Metabolic effects of indinavir in healthy HIV-seronegative men

Abstract

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 x min per microU/ml insulin; 95% confidence interval 0.6--.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.

Fig 1

Homeostasis model assessment [24] (HOMA) insulin resistance index at baseline and after 4 weeks therapy with indinavir (IDV) (see text for calculation). Data are mean ± SEM and represent the average of 2 days.

Fig. 2

Plasma glucose levels 2 h following 75 g oral glucose at baseline and after 4 weeks taking indinavir (IDV). One subject developed diabetes (2 h glucose 11.3 mmol/l), another became glucose intolerant (2 h glucose 7.9 mmol/L), and one nearly developed impaired glucose tolerance (2 h glucose 7.7 mmol/l). (To convert glucose from mmol/l to mg/dl, multiply by 18.1.)

Fig. 3

Glucose (a) and insulin (b) levels during oral glucose tolerance test at baseline (·) and after 4 weeks taking indinavir (IDV; ·). Area under the curve (AUC) for glucose showed a trend towards an increase (P = 0.08). The second-phase insulin secretion at 2 h was increased with IDV but the 3 h AUC did not reach statistical significance (P = 0.25). (To convert insulin from pmol/l to µU/ml, multiply by 0.14.)

Fig. 4

(a) Summary of the steady-state plasma insulin and glucose concentrations and glucose infusion rate during hyperinsulinemic euglycemic clamp: insulin (◆) and glucose (●) levels during baseline study; insulin (◇) and glucose (○) levels during study on indinavir. (b) Insulin-mediated glucose disposal rate (mg/kg per min) per unit of plasma insulin (µU/ml) (M/I) expressed as mean ± SEM during steady state (60–180 min) at baseline and after 4 weeks taking indinavir (IDV).