AEGiS 7LIPO [16] Evaluation of insulin sensitivity in healthy volunteers treated with low-dose ritonavir combined with atazanavir (ATV/RTV) or lopinavir (LPV/RTV): a prospective, randomized study using hyperinsulinaemic, euglycaemic clamp and oral glucose tolerance testing

7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

13–16 November 2005, Dublin, Ireland

Evaluation of insulin sensitivity in healthy volunteers treated with low-dose ritonavir combined with atazanavir (ATV/RTV) or lopinavir (LPV/RTV): a prospective, randomized study using hyperinsulinaemic, euglycaemic clamp and oral glucose tolerance testing

MA Noor¹, OP Flint¹, RA Parker¹, J Maa¹, J Witek¹ and SL Hodder²
¹Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, NJ, USA; ²Department of Medicine, University of Medicine and Dentistry New Jersey, Newark, NJ, USA

Antiviral Therapy 2005; Supplement 3:L11 (abstract no. 16)

OBJECTIVES: Previously it was shown that atazanavir (ATV) does not induce insulin resistance while indinavir, lopinavir/ritonavir (LPV/RTV) and ritonavir (RTV) do. Since many patients receive low-dose RTV combined with another protease inhibitor (PI) for enhanced pharmacokinetics, we assessed the effects on insulin sensitivity of two PI/RTV regimens.

METHODS: Randomized, cross-over study comparing the effects of ATV/RTV (300/100 mg once daily) and LPV/RTV (400/100mg twice daily) on insulin sensitivity in 24 healthy HIV-negative subjects. Change in insulin sensitivity was assessed by euglycaemic hyperinsulinaemic clamp (SI_clamp) and by oral glucose tolerance test (OGTT) expressed as area under the curve (AUC) during 3 h. Subjects were studied at baseline (BL) and after 10 days of treatment, with a wash-out period between the treatments. Differences from BL and between treatments were assessed by ANOVA.

RESULTS: There was no significant change from BL in SI_clamp on ATV/RTV (–10%, P=0.132). SI_clamp decreased significantly on LPV/RTV relative to BL (–25%, P<0.001) and relative to ATV/RTV (–18%, P=0.023). The glucose AUC increased significantly from BL on LPV/RTV (P=0.032) but not on ATV/RTV (P=0.184 vs BL). The insulin AUC increased significantly from BL for both regimens (P=0.023 vs ATV/RTV and P=0.01 vs LPV/RTV). Total cholesterol increased significantly on LPV/RTV (P=0.015 vs BL; P=0.003 vs ATV/RTV). Triglycerides increased significantly from BL on both regimens (P=0.001 vs ATV/RTV, P<0.001 vs LPV/RTV) but the increase was higher on LPV/RTV (P=0.012 vs ATV/RTV).


Table 1.

	BL*	ATV/RTV*	LPV/RTV*

SI_clamp
(mg*min/kg per mU/ml)	11.5 ±0.99	10.4 ±1.10	8.6 ±0.84
Glucose
AUC (mg*hr/dl)	332 ±14	349 ±17	360 ±18

AUC (mU*hr/dl)	106 ±17	132 ±18	136 ±19
Cholesterol (mg/dl)	159 ±5	159 ±6	169 ±6
Triglycerides (mg/dl)	108 ±7	140 ±7	161±10

*Adjusted mean ±SEM PI/RTV regimens.

CONCLUSIONS: Treatment with RTV in combination with ATV for 10 days did not significantly affect insulin sensitivity by clamp. A small increase from BL in insulin AUC during OGTT was perhaps due to an increase in triglycerides. In contrast administration of LPV/RTV induced insulin resistance by clamp and OGTT with greater increases in triglycerides. Further data should assess clinical significance for diabetes outcome.

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2005-11-13
16

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