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Atazanavir: preliminary week 24 study results show no increase in glucose, cholesterol and triglycerides
Reported by Jules Levin
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A main story at this year's Lipodystrophy Workshop is the preliminary data from a study of the new once daily PI atazanavir regarding this drug's effects on glucose as well as cholesterol and triglycerides. The metabolic or lipid preliminary week 24 data is being presented first at this Workshop while the full study is being presented at the ICAAC conference next week here in San Diego. In this study efavirenz is compared to atazanavir in 800 patients and next week the effects on viral load and CD4 after 48 weeks will be presented. Previous smaller studies found that atazanavir did not increase cholesterol & tryglicerides. This larger study provides additional preliminary confirmation. A key remaining question is how will atazanavir affect body changes. Obviously this drug will have to be combined with other antiretroviral HIV drugs like nukes or NNRTIs. But will less body changes occur and if they do occur will it occur much more slowly because of this drug effects on glucose and lipids? We don't know yet. Longer follow-up time is needed to assess this. So, how will this drug be used. NATAP writers will be reporting on the phase III 48 week study comparing efavirenz to atazanavir being presented in a few days at ICAAC. This study will be used by the FDA to review approval for the drug. That NATAP report will be a more detailed discussion addressing this question of how atazanavir will be used. In the end, treating physicians decide after a drug is approved and available in the pharmacy how to use a drug.
BACKGROUND
At last year's Lipodystrophy Workshop, Michael Dube, MD, reported coverage for NATAP on key new developments in understanding diabetes and insulin resistance in HIV; he said: "...studies in both rats (Hruz et al) and humans (Noor et al) both documented that insulin resistance occurs rapidly when using indinavir, that is with just a single dose (edit note: researchers of these studies suggested other protease inhibitors can have similar effects but indinavir appeared to be the worst offender). As suspected from clinical experience, this insulin resistance appears to be rapidly reversible...in the Noor study a single 1200 mg oral dose of indinavir achieved standard steady
plasma concentrations (10 uM) acutely reduced insulin stimulated glucose disposal by average of 34% in the 6 HIV-negative subjectsŠscientists from Bristol-Myers-Squibb found a significant reduction in insulin-stimulated glucose uptake (roughly comparable to insulin resistance) with ritonavir but not atazanavir. Further clarification of their results and methods are needed, but these results suggest that atazanavir may have a lesser tendency to
provoke insulin resistance in patients. Clinical studies of this drug in insulin
resistance are needed."
Abnormalities of Glucose Metabolism, Including Insulin Resistance (2001 Lipodystrophy Workshop)
Michael Dube, MD, University of Indiana and ACTG researcher
www.natap.org/lipod/110201_1.htm
The following 2 studies were reported at this year's Lipodystrophy Workshop.
Jacqueline Capeau (abstract 1) and French research group looked at indinavir in fat cells (adipocytes) in the test tube (in vitro). She reported finding that indinavir disrupted the normal functioning of fat cells. Of course, this study is in the test tube but we know from other studies that indinavir may affect fat cells.
JC Koster (abstract 6) reported on a study to determine whether pancreatic B-cell function is acutely affected by indinavir; glucose stimulated insulin secretion was measured in mice and rat cells in the test tube. Koster found that glucose stimulated insulin release was significantly inhibited following 1 hour treatment with indinavir. Intravenous infusion of indinavir (0.5 mg/kg/min) during hyperclycemic clamps on PI-naive Wistar rats significantly suppressed first phase insulin response compared with water placebo. Koster concluded that these data suggest that therapeutic levels of indinavir are sufficient to inhibit glucose uptake via the pancreatic glucose transporters, leading to decreased glucose sensing by B-cells.
Glucose, Cholesterol, and Triglycerides after 24 weeks of Atazanavir
At last year's meeting Bristol Myers Squibb investigator Rex Parker reported that atazanavir does not inhibit insulin-stimluated glucose transport through GLUT-4, the mechanism by which other protease inhibitors induce insulin resistance. Parker reported similar findings in a study reported at this year's Workshop. Sension, from FT Lauderdale, Florida reported (abstract 36) that after 24 weeks in a study atazanavir had not increased fasting glucose, fasting insulin, and fasting c-peptide, as well as fats.
In this study 805 treatment-naive patients were randomized to efavirenz or atazanavir, each in combination with AZT/3TC. The 48 week results of viral load and CD4 will be presented at the ICAAC Conference next week here in San Diego. Sension reported here this preliminary data on insulin resistance as well as total cholesterol and HDL-C (good cholesterol). This is a randomized , double-blinded, ongoing study. Before starting study drugs fasting glucose for the patients receiving atazanavir was 90 mg/dL and it was 92 mg/dL after 24 weeks, no increase. Fasting insulin was 11 uU/mL at baseline and 12 after 24 weeks, no real increase. C-peptide was 2.2 ng/mL at baseline and 2.4 at week 24.
Sension concluded that atazanavir was not associated with development of hyperglycemia as assessed by these tests. I think we need further follow-up for a longer period to confirm this finding but certainly these results are encouraging. Also in this study Sension reported that total cholesterol did not increase after 24 weeks on atazanavir. Total cholesterol was about 160 at baseline and the same after 24 weeks. Total cholesterol increased 20% for patients taking efavirenz from 160 to 200 mg/dL. Fasting LDL-C (bad cholesterol) remained the same for patients taking atazanavir (100 at baseline and 101 at week 24). For patients taking efavirenz LDL-C was 100 at baseline and 120 (+18%) after week 24. Fasting triglycerides also increased for patients on efavirenz by 16% but nor for patients on atazanavir (-11%).
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