7. Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998;44:77883.


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KR Ragucci and BJ Wells 8. Bettinger TL, Mendelson SC, Dorson PG, Crismon ML. Olanzapine-induced glucose dysregulation. Ann Pharmacother 2000;34:865-7. 9. Lindenmayer JP, Patel R. Olanzapine-induced ketoacidosis with diabetes mellitus (letter). Am J Psychiatry 1999;156:1471. 10. Gatta B, Rigalleau V, Gin H. Diabetic ketoacidosis with olanzapine treatment. Diabetes Care 1999;22:1002-3. 11. Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999;156:312-4. 12. Casey DE. Side effect profiles of new antipsychotic agents. J Clin Psychiatry 1996;11:40-5. 13. Isojarvi JT, Laatikainen TJ, Knip M. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:579-84. 14. Yadav D, Nair S, Norkus EP, Pitchumoni CS. Nonspecific hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities. Am J Gastroenterol 2000;95: 3123-8. 15. Nair S, Yadav D, Pitchumoni CS. Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA. Am J Gastroenterol 2000;95:2795-800. 16. Vantyghem MC, Haye S, Balduyck M, Hober C, Degand PM, Lefebvre J. Changes in serum amylase, lipase and leukocyte elastase during diabetic ketoacidosis and poorly controlled diabetes. Acta Diabetologica 1999;36:39-44. 17. Nair S, Pitchumoni CS. Diabetic ketoacidosis, hyperlipidemia, and acute pancreatitis: the enigmatic triangle. Am J Gastroenterol 1997;92:1560-1. 18. Vinicor F, Lehrner LM, Karn RC, Merritt AD. Hyperamylasemia in diabetic ketoacidosis: sources and significance. Ann Intern Med 1979;91: 200-4. 19. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.

EXTRACTO OBJETIVO: Reportar un caso clínico de un paciente que desarrollo cetoacidosis diabética (DKA, por sus siglas en inglés) con olanzapine. RESUMEN DEL CASO: Una paciente de 46 años de edad de raza negra fue admitida al hospital con el diagnóstico de DKA y pancreatitis aguda. La paciente no tenia historial previo de diabetes y estaba tomando olanzapine, ácido valproíco, carbamazepina, hidroclorotiazida/ triamtereno y estrogenos conjugados. Olanzapine fue el último medicamento que se le añadio a su regimen de medicamentos. La paciente recibió tratamiento para la DKA y pancreatitis aguda. El

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olanzapine fue descontinuado debido a su potencial para causar hiperglicemia y DKA, y el ácido valproíco fue descontinuado por su potencial de causar pancreatitis aguda. La paciente fue dada de alta, y los últimos resultados de la hemoglobina glicosilada (HbA1c, por sus siglas en inglés) y los niveles de glucosa fueron normales. DISCUSIÓN: Los antipsicóticos atipicos como lo son la olanzapine pueden causar hiperglicemia y posiblemente DKA. Nosotros creemos que esto fue lo que sucedió con nuestra paciente la cual no tenía un historial previo de diabetes. En este artículo se discuten posibles mecanismos de acción y otras variables que se creen contribuyen a que esta reacción ocurra. CONCLUSIONES: En pacientes que esten tomando olanzapine, los níveles de azúcar en la sangre deben ser evaluados regularmente, especialmente en aquellos pacientes que tengan factores de riesgo para el desarrollo de la diabetes. Magaly Rodríguez de Bittner RÉSUMÉ

Discuter du cas d’une patiente qui a développé une acidocétose diabétique (ACD) suite à la prise d’olanzapine. RÉSUMÉ DU CAS: Il s’agit d’une femme d’origine africaine-américaine sans antécédent de diabète qui fut admise à l’hôpital et subséquemment diagnostiquée avec une ACD et une pancréatite aigue. La patiente consommait les médicaments suivants lors de son admission: olanzapine, acide valproique, carbamazepine, hydrochlorothiazide/ triamterene et des estrogènes conjuguées. L’olanzapine fut le dernier médicament introduit chez cette patiente. En plus de traiter son ACD à l’aide d’interventions appropriées, l’olanzapine (à cause d’une possible association avec l’hyperglycémie et l’ACD) et l’acide valproique (à cause d’une possible association avec la pancréatite) furent cessés. La patiente a obtenu son congé de l’hôpital et ses plus récents résultats de HbA1c et de glycémie à jeun étaient dans les valeurs normales. DISCUSSION: Les antipsychotiques atypiques comme l’olanzapine peuvent être associés avec une hyperglycémie et même une ACD. Nous croyons que c’est ce qui est arrivé chez cette patiente qui n’avait pas d’antécédents de diabète. Les mécanismes d’actions possibles et certaines variables sont discutés et élaborés. CONCLUSIONS: Les médecins devraient périodiquement mesurer la glycémie chez les patients prenant de l’olanzapine, surtout chez ceux avec des facteurs de risque pour le diabète. OBJECTIF:


Pierre Dion

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