Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy

Background

Diabetes is a substantial risk factor for coronary artery disease, stroke, and peripheral vascular disease, as well as for a number of other conditions including retinopathy and kidney disease. Patients taking antiretroviral (ARV) medications, especially certain protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), appear to have an increased risk of hyperglycemia and diabetes mellitus. In particular, the ARVs indinavir and stavudine (now seldom used in the United States) have been shown to induce insulin resistance in short-term studies of healthy HIV-uninfected volunteers, but other ARVs also perturb glucose homeostasis.

Disorders of glucose metabolism may present as the following:

  • Insulin resistance: a state in which higher concentrations of insulin are required to exert normal effects; blood glucose levels may be normal but fasting insulin levels may be high because of compensatory insulin secretion by the pancreas
  • Impaired glucose tolerance: glucose 140-199 mg/dL 2 hours after a 75 g oral glucose load
  • Impaired fasting glucose: glucose 100-125 mg/dL after an 8-hour fast
  • Diabetes mellitus: any of the following four criteria may be used (results must be confirmed by retesting on a subsequent occasion):
    • Fasting glucose ≥126 mg/dL
    • Glycosylated hemoglobin (HbA1c) level ≥6.5% (note that HbA1c testing has not been validated in HIV-infected persons; see "Diagnostic Evaluation," below)
    • 2-hour glucose level ≥200 mg/dL during glucose tolerance testing
    • Random glucose values ≥200 mg/dL in the presence of symptoms of hyperglycemia

The incidence of new-onset hyperglycemia among HIV-infected patients on ARV therapy (ART) has been reported as about 5%, on average. Even if fasting glucose levels remain normal in patients taking ARVs, 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 probably is multifactorial, with varying contributions from traditional risk factors (e.g., obesity, family history), comorbid conditions (e.g., hepatitis C virus infection), and ARV-related factors (e.g., direct effects of PIs, cumulative exposure to NRTIs, hepatic steatosis, and fat redistribution).

Patients who have preexisting diabetes should be monitored closely when starting ART; some experts would consider avoiding PIs for these patients, if other options are feasible. Alternatively, PIs with favorable metabolic profiles (e.g., atazanavir) may be preferred for such patients. Patients 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

Clinicians should consider the potential for abnormal glucose metabolism in the following types of patients:

  • Those who are about to begin ART
  • Those on an ARV regimen that includes a PI
  • Those with extensive exposure to NRTIs
  • Those who are obese or overweight
  • Those with central fat accumulation or lipoatrophy

Although most patients with hyperglycemia are asymptomatic, some (rarely) may report polydipsia, polyuria, polyphagia, or blurred vision.

When recording the patient's history, ask about the following:

  • Risk factors:
    • Family history of diabetes
    • Obesity
    • Habitual physical inactivity
    • Racial or ethnic heritages (higher risk: African-American, Hispanic, Native American, Asian/Pacific Islander)
    • Gestational diabetes or delivery of an infant weighing >9 lb (4.1 kg)
    • Current pregnancy
    • Hepatitis C virus coinfection
    • Polycystic ovary syndrome
    • Medications, including PIs, NRTIs, niacin, corticosteroids, antipsychotics
  • Comorbidities:

O: Objective

Perform a physical examination that includes the following:

  • Blood pressure, weight, body mass index (BMI) (see chapter Dyslipidemia)
  • Heart and lung examination
  • Peripheral pulses
  • Examination of neck, dorsocervical area, breasts, and abdomen for fat accumulation; measurement of waist circumference
  • For patients with hyperglycemia or diabetes:
    • Retinal examination (refer to ophthalmologist for dilated examination)
    • Visual inspection of feet (for ulcers)
    • Sensory examination of feet (for neuropathy)

A/P: Assessment and Plan

Diagnostic Evaluation

Determine whether the patient has normal blood glucose, impaired fasting glucose, or diabetes.

Most experts recommend routine checks of fasting blood glucose levels at baseline and within 3-6 months after starting or changing ART, if baseline results are normal. For patients with normal glucose levels, recheck every 6-12 months. Monitoring should be more frequent if abnormalities are detected or if any additional risk factors exist. Patients with risk factors for diabetes must be counseled about prevention of hyperglycemia before starting ART.

The role of 2-hour postprandial glucose measurements or the 75 g oral glucose tolerance test for diabetes is uncertain but these screenings may be appropriate for patients with multiple risk factors. The use of HbA1c testing to screen for diabetes has yet to be validated for the HIV-infected population. Of note, HbA1c values may underestimate glycemia in HIV-infected patients, especially in the setting of elevated red blood cell mean corpuscular volume (MCV) (e.g., owing to zidovudine) or anemia.

For patients with diabetes, monitor the following:

  • HbA1c, every 3 months for patients who have elevated HbA1c or whose therapy has changed, every 3-6 months for patients with stable and adequate glucose control
  • Fasting lipid panel
  • Electrolytes, creatinine, estimated glomerular filtration rate (eGFR) (see chapter Renal Disease)
  • Urine albumin/creatinine ratio (microalbuminuria: 30-299 mg/g)

Treatment

Patients with insulin resistance

For patients with insulin resistance who have normal blood glucose levels, current evidence is inadequate to recommend drug treatment. However, it may be possible to prevent the development of diabetes, and lifestyle modifications can be recommended, including exercise, avoidance of obesity, weight loss if indicated, and diet changes. Weight loss is strongly recommended if the patient is overweight. Refer the patient to a dietitian, if possible. Studies of insulin resistance in HIV-infected individuals are under way, and patients with access to clinical trials may be referred to these studies.

Patients with insulin resistance and hyperglycemia require treatment. A trial of lifestyle modifications may be attempted, including weight loss (if indicated), diet changes, and exercise.

For patients with diabetes and those whose lifestyle changes are not adequate to control blood glucose, specific treatment should be started.

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 HbA1c level at <7%, while avoiding hypoglycemia.
    • For hyperglycemia that is associated with the use of PIs, switching to an alternative agent (e.g., a nonnucleoside reverse transcriptase inhibitor, an integrase inhibitor, or a different PI) may be effective if the HIV treatment history and resistance profile permit.
    • Metformin usually is the initial drug of choice for overweight patients; other options include sulfonylureas and thiazolidinediones.
    • Metformin can worsen lipoatrophy and should be avoided in the presence of significant lipoatrophy. Metformin increases risk of lactic acidosis; it should not be used for patients with elevated serum creatinine (>1.5 mg/dL in men or >1.4 mg/dL in women), hepatic impairment, or metabolic acidosis.
    • Sulfonylureas may cause hypoglycemia. In starting therapy, shorter-acting agents (e.g., glipizide) may be preferable to longer-acting agents (e.g., glyburide). Some agents should not be used for patients with renal impairment (CrCl <50 mL/min).
    • Thiazolidinediones should be avoided in patients with significant liver disease. Rosiglitazone may increase the risk of myocardial infarction and death (study results conflict); both rosiglitazone and pioglitazone have been associated with congestive heart failure and are contraindicated for use by patients with this condition.
    • In some cases, insulin may be the safest drug therapy for patients with symptomatic hyperglycemia, although episodes of hypoglycemia are much more common with insulin than with most oral agents.
  • Treat dyslipidemia: maintain low-density lipoprotein (LDL) at <100 mg/dL and maintain triglycerides at <150 mg/dL. (Note that diabetes is considered a coronary heart disease equivalent state when evaluating goals for lipid management; see chapter Dyslipidemia.)
  • Treat hypertension: Maintain systolic blood pressure at <130 mm Hg and diastolic blood pressure at <80 mm Hg.
  • Reduce cardiovascular risks through lifestyle modifications such as smoking cessation, exercise, weight loss, nutritional counseling, and moderation of alcohol intake.
  • 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 (ACEI) or angiotensin receptor blocker (ARB) to slow the progression of nephropathy.
    • Schedule annual retinal examination by an ophthalmologist.
    • Perform an annual foot examination.
  • Start aspirin therapy (75-162 mg daily) if the patient has evidence of macrovascular disease or a history of vascular events. Consider daily aspirin for those with increased coronary heart disease risk (e.g., men >50 years and women >60 years of age with ≥1 coronary heart disease risk factor, such as a family history of coronary artery disease or a history of smoking) (see chapter Coronary Heart Disease Risk).

For further information, see the American Diabetes Association, Clinical Practice Recommendations, Diabetes Care.

Patient Education

  • ART 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 report the presence of any symptoms.
  • Review the patient's eating habits and explain the need to work with a dietitian to keep blood glucose (and triglycerides) within normal limits. Eating a proper diet can reduce the risk of permanent damage to the blood vessels of the eye, the kidney, and the brain, and it can reduce the risk of a heart attack.
  • Emphasize other lifestyle modifications, such as weight loss (if appropriate).
  • Encourage patients to get regular cardiovascular exercise; work with them to identify activities that might be realistic and acceptable for them.
  • Provide medication-specific education, especially if the patient will be taking diabetes medications.
  • Consider referral to a diabetes clinic for specialty needs.

References

  • Aberg JA, Gallant JE, Ghanem KG et al.; HIV Medicine Association of the Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jan;58(1):e1-e34.
  • American Diabetes Association. Standards of Medical Care in Diabetes - 2010. Diabetes Care. 2010; 33:S11-61.
  • Dubé MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus. Clin Infect Dis. 2000 Dec;31(6):1467-75.
  • Eckhardt BJ, Holzman RS, Kwan CK, et al. Glycated hemoglobin A(1c) as screening for diabetes mellitus in HIV-infected individuals. AIDS Patient Care STDS. 2012 April; 26(4): 197-201.
  • Kim PS, Woods C, Georgoff P, et al. Hemoglobin A1c underestimates glycemia in HIV Infection. Diabetes Care. 2009 Sep;32(9):1591-3.
  • Samaras K. Prevalence and pathogenesis of diabetes mellitus in HIV-1 infection treated with combined antiretroviral therapy. J Acquir Immune Defic Syndr. 2009 Apr 15;50(5):499-505.
  • 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.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly