d4T associated with significantly increased risk of type-2 diabetes mellitus
Simon Collins, HIV i-Base
The use of d4T (stavudine) has dramatically fallen in most Western countries, primarily due to high risk of lipoatrophy, and additive mitochondrial-related toxicity with other reverse transcriptase inhibitors. However, globally it remains one of the most widely ARVs prescribed first line therapy (in d4T/3TC/nevirapine), as the basis for the least expensive WHO-recommended fixed dose combinations (FDCs).
Further caution against use of d4T as a long-term treatment option was highlighted in an analysis of the use of d4T and the risk of diabetes mellitus (DM) from the D:A:D Study, given in an oral presentation by Stephane de Wit
D:A:D is a prospective observational study of 23,437 HIV patients that has a focus on toxicity and safety issues relating to ARV treatment, including lipodystophy, cardiovascular risk and heaptotoxicity and where DM is collected as a study endpoint.
The incidence of diabetes mellitus (DM) in the D:A:D study is comparable to that in HIV-negative populations, and this analysis aimed to identify whether specific antiretrovirals (ARV) were associated with new onset DM.
However, the rate of DM (/1000 PY) increased from 3.96 in those unexposed to d4T to 8.20 in those exposed for 2-3 years and then decreased. No other ARV was significantly associated with DM after controlling for d4T use.
Time-updated total cholesterol, HDL-cholesterol and triglycerides were all associated with DM. Adjusting for each of these separately reduced slightly the relationship between d4T and DM. While lipodystrophy was significantly associated with DM (1.37, p=0.008), adjustment for this did not modify the relationship between d4T and DM. This led the authors to conclude that d4T potentially directly contributes to insulin resistance, rather than through lipodystrophy.
De Wit S, Sabin CA, Weber R et al. Relationship between use of stavudine and diabetes mellitus. 8th International Congress on Drug Therapy in HIV Infection, 12-16 November 2006, Glasgow. Oral abstract PL9.5.