Correspondence

Abacavir and Diabetes

N Engl J Med 2001; 344:142-144January 11, 2001

Article

To the Editor:

We describe a patient infected with the human immunodeficiency virus (HIV) in whom diabetes mellitus developed in association with treatment with abacavir, a new nucleoside reverse-transcriptase inhibitor.

A 47-year-old homosexual man who was known to have had HIV infection since 1990 also had hypertension, which was treated with lisinopril and hydrochlorothiazide. He had no family history of diabetes. Antiretroviral therapy was begun in 1997. The patient had adverse reactions to both zidovudine and stavudine and was then treated with didanosine, lamivudine, and hydroxyurea. Subsequently, his plasma HIV RNA load was less than 400 copies per milliliter and his CD4 cell counts were between 700 and 950 per cubic millimeter. In March 1999 Kaposi's sarcoma developed; it was treated effectively with local radiation. Hydroxyurea was then discontinued because it was thought to be causing a decrease in the CD4 cell count, and twice-daily treatment with 300 mg of abacavir was begun.

During this period, the patient's blood glucose concentration was 106 mg per deciliter. Subsequently, lethargy developed in association with marked hyperglycemia, for which treatment with metformin was begun. Because of persistent hyperglycemia, glyburide was added to the regimen, and at the same time, abacavir was discontinued, because its initiation was temporally related to the development of diabetes, and treatment with efavirenz was begun. Within two weeks the patient's blood glucose concentration was normal. Metformin and glyburide were then discontinued. His blood glucose concentrations remained normal, and the glycosylated hemoglobin values on his two most recent visits were also normal (Table 1Table 1Blood Glucose Values, CD4 Cell Counts, and Medications in a Patient with Diabetes Mellitus Associated with Abacavir Therapy.). At no time during the period of hyperglycemia did the patient have detectable levels of HIV RNA in plasma or evidence of another infection.

These findings suggest a link between abacavir and diabetes. The manufacturer has documented an increased incidence of hyperglycemia with abacavir, but no differences from that observed in control groups were noted in controlled clinical trials (Hetherington S, Glaxo Wellcome: personal communication). The only cases of sustained hyperglycemia that were reported were in patients who were also taking protease inhibitors, which are known to be associated with lipodystrophy, insulin resistance, and hyperlipidemia.1,2

Geoffrey A. Modest, M.D.
Upham's Corner Health Center, Dorchester, MA 02125

Jon Fuller, M.D.
Boston Medical Center, Boston, MA 02118

2 References

1. 1

   Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 1999;353:2093-2099
   CrossRef | Web of Science | Medline

2. 2

   Kaufman MB, Simionatto C. A review of protease inhibitor-induced hyperglycemia. Pharmacotherapy 1999;19:114-117
   CrossRef | Web of Science | Medline

Author/Editor Response

The above letter was referred to Glaxo Wellcome, the manufacturer of abacavir, which offers the following reply:

To the Editor: The salient points about this case report of a patient in whom hyperglycemia developed while he was receiving combination therapy for HIV infection that included the nucleoside reverse-transcriptase inhibitor abacavir are the absence of a history of hyperglycemia; the onset of hyperglycemia 10 months after abacavir was first given; concomitant therapy with hydrochlorothiazide and didanosine, both of which have been reported to cause hyperglycemia1; and the resolution of the hyperglycemia within 2 weeks after abacavir was stopped and glyburide was begun. The temporal association notwithstanding, abacavir may have potentiated the contributions of other drugs to the development of hyperglycemia.

A review of data from more than 28,000 patients in clinical trials and expanded-access programs does not indicate an association between abacavir therapy and the development of diabetes. In controlled clinical trials, there were no differences in the incidence of hyperglycemia (glucose >250 mg per deciliter) between the abacavir groups and the control groups. Among 1639 patients who were receiving abacavir in single-group or controlled studies, 18 had nonfasting blood glucose concentrations of at least 250 mg per deciliter (8 on one occasion only). In only two patients (0.1 percent) was treatment for hyperglycemia begun during the study. One patient with diabetes required an increase in the dose of insulin. None of the patients discontinued abacavir therapy. In an ongoing study, diabetes developed in one patient who was receiving a regimen containing abacavir, and who had a history of hyperglycemia, chronic pancreatitis, hepatopathy, alcoholism, and heroin use.

Hyperglycemia and insulin resistance are associated with the use of protease inhibitors in 5 percent of patients. In addition, mitochondrial dysfunction has been implicated in the development of glucose intolerance.2 It has been linked to treatment with nucleoside reverse-transcriptase inhibitors through a hypothesized mechanism of inhibition of DNA polymerase.3 Evidence obtained in vitro indicates that among the nucleoside reverse-transcriptase inhibitors, abacavir is the least specific inhibitor of this enzyme.4 An improvement in insulin sensitivity has been reported in patients who were switched from a regimen that included a protease inhibitor to one that included abacavir.5

In conclusion, although mild elevations in blood glucose concentrations have been noted in patients who were receiving abacavir, the current data are insufficient to link this drug to the development of diabetes. The reported spontaneous development of diabetes appears to be a rare event. The use of concomitant medications, complications of HIV infection, and predisposing factors make it difficult to determine the cause in these types of cases. On the basis of clinical experience and in vitro studies, a clinically important connection between abacavir therapy and the development of diabetes is unlikely.

Seth V. Hetherington, M.D.
James M. Lenhard, Ph.D.
Gwendolyn S. Powell, M.D.
Glaxo Wellcome, Research Triangle Park, NC 27709-3398

5 References

1. 1

   Munshi MN, Martin RE, Fonseca VA. Hyperosmolar nonketotic diabetic syndrome following treatment of human immunodeficiency virus infection with didanosine. Diabetes Care 1994;17:316-317
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2. 2

   Wollheim CB. Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes. Diabetologia 2000;43:265-277
   CrossRef | Web of Science | Medline

3. 3

   Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:1112-1115
   CrossRef | Web of Science | Medline

4. 4

   Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994;38:2743-2749
   Web of Science | Medline

5. 5

   Walli R, Huster K, Bogner JR, Goebel FD. Effect of switching from PI to ABC on insulin sensitivity and fasting lipids — 12 month follow-up. Presented at the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Toronto, September 2000. abstract.
   

Citing Articles (7)

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   Sean T Nguyen, Susan A Eaton, Amy M Bain, Anita P Rahman, Kenna D Payne, Roger Bedimo, Jon D Herrington, Darego O Maclayton, Maria C Rodriguez-Barradas, Anthony J Busti. (2008) Lipid-Lowering Efficacy and Safety After Switching to Atazanavir-Ritonavir–Based Highly Active Antiretroviral Therapy in Patients with Human Immunodeficiency Virus. Pharmacotherapy 28:3, 323-330
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   B. Ledergerber, H. Furrer, M. Rickenbach, R. Lehmann, L. Elzi, B. Hirschel, M. Cavassini, E. Bernasconi, P. Schmid, M. Egger, R. Weber, . (2007) Factors Associated with the Incidence of Type 2 Diabetes Mellitus in HIV-Infected Participants in the Swiss HIV Cohort Study. Clinical Infectious Diseases 45:1, 111-119
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   2006. Abacavir. , 3-4.
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   E. M. Evans, F. Nye, N. J. Beeching, G. V. Gill. (2005) 'Disappearing diabetes'-resolution of apparent Type 1 diabetes in a patient with AIDS and cytomegalovirus (CMV) infection. Diabetic Medicine 22:2, 218-220
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   Patrick G. Clay. (2002) The abacavir hypersensitivity reaction: A review. Clinical Therapeutics 24:10, 1502-1514
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   Renu G Jain, Eric S Furfine, Louise Pedneault, Alex J White, James M Lenhard. (2001) Metabolic complications associated with antiretroviral therapy. Antiviral Research 51:3, 151-177
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7. 7

   &NA;. (2001) Abacavir. Reactions Weekly &NA;:835, 6
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