It has been shown that protease inhibitors (PIs) can alter insulin sensitivity. This has led to infrequent reports of not only insulin resistance, but the actual development of diabetes. Prior work, for example, showed a drop in insulin sensitivity after just one 1,200-mg dose of indinavir (IDV, Crixivan). However, studies in recent years have focused on how individual agents may differ on this adverse effect. This current study focused on measuring the impact of atazanavir (ATV, Reyataz) versus lopinavir/ritonavir (LPV/r, Kaletra) on insulin sensitivity. Overall, the outcomes support that atazanavir, given without ritonavir (RTV, Norvir), has less of an impact on this measurement when compared to lopinavir dosed with ritonavir.

Thirty HIV-negative persons were enrolled in this study. They took either atazanavir 400 mg once a day, or three capsules twice a day of lopinavir/ritonavir or a placebo for five days, and then they had measurements done.

The technique in this study is to assess how much blood glucose undergoes cellular uptake given a certain amount of IV insulin. This allows a measurement of relative insulin resistance, in that this compares how much glucose levels change given the presence of a PI. If there is insulin resistance caused by a PI, there will be less effect from an amount of insulin on glucose uptake, and therefore a lower glucose "disposal rate" is seen when there is insulin resistance. The study results demonstrate that nearly identical measurements were seen in patients on placebo and on atazanavir, thus showing no impact of atazanavir on insulin resistance. However, those on lopinavir/ritonavir did show evidence of insulin resistance.

In addition, lipid fractions were altered after six days on lopinavir/ritonavir, with a statistically significant increase in triglycerides noted, and no change on atazanavir versus placebo. There were no changes seen in the other measurements of lipids, such as cholesterol, HDL and LDL at this time point.

The study authors conclude that atazanavir, after five days dosing, does not impact insulin resistance in contrast to what was seen on lopinavir/ritonavir. It confirms the lipid differences reported in clinical studies of these two agents. The study did not yet study atazanavir combined with ritonavir, so there is some limitation to these results given that atazanavir can be clinically used either boosted by low-dose ritonavir or as an unboosted PI. Nevertheless, given the increasing focus on adverse event differences between treatments, and the potential role that insulin resistance has as a marker for lipodystrophy, these results add to the growing body of data supporting the role of atazanavir as an option for the treatment of HIV infection.

Reference

Abstract: The Effect of Atazanavir vs. Lopinavir/Ritonavir on Insulin-Stimulated Glucose Disposal Rate in Healthy Subjects (Poster 702)
Authored by: M. Noor, D. Grasela, R. Parker, U. Chaudhari, H. Uderman, A. Currie, S. Agarwala, C. Grunfeld, M. Giordano, S. Hodder, F. Fiedorek, E. O'Mara
Affiliations: Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ; Univ. of California, San Francisco, CA; Bristol-Myers Squibb Pharm. Res. Inst., Wallingford, CT, NJ; Bristol-Meyers Squibb, Virology Med. Affairs, Plainsboro, NJ