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OBJECTIVE:
To review the impact that factors such as HIV infection, antiretrovirals, and other commonly used drug therapies have
on glucose metabolism in HIV-infected patients.
DATA SOURCES: Pertinent literature was identified via a MEDLINE search from 1980 to April 2000 and through secondary sources
(abstracts presented at recent scientific meetings, manufacturers package inserts). The key words used were antiretroviral therapy,
HIV infection, insulin resistance, and metabolic abnormalities. All information deemed relevant to evaluate the impact that HIV
infection and drug therapy have on glucose metabolism in HIV-infected patients was included.
DATA SYNTHESIS: The viral burden and stress that are present in HIV-infected patients elicit a complex hormonal and immunologic
response that may alter various biochemical pathways, including glucose metabolism. Although rare before the era of potent
antiretroviral therapy, insulin resistance has now been described as an important component of the lipodystrophy syndrome. The
complex and multifactorial nature of glucose metabolism dysregulation makes management of hyperglycemia or diabetes mellitus
challenging in HIV-infected patients. In such a context, a set of recommendations was developed to guide practitioners in assessing,
treating, and monitoring hyperglycemia or diabetes mellitus in HIV-infected patients.
CONCLUSIONS:
Alterations of glucose metabolism observed in HIV-infected patients are more frequent since the introduction of
potent antiretroviral therapy. Although the etiology of such abnormalities remains unknown, protease inhibitors and, to a lesser
extent, nucleoside reverse transcriptase inhibitors are believed to participate in their pathogenic mechanisms. Because of
similarities to the pathogenesis of diabetes mellitus, management of antiretroviral-induced hyperglycemia could follow that the
recommendations of the American Diabetes Association, with special considerations for monitoring patients with HIV infection.
Future studies of altered glucose metabolism in HIV-infected patients should focus on understanding the precise mechanism or
causes of this complication so that preventive and therapeutic guidelines can be further evaluated.
ties include, but are not limited to, lipid and glucose homeostasis abnormalities and gonadal dysfunction. Most investigations preceding the institution of potent antiretroviral
therapy focused on the AIDS-associated wasting syndrome and its relationship to altered metabolism, as it represented an identifying characteristic of advancing HIV infection.5,6 The introduction of potent antiretroviral therapy
enabled clinicians to treat HIV-infected patients with drug
regimens capable of decreasing viral burden below the level
of assay quantification, enabling them to live longer, more
productive lives.7-9 However, as we progress into the era of
HIV as a chronic disease, additional clinical complications
Author information provided at the end of the text.
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H Hardy et al.
plasma glucose29
glucagon concentration29
insulin concentration
participation in insulin
resistance29
CRF = corticotropin-releasing factor; FFA = free fatty acids; HPA axis = hypothalamicpituitaryadrenal axis; IFN- = interferon alfa; IL-1 = interleukin-1; IL-6 = interleukin-6; LPL = lipoprotein lipase; TNF- = tumor necrosis factor alfa; VLDL =
very-low-density lipoprotein.
a
The indirect effect of cytokines on glucose metabolism mainly consists of alteration of lipid metabolism. Increased lipogenesis can prevent hepatic oxidation of
fatty acids and increase re-esterification of triglycerides, leading to hypertriglyceridemia, which results in the development of glucose intolerance and, in some patients, insulin resistance.
b
During inflammatory states, TNF- is secreted first and promotes the cellular secretion of IL-1. The release of both cytokines leads to the secretion of IL-6, which in
turn acts in conjunction with glucocorticoids to elicit the production of many mediators of the acute-phase response by the liver.16,32
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Although HIV-induced metabolic alterations appear responsible for some cases of hyperglycemia before the antiretroviral era, most of the cases were related to medications commonly taken by HIV-infected patients.
Glucocorticoids are known to cause hyperglycemia
through the promotion of gluconeogenesis in the liver and
decreased use of glucose in muscle, adipose tissue, and
lymphatic tissues. The development of glucose intolerance
associated with the use of glucocorticoids is likely due to
peripheral insulin resistance secondary to a reduction of
the number and affinity of insulin receptors, and its intensity is dependent on the dosage and duration of therapy.38,39
When the use of glucocorticoids is required, the dose should
be tapered to the smallest effective dose, and diet modification with or without the use of oral hypoglycemic agents
or insulin therapy should be considered. Patients should be
monitored closely for manifestations of pancreatitis.
Megestrol acetate, used for appetite stimulation, has structural similarities to glucocorticoids, and therefore its mechanism for causing peripheral insulin resistance is likely
secondary to a reduction of the number and affinity of insulin receptors, similar to the proposed mechanism for glucocorticoids.40-43 The majority of hyperglycemic episodes
are reversible on discontinuation of megestrol acetate, and
dronabinol can be substituted if necessary. If megestrol acetate must be continued, insulin can be added to the regimen for as long as megestrol acetate is required.44,45
Pentamidine, a drug used for prevention and treatment
of Pneumocystis carinii pneumonia, can be directly toxic to
the pancreas, inducing extensive islet necrosis. Consequently, its use can be initially associated with hypoglycemia
due to extensive insulin release and later associated with
hyperglycemia due to the loss of pancreatic function.46,47
Most cases of hyperglycemia have been reported with the
injectable rather than the aerosolized formulation of pentamidine.48 If hyperglycemia is mild, diet modification with
possible insulin therapy can be considered; however, if severe hyperglycemia occurs, discontinuation of pentamidine and initiation of insulin therapy are usually required.49
Alterations in Glucose Metabolism
Associated with Potent Antiretroviral Therapy
Since the introduction of potent antiretroviral therapy,
the frequency of metabolic abnormalities has significantly
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H Hardy et al.
Although the mechanism responsible for the development of insulin resistance in patients on PI therapy remains
unknown, two potential mechanisms have been described.65,66
The first hypothesized that due to a 60% homology between
the HIV-1 catalytic site and lipoprotein receptorrelated
protein (LRP), PIs could bind to the LRP-LPL complex on
vascular endothelium, impairing chylomicron uptake and
triglyceride clearance.65 The resulting hyperlipidemia would
participate in the development of insulin resistance by allowing a competition between glucose and lipid oxidation
pathways in skeletal muscles, interference of lipids with
post-receptor signaling insulin, or inhibition of glycogen
synthase. However, since low LPL activity has been described in HIV-infected patients well before the introduction of PIs, PI therapy would be expected only to worsen
preexisting lipid abnormalities rather than induce them.4
Since the constellation of metabolic abnormalities observed in the lipodystrophy syndrome resembles that in
type 2 diabetes mellitus, the mechanism responsible for the
development of insulin resistance may mimic the pathogenesis in type 2 diabetes mellitus.66 Several mechanisms
are known to lead to peripheral insulin resistance in type 2
diabetes mellitus, including reduced binding of insulin to
its receptors, alterations in intracellular pathways, and defective cellular uptake of glucose.66,67 In such a context, the
initial decrease in insulin sensitivity would most likely be
compensated by an increased secretion of insulin by the cells of the pancreas, resulting in a hyperinsulinemic state
and normal glucose tolerance. The inability of the pancreas
to maintain hyperinsulinemia would result in severe hyperglycemia and hyperlipidemia secondary to the inability of
insulin to maintain FFA concentration within a normal
range.68 As an extension to this proposed mechanism,
some authors have suggested that, as in extreme cases of
type 2 diabetes, the greater demand placed on pancreatic
-cells by insulin resistance may lead to a progressive loss
of -cell function in the pancreas and, therefore, progression from impaired glucose tolerance to diabetes mellitus.69,70 This finding remains controversial, and further direct measurement of -cell dysfunction is required to support this hypothesis.58,71
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR
ASSOCIATED GLUCOSE METABOLISM ALTERATIONS:
MITOCHONDRIAL TOXICITY
Although the lipodystrophy syndrome has been described in patients on nucleoside reverse transcriptase in346
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Although the frequency of hyperglycemia and/or diabetes mellitus has significantly increased in HIV-infected
patients since the introduction of potent antiretroviral therapy, this metabolic complication remains rare.55 The paucity of data regarding definitive factors for hyperglycemia
and optimal treatment options has made the development
of management guidelines difficult and has led most physicians to treat cases of severe hyperglycemia or frank diabetes mellitus independently, based on personal clinical experience. In this context, it is crucial to develop treatment
and monitoring recommendations for management of hyperglycemia in HIV-infected patients. A set of recommendations for assessment, treatment, and monitoring of glucose metabolism abnormalities encountered in HIV-infected patients on potent antiretroviral therapy is proposed
here based on the American Diabetes Association Guidelines.79,80
BASELINE EVALUATION
Risk Factors
In attempts to evaluate the association between antiretroviral therapy and abnormalities in glucose metabolism, baseline parameters must be obtained. Age, duration
of antiretroviral therapy, stage of HIV infection, and gender have been associated with an increased risk of development of the lipodystrophy syndrome; however, the subpopulation of HIV-infected patients on antiretroviral therapy at risk for developing altered glucose metabolism has
yet to be identified. In type 2 diabetics, central obesity, age,
sedentary lifestyle, hypertension, dyslipidemia, and specific medications (glucocorticoids, valproate, fluoxetine, progestin) have been identified as risk factors for the development of insulin resistance in the general population.80 By
homology with the general population, the subpopulation
of HIV-infected patients at risk for developing insulin resistance can be defined using the same risk factors, with
additional factors being PI therapy, family history of diabetes, as well as medications such as megestrol acetate and
pentamidine.
Baseline Glucose Monitoring
the patient should be assessed and treated with a steppedcare approach similar to patients with a baseline FPG of
126200 mg/dL.
ABNORMALITIES
The initial management approach applies to all HIV-infected patients with hyperglycemia or diabetes mellitus
who are receiving antiretroviral therapy regardless of their
virologic and immunologic status. It is recommended that
aerobic physical activity be increased, since it favors the
development of lean muscle mass, reduces triglyceride
concentrations, and is particularly effective in reducing abdominal fat.81 Diabetic HIV-infected patients with dyslipidemia should also follow the dietary recommendations of
the National Cholesterol Education Program.82 If glucose
control has been achieved after eight weeks, it is recommended to monitor FPG every three to six months. If diet
and exercise fail to achieve the desired level of glucose
control after eight weeks, pharmacologic intervention
should be considered.
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H Hardy et al.
Pharmacologic Interventions
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HIV-infected patients treated for hyperglycemia or diabetes mellitus should be monitored in a similar manner as
non-HIVinfected patients with hyperglycemia or diabetes
mellitus once glucose control is achieved. FPG concentrations as well as glycosylated hemoglobin (HbA1c) should
be incorporated into patients routine care. HbA1c should
be obtained two to four times a year for tracking long-term
glucose control with the goal of preventing micro- and
macrovascular complications. FPG concentrations should
be measured every three to six months. In addition, home
glucose monitoring should be considered to guide pharmacotherapeutic changes. Home glucose monitoring should
be performed once a day in patients with well-controlled
glucose concentrations, varying the time from fasting, to
postprandial, to bedtime. In other patients, home glucose
monitoring should be done before each meal, postprandially, and at bedtime.
Summary
Although the pathogenic mechanisms responsible for
abnormalities in glucose metabolism in HIV-infected patients are not fully elucidated, potent antiretroviral therapy
is believed to play a central role in their development. Insulin resistance appears to be a fundamental abnormality
of these metabolic alterations, and its degree of severity
can vary widely among patients. Because of similarities to
the pathogenesis of diabetes mellitus, management of antiretroviral-induced hyperglycemia could follow those
guidelines recommended by the American Diabetes Association, with special considerations for monitoring patients
with HIV infection. Larger, multicenter, controlled trials
are needed to better understand the mechanism of altered
glucose metabolism in HIV patients and to define the subpopulation of HIV-infected patients at risk for hyperglycemia or diabetes mellitus.
Hlne Hardy PharmD, Clinical Pharmacist Specialist, Infectious
Diseases, New England Medical Center, Boston, MA
Lori D Esch PharmD, Clinical Assistant Professor, Department of
Pharmacy Practice, University at Buffalo, Buffalo, NY; Antiviral Clinical Pharmacology Unit, Immunodeficiency Services, HIV Pharmaceutical Care Specialist, Erie County Medical Center, Buffalo
Gene D Morse PharmD, Professor and Chairman, Associate Dean,
Clinical Education and Research, Department of Pharmacy Practice, University at Buffalo
Reprints: Lori D Esch PharmD, BB110 SUNY Clinical Center, Erie
County Medical Center, 462 Grider St., Buffalo, NY 14215, FAX
716/898-3187, E-mail lswick@acsu.buffalo.edu
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EXTRACTO
OBJETIVO:
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Marie Larouche
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