702 - Abstract (11th CROI)

Session 99 Poster Abstracts
Pathogenetic Mechanisms of Abnormalities of Glucose, Insulin, Lipid, and Mitochondrial Metabolism
Monday, 1:30 - 3:30 pm
Poster Hall

702
The Effect of Atazanavir vs Lopinavir/ritonavir on Insulin-stimulated Glucose Disposal Rate in Healthy Subjects
M Noor*¹, D Grasela¹, R Parker¹, U Chaudhari¹, H Uderman¹, A Currie¹, S Agarwala¹, C Grunfeld², M Giordano³, S Hodder⁴, F Fiedorek¹, and E O'Mara¹
¹Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ, USA; ²Univ. of California, San Francisco, USA; ³Bristol-Myers Squibb Pharm. Res. Inst., Wallingford, CT, NJ, USA; and ⁴Bristol-Myers Squibb, Virology Med. Affairs, Plainsboro, NJ, USA

Background: Therapy with some HIV protease inhibitors (PI) contributes to insulin resistance, type 2 diabetes, dyslipidemia and changes in body composition. A proposed mechanism is by blockade of glucose transporters. Atazanavir (ATV) is a new PI that, unlike indinavir, lopinavir, and ritonavir, does not contribute to dyslipidemia or block glucose transport through the glucose transporter-4 insulin-sensitive transporter in vitro. This study compared the effects of ATV and lopinavir/ritonavir (LPV/r) to placebo on insulin-stimulated glucose disposal rates.

Methods: Randomized, double-blind, cross-over study of the effect of 5 days of treatment with ATV, LPV/r, or placebo on insulin-stimulated glucose disposal in healthy HIV-negative volunteers. Each subject was studied on 2 of 3 possible treatments using the hyperinsulinemic euglycemic clamp technique (180 minutes) with ł14 days of wash-out. Difference among groups in insulin-stimulated glucose disposal per unit of insulin and glycogen storage rate (proportion of total glucose disposal taken up by the tissue but not oxidized) was analyzed by ANOVA.

Results: We studied 30 healthy adult men with median age of 35 years (range 19 to 49), mean weight of 76.4 kg (SD = 9.9), mean body mass index of 24.0 kg/m² (SD = 2.4). During steady-state euglycemia (60 to 180 minutes), insulin levels were raised comparably (65.4, 63.0, 63.9 mU/mL) and glucose was clamped at ~75 mg/dL under all conditions.

Treatment	M/I *mg/kgmin/mU/mL**	GSR *mg/kgmin**
Treatment	Adjusted Mean ą SE
LPV/r	7.54 ą 0.84	2.61 ą 0.37
ATV	9.80 ą 0.84	4.21 ą 0.37
Placebo	9.87 ą 0.84	4.01 ą 0.37
	Difference (95% CI) p-value
LPV/r vs. ATV	-2.26 (-3.95, -0.58) p=0.011	-1.60 (-2.49, -0.71) p=0.001
LPV/r vs. Placebo	-2.33 (-4.02, -0.64) p=0.009	-1.41 (-2.30, -0.52) p=0.003
ATV vs. Placebo	-0.07 (-1.76, 1.62) p=0.935	0.20 (-0.69, 1.09) p=0.655

LPV/r decreased M/I by 24% compared to placebo and by 23% compared to ATV. LPV/r decreased GSR by 35% compared to placebo and by 38% compared to ATV.

Conclusions: ATV did not reduce insulin sensitivity and had no effect on insulin-stimulated glucose disposal or GSR. In contrast LPV/r induced insulin resistance and reduced the glucose disposal per unit of insulin and glycogen storage rate. These data are consistent with in vitro studies showing that ATV does not interfere with glucose transporter-4 activity and does not induce fasting hyperinsulinemia, substantiating the findings of large clinical trials. Further data are needed to assess the clinical implications of these findings on fat redistribution and body composition.

Keywords: Insulin resistance; lipodystrophy; protease inhibitors