Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 4: Complications of Antiretroviral Therapy

Insulin Resistance and Hyperglycemia on Antiretroviral Therapy

Background

Patients taking antiretroviral therapy (ART), particularly certain regimens containing a protease inhibitor (PI), appear to have an increased risk of hyperglycemia and diabetes mellitus. Hyperglycemia with or without diabetes has been reported in 3-17% of patients and has occurred at a median of about 60 days, with a range of 2 days to more than a year, after starting therapy. Disorders of glucose metabolism may present as the following:

• Insulin resistance, in which higher concentrations of insulin are required to exert normal effects; blood glucose levels may be normal but fasting insulin levels will be high because of compensatory insulin secretion by the pancreas
• Impaired glucose tolerance (ie, a glucose level of 140-199 mg/dL 2 hours after a 75-g oral glucose load)
• Impaired fasting glucose (ie, 110-125 mg/dL)
• Diabetes mellitus, which is diagnosed when the fasting blood sugar is ≥126 mg/dL, or the confirmed 2-hour glucose level is ≥200 mg/dL during glucose tolerance testing

The incidence of new-onset hyperglycemia in HIV-infected patients taking ART has been reported as about 5%, on average. Even if fasting glucose levels remain normal in patients taking ART, up to 40% of those on a PI-containing regimen will show impaired glucose tolerance. The etiology of insulin resistance and hyperglycemia in HIV-infected patients is probably multifactorial, with varying contributions from traditional risk factors (eg, obesity, family history), comorbid conditions (eg, hepatitis C virus infection), and antiretroviral-related factors (eg, direct effects of PIs, hepatic steatosis, and fat redistribution).

Patients who have preexisting diabetes must be monitored closely when starting ART; some experts would consider a PI-sparing regimen for these patients. Alternatively, PIs with favorable metabolic profiles (eg, atazanavir) may be preferred for such patients. Those with no history of diabetes should be advised about the warning signs of hyperglycemia (polydipsia, polyuria, and polyphagia) and the need to use diet and exercise to maintain an ideal body weight.

S: Subjective

The patient is about to begin ART, has been on an antiretroviral (ARV) regimen that includes a PI, or is overweight, has central fat accumulation, or has lipoatrophy. Although most patients with hyperglycemia are asymptomatic, some may report polydipsia, polyuria, and polyphagia.

Determine the following in performing a patient history:

• Fat redistribution on ART (see chapter Abnormalities of Body Fat Distribution)
• Family history of diabetes
• Obesity, or habitual physical inactivity
• Racial or ethnic heritages at higher risk: African, Hispanic, Native American, Asian-Pacific Islander
• Hypertension
• History of low level of high-density lipoprotein
• History of elevated triglycerides
• Gestational diabetes or delivery of infant weighing >9 lbs
• Current pregnancy
• Hepatitis C virus coinfection
• Polycystic ovary syndrome

O: Objective

Review previous or baseline blood glucose levels. Document weight and any weight changes or fat redistribution.

A: Assessment

Determine whether the patient has normal blood glucose, impaired fasting glucose, or diabetes (see laboratory recommendations and definitions below).

P: Plan

Diagnostic Evaluation

Most experts (eg, the International AIDS Society-USA) recommend monitoring routine fasting blood glucose levels at baseline and 3-6 months after starting therapy if baseline results are normal. Some recommend 2-hour postprandial measurements or a 75-g oral glucose tolerance test within the first 3-4 months of starting therapy and every 3-4 months thereafter. Monitoring should be more frequent if abnormalities are detected, or any additional risk factors exist, as noted earlier. Patients with these risk factors must be counseled about prevention of hyperglycemia before starting ART.

Treatment

Patients with insulin resistance

For patients with insulin resistance (impaired glucose tolerance) and normal blood glucose levels, current evidence is inadequate to recommend drug treatment. However, lifestyle modifications can be recommended, including exercise, weight loss, and diet changes. Weight loss is strongly recommended if the patient is overweight. Refer the patient to a dietitian. Some studies of insulin resistance in HIV-infected individuals are under way, and patients with access to clinical trials may be interested in these studies.

Patients with hyperglycemia and insulin resistance require treatment. A trial of lifestyle modifications may be attempted, including weight loss (if indicated), diet changes, and exercise. When drug treatment is required, because patients meet the diagnosis of diabetes and lifestyle changes are not adequate, the insulin sensitizers metformin or thiazolidinediones (pioglitazone or rosiglitazone) should be considered. Oral antidiabetic agents may increase the risk of hepatic and renal abnormalities, so patients should be monitored for hepatic toxicity (thiazolidinediones) and lactic acidosis (metformin). Thiazolidinediones should be avoided in patients with significant liver disease. Patients with elevated serum creatinine (>1.5 mg/dL in men or >1.4 mg/dL in women), hepatic impairment, or metabolic acidosis should not take metformin. In some cases, insulin may be the safest drug therapy for symptomatic hyperglycemia, although episodes of hypoglycemia are much more common with insulin than with most oral agents. For hyperglycemia that is associated with the use of PIs, switching to an alternative agent (eg, a nonnucleoside reverse transcriptase inhibitor or a different PI) may be effective if the HIV treatment history and resistance profile permit.

Patients with diabetes

Treatment should be instituted to control blood sugar and to modify other cardiovascular risk factors, with the aim of preventing heart disease and other end-organ disease.

• Control glucose: maintain the glycosylated hemoglobin (HbA1c) level at <7%.
• Treat dyslipidemia: maintain low-density lipoprotein (LDL) at <100 mg/dL and maintain triglycerides at <200 mg/dL.
• Treat hypertension: maintain systolic blood pressure at <130 mm Hg and diastolic blood pressure at <85 mm Hg.
• Reduce cardiovascular risk with lifestyle modifications: smoking and alcohol cessation, exercise, weight loss, nutritional counseling.
• Decrease the risk of end-organ complications:
  • Measure urine microalbumin and creatinine; if the urine albumin/creatinine ratio is >30 mg/g, treat with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to slow the progression of nephropathy.
  • Schedule annual retinal examination by an ophthalmologist.
  • Perform an annual foot exam.
• Start aspirin therapy if the patient has evidence of macrovascular disease, a family history of coronary artery disease, a history of smoking, or previous vascular events.

For further information, see the American Diabetes Association, Clinical Practice Recommendations, Diabetes Care, at: http://care.diabetesjournals.org.

Patient Education

• Antiretroviral therapy can increase the risk of diabetes in some individuals. Patients should report any difficulty with excessive hunger and thirst and increased urination. Health care providers will monitor blood glucose when doing laboratory work, but it is important for the patient to call if any symptoms are present.
• Review exercise possibilities to determine what activities might be realistic and acceptable for the patient.
• Review the patient's eating habits and explain the need to work with a dietitian to keep blood glucose (and triglycerides) within normal limits. A proper diet can reduce the risk of permanent damage to the blood vessels of the eye, the kidney, the brain, and can reduce the risk of a heart attack.
• Emphasize other lifestyle modifications, such as weight loss (if appropriate).
• Provide medication-specific education, especially if the patient will be taking metformin or insulin.
• Consider referral to a diabetic clinic for specialty needs.

References

• Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003 Sep 1;37(5):613-27.
• Hardy H, Esch LD, Morse GD. Glucose disorders associated with HIV and its drug therapy. Ann Pharmacother. 2001 Mar;35(3):343-51.
• Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• Wlodarczyk D. Managing Medical Conditions Associated with Cardiac Risk in Patients with HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; August 2004. Available online at hivinsite.ucsf.edu/InSite?page=kb-03-01-20. Accessed February 7, 2006.