Can nucleoside RT inhibitors directly cause insulin resistance?

Current dogma has early insulin resistance from ART blamed on protease inhibitors, and late insulin resistance attributed to lipoatrophy induced by nucleoside drugs. But studies in healthy subjects have suggested that at least some NRTIs may cause early insulin resistance as well.

The central finding presented by Marit van Vonderan from Amsterdam was that peripheral tissue insulin resistance (as measured by the gold standard hyperinsulinemic clamp procedure) occurred only occurred in subjects (all male) who initiated zidovudine-lamivudine plus Kaletra and not in those who received nevirapine plus Kaletra.

This ZDV-3TC associated insulin resistance was present at 3 months, a time point where limb fat was actually increased from baseline. At 24 months limb fat was down in the ZDV-3TC group, but this insulin resistance occurred well before limb fat had decreased, suggesting a more direct effect of the NRTI therapy. This data suggests that we need to pay attention to insulin resistance in future clinical studies that compare nucleoside backbones, not just PI vs no PI.

And whilst it is tempting to speculate that, among the nucleoside RT inhibitors, only the thymidine analogs should adversely affect insulin resistance, it would be wise to actually obtain the data rather than assume – and be certain that the other NRTIs are in fact not involved in these effects.

van Vonderan M et al. Zidovudine/lamivudine persistently contributes to peripheral insulin resistance by a body composition-independent mechanism demonstrated by repeated clamp studies during 2 years of first-line ART with zidovudine/lamivudine/lopinavir/ritonavir