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d4T and Lipodystrophy Raise Diabetes Risk in D:A:D Cohort; Nevirapine Protects
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8th International Congress on Drug Therapy in HIV Infection
November 12-16, 2006
Glasgow, Scotland
Mark Mascolini
Taking d4T (stavudine) independently inflated the risk of diabetes mellitus in the multinational D:A:D cohort, as did AZT and ddI, though to a lesser extent [1]. Nevirapine and, surprisingly, ritonavir appeared to protect against diabetes, while lipodystrophy and unruly lipids raised the risk. Although few physicians in developed countries prescribe d4T today, the drug is widely used in fixed-dose combinations throughout the developing world.
D:A:D--already famed for linking longer antiretroviral therapy to myocardial infarction [2]--now embraces 33,389 HIV-infected people from 11 cohorts. For this analysis the D:A:D team defined diabetes mellitus as (1) a fasting plasma glucose above 7 mmol/L (126 mg/dL) measured at least twice consecutively or (2) starting antidiabetic therapy including dietary advice, insulin, or oral antidiabetic drugs. Clinicians counted 952 people with diabetes when they signed up for D:A:D and eliminated them from the analysis. Among the remaining 32,437 people, 745 got diabetes during 130,148 person-years of follow-up. Those numbers translated into an incidence of 5.72 cases per 1000 person-years of follow-up.
A statistical analysis adjusted for age, gender, body mass index, race, smoking, calendar year, and primary cohort determined that cumulative exposure to d4T upped the risk of diabetes 1.19 times per year (P = 0.0001), exposure to AZT 1.06 times per year (P = 0.0003), and exposure to ddI 1.06 times per year (P = 0.008). On the other hand, taking ritonavir lowered odds of a diabetes diagnosis 6% per year of use (P = 0.02), and taking nevirapine lowered the risk 11% per year (P = 0.0003). Even after adjustment for other diabetes risk factors (total cholesterol, triglycerides, lipoatrophy, lipohypertrophy, age, gender, body mass index), taking d4T still boosted the diabetes risk.
The D:A:D analysis also confirmed several traditional risk factors for diabetes in people with HIV--older age male gender, greater body mass index, black race, injecting drug use, and earlier calendar year. Current smoking marginally and nonsignificantly trimmed the risk of new-onset diabetes. Lowest-ever (nadir) CD4 count and duration of HIV infection had no impact on diabetes risk.
Presenting these results for D:A:D, Stephane De Wit of St.-Pierre Hospital in Brussels noted that diabetes incidence in this collective cohort is a bit lower than in other HIV cohorts, perhaps because of differences in diet and sociodemographic factors. The d4T link confirms an earlier Multicenter AIDS Cohort Study (MACS) analysis that tied this nucleoside to impaired insulin sensitivity [3].
De Wit suggested three hypotheses to explain why protease inhibitors (PIs) did not raise the risk of diabetes, as would be expected from earlier work. First, use of more recent, less toxic PIs could partly explain both the calendar-year effect and the weak protective effect of ritonavir. Second, diabetes mellitus could represent the "tip of the iceberg" of upset glucose metabolism; incidence of glucose intolerance could still be higher with PIs than without them in D:A:D, but this analysis did not address glucose intolerance. Third, the PI-related component of insulin resistance may be small compared with the lipodystrophy component in people with HIV.
References
1. De Wit S, Sabin CA, Weber R, et al. 8th International Congress on Drug Therapy in HIV Infection, November 12-16, 2006, Glasgow. Abstract PL9.5.
2. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993-2003. Erratum in N Engl J Med. 2004;350:955.
3. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS. 2005;19:1375-1383.
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