Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically

BACKGROUND: The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations. OBJECTIVE: To test the hypothesis that atazanavir combined with a lower dose of ritonavir would have significantly less effect on glucose metabolism than lopinavir/ritonavir in vitro and clinically. METHODS: Glucose uptake was measured following insulin stimulation in differentiated human adipocytes in the presence of ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l). These data were examined clinically using the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing (OGTT) in 26 healthy HIV-negative men treated with atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) for 10 days in a randomized cross-over study. RESULTS: Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations. Ritonavir (2 micromol/l) combined with either atazanavir or lopinavir (3-30 micromol/l) did not further inhibit glucose uptake. During euglycemic clamp, there was no significant change from baseline insulin sensitivity with atazanavir/ritonavir (P = 0.132), while insulin sensitivity significantly decreased with lopinavir/ritonavir from the baseline (-25%; P < 0.001) and from that seen with atazanavir/ritonavir (-18%; P = 0.023). During OGTT, the HOMA insulin resistance index significantly increased from baseline at 120 min with atazanavir/ritonavir and at 150 min with lopinavir/ritonavir. The area under the curve of glucose increased significantly with lopinavir/ritonavir but not with atazanavir/ritonavir. CONCLUSIONS: Both glucose uptake in vitro and clinical insulin sensitivity in healthy volunteers demonstrate differential effects on glucose metabolism by the combination PI atazanavir/ritonavir and lopinavir/ritonavir.