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Insulin Resistance and Diabetes Mellitus Associated With Antiretroviral Use in HIV-Infected Patients: Pathogenesis, Prevention, and Treatment Options

Tebas, Pablo MD

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1st, 2008 - Volume 49 - Issue - p S86-S92
doi: 10.1097/QAI.0b013e31818651e6
Supplement Article
Free

The contribution of current antiretroviral treatment regimens to the long-term survival of HIV-infected individuals is accompanied by increased risk of glucose metabolism abnormalities in this patient population. The risk of insulin resistance and diabetes in HIV-infected patients receiving antiretroviral treatment stems from 2 sources: exposure to the same environmental factors that have led to an increased incidence of these conditions in the general population and the negative effects on glucose metabolism inherent to components of antiretroviral treatment regimens. This article reviews the pathogenesis and diagnosis of insulin resistance and diabetes and the contribution of components of antiretroviral therapy regimens to increased risk for these conditions. Optimization of antiretroviral treatment regimens for HIV-infected patients with or at increased risk for development of abnormalities in glucose metabolism is discussed.

From the AIDS Clinical Trials Unit, University of Pennsylvania, Philadelphia, PA.

Disclosure: Dr. Tebas has received grant/research support from Boehringer Ingelheim, Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, Roche Pharmaceuticals, Schering-Plough, Tibotec Pharmaceuticals Limited, VGX Pharmaceuticals Inc., and VIRxSYS. He is a consultant for Boehringer Ingelheim, Bristol-Myers Squibb Company, Merck & Co., Inc., Tibotec Pharmaceuticals Limited, and VGX Pharmaceuticals Inc.

Correspondence to: Pablo Tebas, MD, Associate Professor of Medicine, University of Pennsylvania, Principal Investigator, AIDS Clinical Trials Unit, 8 Penn Tower, 34th and Civic Center Boulevard, Philadelphia, PA 19104-4283 (e-mail: pablo.tebas@uphs.upenn.edu).

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INTRODUCTION

The metabolic syndrome is a constellation of findings that encompasses defects in glucose metabolism, lipid metabolism, and hypertension, with abdominal obesity and insulin resistance playing a central role in its pathogenesis. Depending on the definition used, it is estimated that 25%-40% of American adults have the metabolic syndrome,1,2 a diagnosis of which requires the presence of at least 3 of the following components: impaired glucose tolerance, hypertension, elevated waist circumference or waist-hip ratio, and high triglyceride and/or low high-density lipoprotein cholesterol (HDL-C) levels.3 The presence of the metabolic syndrome increases the risk of cardiovascular disease 3-fold4 and the development of frank diabetes.5,6 According to the American Diabetes Association (ADA) classification criteria, type 2 diabetes results from a progressive defect in insulin secretion on a background of insulin resistance.7 The risk of type 2 diabetes increases with age, obesity, and lack of physical activity-risk factors that can also affect HIV-positive individuals. Other risk factors for developing type 2 diabetes include having a first-degree relative with diabetes; being a member of a high-risk ethnic population (eg, African American, Latino, Native American, Asian American, and Pacific Islander); hypertension (blood pressure ≥140/90 mm Hg); HDL-C <35 mg/dL and/or a triglyceride level >250 mg/dL; impaired glucose tolerance or fasting glucose on previous tests; a history of cardiovascular disease and/or other conditions associated with insulin resistance; and, for women, a past diagnosis of gestational diabetes, delivery of a baby weighing more than 9 lb, or presence of polycystic ovarian syndrome.7 The pathology associated with diabetes results primarily from a loss of glycemic control, leading to abnormally increased levels of blood glucose.8 As is also true for the general population, the high insulin levels and insulin resistance frequently seen in HIV-positive individuals are also associated with an increased risk of cardiovascular events that are independent of lipoprotein levels; for every standard deviation increase in insulin levels, the risk for cardiovascular events increases by a factor of 1.6 (1.1-2.3).9

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THE METABOLIC SYNDROME AND DIABETES IN HIV-INFECTED PATIENTS

The success of highly active antiretroviral therapy (HAART) has resulted in the prolongation of life for HIV-positive individuals. This, in turn, has exposed this population to the same environmental factors that have led to an epidemic of obesity and diabetes in the general population of developed societies.1,10 In addition, the side effects inherent to many antiretroviral treatments can also significantly contribute to the development of metabolic syndrome and diabetes. A recent study evaluated the risk of developing metabolic syndrome for up to 3 years postinitiation of antiretroviral therapy (ART). Before ART, 8.5% of patients were diagnosed with metabolic syndrome as per the criteria of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Third Report (NCEP). During follow-up, 234 patients progressed to metabolic syndrome that was significantly associated with increased risk of both cardiovascular disease and type 2 diabetes.2 Several other studies have demonstrated that patients with HIV infection are also at increased risk of developing diabetes compared with the general population.11,12

An assumption has been made that persons with the metabolic syndrome receiving HAART are at similar cardiovascular risk compared with HIV-seronegative individuals with metabolic syndrome, but the phenotype often differs between these 2 populations. In particular, HIV-infected individuals tend to have significant peripheral lipoatrophy that contributes to insulin resistance and elevated waist-hip ratio.

The frequency of this syndrome among HIV-positive individuals varies according to the definition used in individual studies and the patient's ethnic background, consistent with findings in the general population. The prevalence of metabolic syndrome in HIV-infected individuals has been reported as 18% in Spain,13 14%-18% in a multinational study,14 and 26% in a North American study.15 In general, the prevalence among HIV-positive patients has not been reported as higher than that among HIV-uninfected persons living in the same community.

Recent studies also suggest that HIV-infected individuals on HAART are developing diabetes at increasing rates12,16 and are likely to have a higher risk of cardiovascular disease.17 Thus, these observations lend support to the notion that the metabolic syndrome is likely to predict a higher risk of diabetes and cardiovascular disease in patients on HAART.2 As is true for the general population, by far the most frequent diabetic phenotype associated with HIV infection is type 2 diabetes.18

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EFFECTS OF ANTIRETROVIRAL DRUGS ON INSULIN RESISTANCE

Studies evaluating the metabolic effects of antiretroviral drugs are conducted initially in in vitro systems and animal models. These studies do not always extrapolate well to humans and have a somewhat limited value in clinical practice; however, they are critical for elucidation of the molecular mechanism(s) of the side effects of these medications. Among antiretrovirals, the only class that has been associated with direct effects on glucose metabolism is the protease inhibitors. The other classes of antiretroviral drugs exert their effects on glucose metabolism indirectly by affecting changes to body composition. The effects of nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine, on glucose metabolism are more indirect and related to lipoatrophy as a consequence of long-term use.19 However, results of a recent study of NRTI therapy with zidovudine or stavudine in 20 HIV-negative individuals indicated a significant dysregulation in expression of lipid and mitochondrial genes after only 6 weeks of therapy, without accompanying changes in body composition.20

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Protease Inhibitors

The frequent reports of diabetes and insulin resistance during the initial years of availability of potent ART led the US Food and Drug Administration in 1997 to issue a “class label” warning to all protease inhibitors indicating that physicians should closely monitor patients for hyperglycemia and diabetes mellitus potentially associated with their use.21 However, the effect on glucose metabolism of individual protease inhibitors varies dramatically and is best compared in studies of HIV-seronegative individuals as these compounds can be given alone in a very controlled environment, removing the effects of other drugs and any contribution of the HIV infection itself.

Murata et al22 demonstrated several years ago that the protease inhibitors indinavir, ritonavir, and amprenavir directly affect glucose uptake in 3T3-L1 adipocytes by selectively inhibiting the transport function of Glut4. Indinavir and ritonavir have been found to impair the activation of sterol regulatory element-binding protein 1 (SREBP-1) in adipose and hepatic cells, resulting in abnormal intranuclear accumulation of this protein and a later dysregulation of adipocyte differentiation, glucose, and lipid metabolism.23,24 Additional support for this effect has been demonstrated by a reduced expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is activated by SREBP-1 and a decreased expression of PPAR-γ-dependent adipocytokines and insulin-signaling molecules in fatty tissues of protease inhibitor-treated patients compared with HIV-seronegative controls.25 Nelfinavir has been shown to reduce active SREBP-1 in the nucleus and the levels of receptors for low-density lipoprotein (LDL) and LDL receptor-related protein that are intrinsic to lipoprotein catabolism and vessel wall maintenance, suggesting this as the mechanism for promotion of hypercholesterolemia by this drug.26

Among the protease inhibitors, indinavir has been associated with rapid and dramatic effects on glucose metabolism. A single dose of indinavir given to healthy, HIV-seronegative volunteers led to a significant decrease in insulin-mediated glucose disposal, a very sensitive marker of insulin resistance.27 The administration of indinavir to healthy HIV-seronegative volunteers for a period of 4 weeks also was associated with the development of insulin resistance that was independent of any changes in body composition.28

Data on the effects of nelfinavir on insulin resistance are more limited because no studies have administered this drug to healthy volunteers in the absence of other drugs or factors. In the AIDS Clinical Trials Group Study 5005,29 the administration of nelfinavir was not associated with changes in the reciprocal index of homeostasis model assessment-insulin resistance (HOMA-IR), which is derived from fasting plasma glucose (FPG) and insulin levels (surrogate markers for insulin resistance).30

Unboosted amprenavir had very modest effects on glucose metabolism in a cohort of 14 HIV-infected individuals initiated on antiretroviral treatment.31 In a large randomized study of ritonavir-boosted fosamprenavir (the prodrug of amprenavir), abnormalities in glucose levels were experienced by approximately 1% of the patient population.32 In treatment-naive patients, a favorable lipid profile is generally seen for fosamprenavir.33

In a study of lopinavir/ritonavir administered for 4 weeks to HIV-negative men, although clear changes in lipid parameters were detected, changes in glucose metabolism were not induced, as measured by hyperinsulinemic clamp.34 However, in a larger study, 10 days of treatment with lopinavir/ritonavir was associated with increases in HOMA-IR and a 25% decrease in insulin sensitivity in healthy HIV-negative volunteers,35 suggesting that this combination may have some effect on glucose metabolism, albeit more modest than those of indinavir.

Atazanavir has the reputation of being the most lipid neutral of the protease inhibitors. Atazanavir did not induce insulin resistance after 5 days of administration to healthy HIV-negative volunteers.36 Ritonavir-boosted atazanavir, the most common method of using atazanavir, was not associated with significant changes in insulin sensitivity after 10 days of administration to healthy HIV-negative adults.35 In a large study of atazanavir in HIV-infected individuals, no changes in glucose or insulin were detected after 48 weeks of administration.37

In a recently completed trial of HIV-infected, antiretroviral-naive individuals, saquinavir was not associated with changes in glucose disposal measured by clamps, although the small sample size of the study (16 patients) may have limited the ability of investigators to detect small changes.38

The effects of darunavir on metabolic parameters were similar to those of boosted atazanavir in a 28-day study of 49 healthy volunteers, which did not include intensive clamp measurments,39 demonstrating that this newer protease inhibitor is among those with fewer adverse effects on the metabolic profile.

Data on the glucose effects of tipranavir are more limited. In a recent study of 140 HIV-positive, antiretroviral-naive individuals comparing tipranavir/ritonavir with lopinavir/ritonavir, the effects of both combinations were similar on glucose metabolism and other metabolic parameters and dependent on the dose of ritonavir administered (100 vs. 200 mg).40

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Nucleoside Analogs

Evidence generally suggests that nucleoside analogs exert their effects on glucose metabolism indirectly, through changes in body composition and mitochondrial toxicity.19 However, a recent study showed that stavudine, administered for 4 weeks to healthy volunteers, was associated with modest decreases in glucose disposal ratio as measured by hyperinsulinemic euglycemic clamp when compared with placebo. This suggests that the effects of nucleoside analogs may be more direct than previously thought. However, these acute changes in glucose disposal were small.41

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Other Antiretrovirals

Two of the newer antiretroviral drug classes, chemokine receptor 5 (CCR5) antagonists and integrase inhibitors, seem to have a more favorable metabolic profile than their predecessors. Preliminary reports from the large pivotal trials MOTIVATE and BENCHMRK suggest that maraviroc and raltegravir are not associated with any significant metabolic effects.42-44 Further studies are needed to confirm these data.

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OTHER CONTRIBUTORS TO INSULIN RESISTANCE IN HIV-INFECTED INDIVIDUALS

Comorbid Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection has also been associated with insulin resistance.45 The data are compelling that this is also true in HIV-infected patients coinfected with HCV. In a large cross-sectional study, the association between HCV and diabetes in HIV-infected individuals remained significant after adjusting for body mass index and family history of diabetes (odds ratio = 3.7, 95% confidence interval: 1.3 to 11.1, P = 0.02).46 In patients coinfected with HCV/HIV, increased insulin resistance, higher rates of diabetes, and lower low-density lipoprotein cholesterol (LDL-C) values were seen versus those without HCV after initiation of ART using NRTI treatment regimens with and without nonnucleoside reverse transcriptase inhibitors (NNRTIs).47 Thus, HIV/HCV coinfected individuals are at a higher risk of developing insulin resistance and diabetes while on treatment, warranting close monitoring of these patients.

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Nonantiretroviral Drugs

Drugs used for the management of complications of HIV infection may be associated with worsening insulin resistance or diabetes; these agents include niacin for the treatment of hyperlipidemia,48 steroids for the management of some comorbid infections or immune reconstitution syndrome, and thiazides for the management of hypertension. These drugs should be used with caution or alternatives considered for HIV-infected patients at high risk for developing diabetes.

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MANAGING DIABETES IN PATIENTS WITH HIV INFECTION

Patients with HIV infection are more likely to develop diabetes mellitus than the general population19; data from the Multicenter AIDS Cohort Study (MACS) population indicate a relative risk as high as 4 for the development of this condition.12 The care of patients with diabetes is complex and often requires a multidisciplinary team approach that includes physicians, nurse practitioners, nurses, nutritionists, and pharmacists.7 Many HIV treatment providers are also the primary care providers for their patients whereas others are providing only specialty care. This is an important consideration when managing a long-term disease like diabetes; if a clinical practice is not providing primary care to the HIV-infected patient, then the practice should ensure that diabetes is managed effectively elsewhere.

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Diabetes-Establishing the Diagnosis

According to ADA guidelines,7 an individual with an FPG level of at least 126 mg/dL has diabetes and an individual with an FPG between 110 and 125 mg/dL has impaired fasting glucose (IFG) (Table 1). The oral glucose tolerance test, although more sensitive and specific than FPG, is not recommended for routine clinical use but may be required for the diagnosis of diabetes in some patients with IFG or in women with gestational diabetes.7

TABLE 1

TABLE 1

Measurement of FPG levels is the preferred test to diagnose diabetes and IFG in children and nonpregnant adults. Unless the patient has unequivocal hyperglycemia, an abnormal test should be confirmed by repeat testing on a different day.7 As HIV-positive patients are at high risk for the development of insulin resistance and diabetes, this test should be repeated periodically, as often as yearly, especially among individuals with other genetic predispositions to diabetes and those with high cardiovascular risk or obesity.18

Individuals with IFG and diabetes are at higher cardiovascular risk; diabetes is a cardiovascular risk equivalent that modifies goals for lipids and blood pressure.49 The goal of treatment is to improve glycemic control and to maintain glycosylated hemoglobin (Hb A1C) levels below 7%.7 Aggressive targets for blood pressure (<130/80 mm Hg) and lipid levels should be established (LDL-C <100 mg/dL). Triglyceride and HDL levels also may be targeted49 but reaching these goals may be very difficult in this population. Low-dose aspirin should be considered for all patients.

In patients with IFG or established diabetes, a medical history should be taken that evaluates the individual for the presence of diabetic complications such as retinopathy, nephropathy, neuropathy, cardiovascular disease, peripheral vascular disease, sexual dysfunction, and gastroparesis. The physical examination should include blood pressure testing, fundoscopy, thyroid palpation, evaluation of the skin, testing for evidence of neuropathy, and palpation of distant pulses.7

The laboratory workup should include measurements of Hb A1C, fasting lipids, liver function, microalbuminuria, creatinine clearance calculation, and thyroid-stimulating hormone. Appropriate referrals should be made to ophthalmologists, family planners, and diabetes educators.7

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MANAGING DIABETES IN THE HIV-INFECTED PATIENT

Optimization of HIV Treatment Regimens in Patients With Diabetes

If an HIV-positive patient has diabetes or is at high risk for it, then consideration should be given to initiation of an HIV treatment regimen less associated with the development of this complication. Individual protease inhibitors most associated with development of insulin resistance should be avoided. If IFG or diabetes has occurred while on therapy, then the substitution of one or several of the components of the antiretroviral regimen with another agent that is less associated with this particular metabolic complication is reasonable. For example, if the patient is receiving indinavir, then a consideration should be made to substitute it (if possible, based on antiretroviral history and resistance testing) with an NNRTI, another protease inhibitor less associated with insulin resistance, or a drug from one of the new drug classes (CCR5 antagonists or integrase inhibitors), even though data are limited for these new agents, and it might not be possible to evaluate the tropism of the virus in an individual with well-controlled viral replication. Although “switch studies” have demonstrated significant reductions in lipid levels, their benefit has been more limited in improving glucose parameters.50

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Lifestyle Change-Based Interventions

At the present time, overweight and obese individuals constitute a much larger segment of the HIV-infected population than patients with wasting syndrome.51 As with individuals in the general population, an obese patient with HIV should be advised about the benefits of weight loss and regular physical activity; this is applicable not only to patients with high risk of diabetes but also to individuals who have already developed IFG or frank diabetes. There is considerable evidence that lifestyle changes, including changes in diet (eg, calorie restriction and reduction in intake of carbohydrates, saturated fats, and cholesterol) and increased physical activity can help reverse the progression to type 2 diabetes and improve glycemic control in individuals already diagnosed with the condition.7,52-54 In a randomized study, aggressive lifestyle modification was more effective than metformin in preventing the development of diabetes in individuals with elevated fasting glucose55; however, adherence to lifestyle changes is difficult to maintain over time. The expected improvement in Hb A1C levels in individuals who are able to follow lifestyle modification recommendations is 1%-2%, similar to goals that are attainable with some drug regimens.

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Pharmacologic Treatment of Diabetes

A detailed discussion of the management of patients with diabetes is beyond the scope of this review. The ADA periodically updates its recommendations for the management of individuals with glucose metabolism impairments,7 and the same standards of care used in the general population should be applied to patients with HIV infection.

If modification of a patient's lifestyle is not successful for reaching Hb A1C goals, then metformin should be considered as first-line therapy,7,56 particularly in patients with visceral obesity. Metformin has been used in patients with HIV infection and was particularly effective in a small cohort of individuals with abdominal obesity.57,58 However, metformin should be used with caution in patients with renal failure or history of lactic acidosis. Because the use of this drug is associated with weight loss,56 its use in HIV-infected patients might exacerbate lipoatrophy. Usually a low metformin dosage of 500 mg twice a day is initiated and, if needed, gradually increased to the maximum tolerated dose of 2-3 g daily. The expected improvement in Hb A1C levels with the use of metformin is 1.5%.59 Thiazolidinediones (including the glitazones rosiglitazone and pioglitazone) can be added to the treatment regimen if Hb A1C goals are not reached or they can be used as first-line therapy if the patient has significant lipoatrophy. In a study of HIV-infected patients with hyperinsulinemia and increased waist-hip ratio, combination therapy with metformin and rosiglitazone was not much better at reversing lipoatrophy than either drug alone.58 Rosiglitazone was associated with improved insulin resistance when evaluated in small or uncontrolled trials for the management of lipoatrophy60; however, these results were not seen in a large, properly powered study.61 Rosiglitazone negatively affects lipid profiles by increasing LDL-C and decreasing HDL-C,58 which can be problematic in some patients and may be one of the contributors to the increased frequency of cardiovascular events associated with its use.62 The role of rosiglitazone in the management of diabetes is currently in flux due to the increased risk of cardiovascular events associated with its use62,63-a concern that has become generalized to the thiazolidinedione class. In addition, both rosiglitazone and pioglitazone now carry black box warnings indicating that the thiazolidinediones may cause or exacerbate congestive heart failure in some patients.64 The data for pioglitazone are somewhat more positive; along with exercise, this agent produced small improvements in extremity fat in HIV-positive individuals with lipoatrophy.65 Glitazones have to be used with caution (or not at all) in patients with significant liver and/or cardiovascular disease. In HIV-positive individuals, if the use of this class of drugs is considered, then pioglitazone should be the first choice; the usual dose is 15-45 mg daily.64 The expected improvement of Hb A1C levels with its use is approximately 1%.59

The data for other antidiabetic drugs (eg, glinides, sulfonylureas, exenatide, and alpha-glucosidase inhibitors) in HIV-infected individuals are very limited. Combination therapy can be considered for individuals who have not reached treatment goals with the use of metformin or pioglitazone. The patient who does not reach targets with oral treatments should be initiated on insulin, which is usually started with a long-acting preparation at bedtime with slow dosage increases dependent on the results of glucose level self-monitoring; oral agents can be continued. Referral to a practice with expertise in the management of diabetes and its complications should be considered if these strategies fail to achieve adequate control.

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SUMMARY

Physicians who treat HIV-infected patients must consider a number of factors when deciding on the best therapeutic strategy for an individual. These include determination of a patient's metabolic status before initiation of HAART and continued monitoring of development of metabolic abnormalities during antiretroviral treatment. In patients at high risk for development of the metabolic syndrome or diabetes, antiretroviral drug therapies can be designed to minimize metabolic effects. The HIV caregiver, whose primary area of expertise may be infectious diseases, is also often called upon to treat the metabolic syndrome or diabetes in their patients or be able to recognize these disorders for patient referral to an appropriate expert. In either circumstance, keeping informed of the metabolic risks and latest standards of care for metabolic syndrome and diabetes is essential to maximizing care of the HIV-infected patient.

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Keywords:

antiretrovirals; diabetes mellitus; metabolic effects; metabolic syndrome; insulin resistance; cardiovascular disease

© 2008 Lippincott Williams & Wilkins, Inc.