|
Zerit
(stavudine) or Crixivan (indinavir)-containing Regimens Are Associated
with an Increased Risk of Diabetes Mellitus in HIV-infected Individuals
In the current study, published in
the September 5, 2003 issue of AIDS, dAIDS 2003; 17(13):1993-1995 Diabetes mellitus was diagnosed in 16 out of 1011 HIV positive patients
over a median follow-up of 289 days.
Significant risk factors for the
onset of diabetes were older age and antiretroviral therapy with
stavudine or indinavir. Older men with HIV infection should be considered
at higher risk of diabetes, and caution may be warranted in the
use of both indinavir and stavudine in these patients.
Researchers described
the association between HAART and metabolic
disorders soon after the introduction of the protease inhibitors
(PI). Since that time, clinicians and researchers have noted the
syndrome(s) of hyperlipidemia,
lipodystrophy or diabetes
mellitus (DM) in a significant percentage of patients. These metabolic
abnormalities carry increased risk of producing metabolic disorders
and coronary heart disease, increased diagnostic and therapeutic
costs, and significant patient psychological discomfort secondary
to body image alterations.
Carr
et al (Lancet 353.1999) have reported that hyperglycemia with or
without DM occurs in 3-17% of patients receiving HAART, shortly
after the start of PI or even after their prolonged use. Whether
treatment with PI is the direct cause of this metabolic defect is
still unclear.
In the current study, researchers analyzed retrospective data
from a cohort of 1011 HIV-positive patients (68% men, median age
37 years, range 18-74, median duration of known HIV infection 84
months, range -3 to 210 months); clinical, biochemical, immunological,
virological and therapeutic data were collected from an in-house
database, started on 1 November 1999. Blood tests were obtained
for each patient at regular intervals as a part of routine outpatient
care.
Study patients met the following criteria: normal fasting plasma
glucose levels at study entry, and no previous diagnosis of DM;
at least two fasting plasma glucose determinations during follow-up;
a follow-up of at least 3 months; a stable (without interruption)
antiretroviral regimen (or no therapy) for at least one month before
entry and throughout the follow-up period.
DM was diagnosed on the basis of the 1997 American Diabetes
Association guidelines (fasting plasma glucose ≥ 126 mg/dl on two different occasions).
During the follow-up (median 289 days) DM was diagnosed in
16 out of 1011 patients. Table 1 summarizes the statistical
analyses of putative risk factors for DM. Older age (P
< 0.001) was associated with a higher
risk of developing diabetes, whereas male sex showed a trend towards
it, without reaching conventional statistical significance (P
= 0.07).
AIDS 17(13): 1993-1995. September 5, 2003.
After multivariate analysis adjusted for age and sex, diabetes
onset was unrelated to the CD4 cell count, HIV-RNA level, ART assumption
as a whole, PI therapy versus non-PI-containing regimens.
Of note is the fact that there was no statistically significant
difference in the whole duration of ART between diabetic and non-diabetic
patients, thus including the pre-enrollment time. Furthermore, age
and sex-adjusted Cox regression models of the individual drugs showed
that patients treated with stavudine or indinavir were at significantly
higher risk of developing DM (stavudine: P = 0.001; indinavir
P = 0.018). (See Table 2).
AIDS 17(13): 1993-1995. September
5, 2003.
To address the issue of whether the onset of diabetes may be
stochastic or dose dependent, the investigators evaluated whether
exposure to stavudine or indinavir (in the whole cohort) was significantly
longer compared with other drugs.
They found a potential confounding bias in the case of abacavir,
efavirenz or nelfinavir because these drugs were registered later
in Italy. However, the median duration of exposure was similar among
stavudine and other reverse transcriptase inhibitors, as it was
among indinavir, saquinavir and ritonavir. They therefore tried
to understand a possible synergic role of stavudine and indinavir
therapy in the onset of DM, since after the multivariate analysis
in the subgroup of patients taking indinavir alone did not show
a significant HR for the development of diabetes, whereas patients
on stavudine alone and those on stavudine and indinavir were at
significantly higher risk, (P <
0.0001). Finally, fasting cholesterol and triglyceride levels in
index cases were collected close to the time of diabetes diagnosis.
The results about the drug-related risk of diabetes were partly
surprising. First, the study results clearly showed an increased
risk of DM in patients on indinavir, thus confirming preliminary
results from in-vitro and in-vivo studies, occasionally leading
to some pathogenic models.
As for stavudine, this is the first report suggesting that
this drug may be an independent and strong risk factor for the onset
of DM. At present, data are both anecdotal and controversial with
regard to the causative role of single nucleoside reverse transcriptase
inhibitors (didanosine and abacavir) in diabetes onset, whereas
data on lipoatrophy/lipodystrophy and hypertriglyceridemia after
stavudine use are as yet inconclusive.
The authors conclude, “As a result of our epidemiological results,
we cannot speculate about a pathogenic model for stavudine-related
DM, but we are concerned about the risk of diabetes in patients
on prolonged stavudine or indinavir therapy. In this regard, we
propose that older men with HIV infection are considered at higher
risk of DM, and that caution may be warranted in the use of both
indinavir and stavudine in these patients.”
09/08/03
Reference
AM Brambilla and others. Stavudine or indinavir-containing
regimens are associated with an increased risk of diabetes mellitus
in HIV-infected individuals. AIDS 17(13): 1993-1995. September 5, 2003.
|
