Fehmida Visnegarwala, MD ... MD: Food and Drug Administration; 1997. 3. Tezapsidis N, Noctor S, ... Bartlett J. Protease inhibitors for HIV infection. Am J Med.
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Severe Diabetes Associated with Protease Inhibitor Therapy To the Editor: Protease inhibitors block the action of aspartate protease, which is required to produce new virions. We describe a patient in whom symptomatic hyperglycemia was associated with the protease inhibitor nelfinavir, perhaps as a result of inhibition of the protease that converts proinsulin to insulin. A 46-year-old man with advanced-stage AIDS was receiving didanosine and lamuvidine. His viral load was 380 000 RNA copies/mL, and his CD4 + count was 20 cells/mm3. Treatment was changed to nelfinavir, zidovudine, and lamivudine. Other medications were trimethoprim-sulfamethoxazole, ciprofloxacin, clarithromycin, ethambutol, itraconazole, megestrol acetate, phenytoin, amitryptyline, and carbamazepine. The patient's mother had type 2 diabetes, but the patient was repeatedly euglycemic (Figure). Two weeks after starting nelfinavir therapy, the patient noticed polyuria, blurred vision, oral thrush, dysphagia, and fever. On physical examination, he was thin, weak, and febrile with marked oral thrush. His lung, heart, and abdomen were normal. His leukocyte count was 2200 cells/mm3. The serum glucose level was 657 mg/dL, and the sodium level was 123 mEq/L; results of other laboratory tests were normal. No enzymatic or radiologic evidence showed pancreatitis. All blood cultures were negative, as was the result of an ophthalmoscopic examination for cytomegalovirus. Glucose levels were controlled with neutral protamine Hagedorn insulin (40 U/d), vision improved, and oral thrush responded to fluconazole. In this case, treatment with a protease inhibitor was rapidly followed by new-onset, symptomatic diabetes mellitus. Megestrol acetate (1) was not thought to be responsible because hyperglycemia began with initiation of nelfinavir therapy and continued for 2 months after megestrol acetate therapy had been discontinued. No pancreatitis was present. Before initiation of nelfinavir therapy, the patient was euglycemic; however, a familial predisposition may have played a role. It is estimated that more than 100 000 patients are taking protease inhibitors. The U.S. Food and Drug Administration has received 83 reports of new-onset or worsening diabetes (ranging from mild hyperglycemia to diabetic ketoacidosis) associated with each of the four protease inhibitors used to treat HIV infection (2). The mechanism by which protease inhibitors cause diabetes is unknown. The proteolytic processing of prohormones within neuroendocrine cells is needed to generate biologically active pep-
Figure. Serum glucose levels in a patient with AIDS before and after therapy with the protease inhibitor nelfinavir began. Each symbol indicates a serum glucose evaluation. Duration of megestrol acetate therapy is shown. Insulin therapy (40 U/d) was initiated on 19 June 1997 and was maintained at 45 U/d.
tides (3-5). Three families of proteases, including an aspartate protease, have been localized to the chromaffin granules that process prohormones (3). Human processing of proinsulin to cleave C-peptide requires serine endopeptidases PC1/PC3 and PC2 (3, 4). Genetic deficiency of endopeptidases has recently been implicated as a cause of hyperglycemia (4). In patients who are functionally deficient in these endopeptidases, the mammalian homologue of yeast aspartic protease (YAP3p) may play a more critical role in processing proinsulin and other prohormones (5); as a result, it may be subject to inhibition by nelfinavir, an aspartic protease inhibitor. The mechanism of this effect is under further study. Since this case, we have documented new-onset diabetes in two more patients, both of whom developed diabetes while receiving indinavir. Fehmida Visnegarwala, MD Kurt L. Krause, MD, PhD Daniel M. Musher, MD Veterans Affairs Medical Center Houston, TX 77030-4211 References 1. Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes mellitus induced by megestrol acetate in a patient with AIDS and cachexia. Ann Intern Med. 1992;116:53-4. 2. Murray M, Lumpkin MD. FDA Public Health Advisory: Reports of Diabetes and Hyperglycemia in Patients Receiving Protease Inhibitors for the Treatment of Human Immunodeficiency Virus (HIV). Bethesda, MD: Food and Drug Administration; 1997. 3. Tezapsidis N, Noctor S, Kannan R, Krieger TJ, Mende-Mueller L, Hook VY. Stimulation of "Prohormone Thiol Protease" (PTP) and [Met] encephalin by forskolin. J Biol Chem. 1995;270:13285-90. 4. O'Rahilly S, Gray H, Humphreys PJ, Krook A, Polonsky KS, White A, et al. Impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N Engl J Med. 1996;333:1386-90. 5. Cawley NX, Pu LP, Loh YP. Immunological identification and localization of yeast aspartic protease 3-like prohormone-processing enzymes in mammalian brain and pituitary. Endocrinology. 1996;137:5135-43.
15 November 1997 • Annals of Internal Medicine • Volume 127 • Number 11
947
Table.
Chanacteristic » of Patients Receiving Protease liihibitor Therapy W h o Developeii Hyperglycernia
Patient
Age
Sex
y 1 2 3 4 5
29 54 38 55 44
Male Male Male Male Male
Baseline CD4 Count
Baseline Viral Load
I3aseline Blooci Glucose Level
cells/mm3
copies/mL
mg/dL
45 90 114 97 87
355 000 222 000 7000 43 000 333 000
95 124 62 126 86
Protease Inhibitor
Indinavir Indinavir Ritonavir Indinavir Saquinavir
To the Editor: The use of protease inhibitors has revolutionized the treatment of HIV infection through the ability of these drugs to decrease viral load (1). Although these agents are fairly well tolerated, previously unrecognized adverse reactions will become more evident as the availability of the drugs improves and use becomes more widespread. New-onset diabetes mellitus has been described with several agents commonly used to manage HIV disease (2-4). We noted a strong temporal relation between the onset of hyperglycemia and the initiation or change in protease inhibitor therapy in five HIV-infected patients. The Table shows the characteristics of these patients. All were known to have had HIV infection for more than 5 years, and all experienced disease progression despite extensive use of nucleoside analogues. Before protease inhibitor therapy began, the mean CD4 + count was 87 cells/mm3, and viral loads ranged from 7000 to 355 000 copies/mL. None of the patients had risk factors for diabetes, although one had had elevated random blood glucose levels before treatment. None of the patients had received pentamidine or megestrol. At the time of hyperglycemia onset, the mean CD4 + count had increased to 224 cells/mm3 and the mean decrease in viral load was 128 000 copies/mL. Hyperglycemia was controlled without difficulty through either oral hypoglycemic agents or diet modification and did not necessitate discontinuation of therapy with the protease inhibitor. None of the patients developed diabetic ketoacidosis, and only one patient required hospitalization for glycemic control. In one case, withdrawal of protease inhibitor therapy resulted in correction of hyperglycemia; subsequent rechallenge caused recurrence. The mechanism by which hyperglycemia occurs in association with protease inhibitor use is unclear. Discontinuation of therapy with the drug, which may promote viral resistance (5), is not necessary for glycemic control. Until more data are available, clinicians who treat HIV-infected patients must be aware that protease inhibitors can cause hyperglycemia in patients with or without a history of glucose intolerance. John A. Eastone, MD Catherine F. Decker, MD National Naval Medical Center Bethesda, MD 20889 References 1. Bartlett J. Protease inhibitors for HIV infection. Am J Med. 1996;124: 1086-8. 2. Nasti G, Zanette G, Inchiostro S, Donadon V, Tirelli U. Diabetes mellitus following intravenous pentamidine administration in a patient with HIV infection. Arch Intern Med. 1995;155:645-6. 3. Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes mellitus induced by megestrol acetate in a patient with AIDS and cachexia. Ann Intern Med. 1992;116:53-4. 4. Albrecht H, Stellbrink HJ, Arasteh K. Didanosine-induced disorders of glucose intolerance. Ann Intern Med. 1993; 119:1050. 5. Mellors JW, McMahon DK, Chodakewitz JA, Schleif WA, Emini EA, Condra IH. Correlation between genotypic evidence of HIV-1 resis-
15 November 1997 • Annals of Internal Medicine
Time to Diagnosis of Hyperglycemi,a
mg/dL
mo
427 502 223 274 329
6 6 12 1 2
Glycemic Control
Oral hypoglycemic agent Oral hypoglycemic agent Diet modification Diet modification Diet modification
tance to the protease inhibitor MK-639 and loss of antiretroviral effect in treated patients [Abstract]. In: Program and Abstracts of the Fourth International Workshop on HIV Drug Resistance, 6-9 July 1995, Sardinia, Italy.
New-Onset Diabetes Mellitus Associated with Use of Protease Inhibitor
948
Blood Glucose Level aft
