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HIV-infected patients are at an increased risk for developing Diabetes

More and more patients with HIV are controlling their disease well. When viral loads are under control, patients often are seen by clinicians for other problems. Diabetes seems to be one of those problems that get a lot of attention. My current intern, Amanda Laurenzo, University of Florida PharmD candidate, has prepared a feature on why more HIV patients seem to get diabetes, how their HIV medications affect blood glucose levels and what diabetes medications are best for them.

HIV-infected patients are at an increased risk for developing Diabetes
Amanda Laurenzo, University of Florida
Doctor of Pharmacy Candidate

altNew information on the risk of cardiovascular disease in Human Immunodeficiency Virus (HIV) infected patients has been published in the data collection on the adverse events of anti-HIV drugs (the D:A:D study).  The study objective was to assess if whether any particular combinations of the components on the metabolic syndrome (low HDL, high triglycerides, high body mass index, hypertension, and diabetes mellitus) are associated with a higher risk of cardiovascular disease (CVD) in the HIV-infected population.  The D:A:D study analyzed 33,347 HIV-infected individuals in a prospective observational study. The conclusion of the study was that the presence of the metabolic syndrome in HIV-infected individuals did not increase the cardiovascular disease risk over and above the risk conferred by the components of the syndrome separately. Which means that practitioners need to carefully monitor patients with HIV for the development any of the metabolic syndrome components to reduce the risk of their patients from developing CVD.

According to the Multicenter AIDS Cohort Study (MACS), patients infected with HIV and on HAART are up to five times more likely to develop diabetes than HIV-negative individuals. Two main reasons why they are at increased risk are the effectiveness of highly active anti-retroviral therapy (HAART) regimens and some of the HAART medications themselves. The wide use and effectiveness of HAART has allowed the HIV infected population to live a much longer life. Thus they are now exposed to the same amount of risk factors as the non-HIV infected population such as increased age, obesity, and lack of physical activity. Some HAART medications have either direct or indirect adverse actions to a patient’s glucose metabolism which makes them more likely to develop diabetes. Incidence of medication related diabetes increases as the duration of therapy increases. Further, some medications commonly used to treat patients adverse events related to HAART also increase the risk for development of diabetes.

Of the HAART medications that increase the patients risk to develop insulin resistance and/or diabetes, the most studied and highest risk is associated with the protease inhibitors (PI’s). Protease inhibitors are the only class of HIV medications that have a direct effect on glucose metabolism. In 1997 the FDA put out a class label warning for all PI’s that informed physicians of the increased risk for hyperglycemia and diabetes and that close laboratory monitoring for them is warranted. However, this adverse effect on glucose metabolism is not the same for all PI’s. The protease inhibitors most associated with the adverse events are indinavir (Crixivan), ritonavir (Norvir), and amprenavir (Agenerase). Theses three exert multiple mechanisms by which they effect glucose levels. Among the noted PI’s, indinavir has been reported as having both rapid and dramatic effects on patients glucose metabolism resulting in as little as one dose. 

The nucleoside reverse transcriptase inhibitor (NRTI), stavudine (Zerit) increases the risk for developing diabetes indirectly. By altering body composition, increasing visceral fat, and increasing weight, stavudine leads to altered glucose metabolism and insulin resistance.

The MACS, which enrolled 5622 men over 17 years, was the first study to assess the incidence of diabetes in HIV-infected men. The study did correlate well with previous studies showing an increase risk for diabetes in HIV-infected women on HAART. Surprisingly, the MACS showed an increase risk for diabetes among HIV-infected individuals not taking HAART.  The study showed a prevalence rate in HIV-positive men not on HAART 2.11times higher and in HIV-positive men on HAART 5.36 times higher than the prevalence in HIV-negative men. After stratifying by immune status, the MACS researchers determined that men with lower nadir (lowest ever) CD4 counts (300c/mm³).

Some additional medications that are commonly prescribed for patients with HIV-infection also increase development of insulin resistance and diabetes. . Nicotinic acid (Niacin), megesterol (Megase), and growth hormone are used to manage some adverse effects of HAART therapy, however they are all know to adversely effects glucose metabolism regardless of the patient’s immune status. Pentamidine (NebuPent, Pentam-300) and steroids (Prednisone) are used for opportunistic infection treatment and/or prophylaxis and are also known to cause altered glucose metabolism in healthy individuals.

In the September 2008 issue of the Journal of Acquired Immunodeficiency Syndrome and Human Retrovirlolgy, a large cross-sectional study was published showing that another risk for insulin resistance in HIV-infected patients is Hepatitis C infection. Due to the fact that both Hepatitis C and HIV are transmitted in the blood and risk factors for acquiring them are similar, some HIV-patients may be co-infected with hepatitis C. The study revealed patients co-infected with both HCV/HIV had increased insulin resistance and higher diabetes rates versus HIV-infected patients without HCV infection after initiation of anti retroviral therapy using NRTI regimens with or without NNRTI.  The association remained statistically significant after adjusting for body mass index and family history.

The management of both HIV and diabetes is complex and often requires a multidisciplinary team approach for control. A detailed discussion of management of patients with HIV and/or diabetes is beyond the scope of this article. Nevertheless, consideration should be given at initiation of HIV regimens to select regimens for patients with diabetes, or risk factors for developing diabetes thoughtfully. For example, if a diabetic patient is started on HAART, the practitioner may select a PI with less effect on glucose (of course with a full-ART history and resistance testing with no contraindications to the substitution). To assess the patients at risk for developing diabetes, practitioners should ascertain the family history, patients’ weight, body mass index, comorbidities, and oral glucose tolerance test. It is also best practice to monitor fasting blood sugar at baseline, every three months then every six months. For patients who cannot be initiated or switched to other ARV medications because of history/resistance practitioners should encourage and discuss at lengths therapeutic lifestyle modifications LSM). Randomized studies have shown that aggressive LSM were more effective than metformin (Glucophage) in preventing the development f diabetes in patients with elevated fasting glucose. LSM that have been demonstrated to reduce the development and reverse diabetes are as follows:

  • Increasing physical activity to 30-60minutes at least 3 days per week
  • Calorie restrictions
  • Reducing daily carbohydrate intake
  • Reducing daily saturated fat intake
  • Reducing daily cholesterol intake

Once pharmacological options are necessary for a patient, metformin should be considered as first-line. Metformin has been studied in patients with HIV-infection and was effective, especially in patients with abdominal obesity. However, metformin should be used with caution as it may exacerbate lipoatrophy in some patients due to its side effect of weight loss. Thiazolidinediones may be combined with metformin if the patient does not reach goal on metformin alone or as first line if patient has significant lipoatrophy. In a study of HIV-infected patients with hyperinsulinemia and increased waist-hip ratio, combination with metformin and rosiglitazone was not more effective than either drug alone. Data for other antidiabetic dugs in HIV-infected patients is not well established to date.  Patients who do not reach goal on combination oral antidiabetics may advance to either insulin (Humulin, Novolog), exenatide (Byetta), sitagliptin (Januvia), or pranlintide (Symilin) as stepwise therapy options.

References

  1. Brown et al. Prevalence and incidence of pro-diabetes and diabetes in the Multicenter AIDS Cohort Study. Eleventh conference on retroviruses and opportunistic infection, San Francisco, 2004
  2. Highleyman. Diabetes and high glucose levels more common in HIV-positive men on HAART, aids map news. www.aidsmap.com 5 November 2008
  3. Lee, Walmsley, Fantus. New-onset diabetes mellitus associated with protease inhibitor therapy in an HIV-positive patient: a case report and review; Canadian Medical Association Journal, 327 July 1999
  4. Tebas. Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients. Pathogenesis, prevention and treatment options, Journal of AIDS, volume 49, September 2008
  5. Worm, Reiss, Prasier, Law, DeWit, Moller. Presence of the metabolic syndrome is not a better predictor of cardiovascular disease then e sum of it components in HIV-infected individuals. Diabetes Care Journal. 3 December 2008
  6. Yoon et al. Case-control study of diabetes mellitus in HIV-infected patients. Journal of AIDS 37;1464:1469, 2004

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