Metabolic effects of indinavir in healthy HIV-seronegative men

Noor, Mustafa A.a,c; Lo, Joan C.a,d; Mulligan, Kathleena,d; Schwarz, Jean-Marca,d,e; Halvorsen, Robert A.b; Schambelan, Morrisa,d; Grunfeld, Carla,c

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Background: Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition.

Methods: Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy.

Results: Fasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5; P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l; P < 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l; P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg ⋅ min per μU/ml insulin; 95% confidence interval 0.6–3.0; P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg; P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography.

Conclusions: In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

Author Information

From the Departments of aMedicine and bRadiology, University of California at San Francisco, the cMetabolism and Endocrine Sections, San Francisco Department of Veterans Affairs Medical Center, the dDivision of Endocrinology, San Francisco General Hospital, San Francisco and the eDepartment of Nutritional Sciences, University of California Berkeley, Berkeley, California, USA. *Present address: University Hospital, University of Medicine and Dentistry of New Jersey, USA.

Requests for reprints to Dr M. A. Noor, Department of Veterans Affairs Medical Center, Metabolism Section (111F), 4150 Clement St, San Francisco, California 94121, USA.

Date of receipt: 22 January 2001;

revised: 1 February 2001; accepted: 14 February 2001.

Sponsorship: grants from Merck Research Laboratories (Merck & Co. Inc., Rahway, New Jersey, USA), the AIDS Clinical Research Center of University of California, San Francisco, and the Universitywide AIDS Research Program F99SF-044 (M.N) and by grants from the National Institutes of Health (NIH) DK45833 (M.S) and DK52615 (K.M). The studies were conducted in the General Clinical Research Center (GCRC) at San Francisco General Hospital supported by a grant (RR-00083) from the National Center for Research Resources (NCRR) NIH. J.L. is a Clinical Associate Physician supported by the NCRR. C.G. is supported by the University of California AIDS Clinical Research Center and the Research Service of the Department of Veterans Affairs.

© 2001 Lippincott Williams & Wilkins, Inc.