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Nukes and diabetes—is there a link?

In Canada and other high-income countries, the widespread availability of highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in AIDS-related deaths. However, HIV therapy is associated with side effects, many of which were not expected when HAART first became available.

For instance, a group of drugs called thymidine analogues, such as d4T (Zerit, stavudine) and AZT (Retrovir, zidovudine), has been linked to the disappearance of the fatty layer just under the skin (subcutaneous fat).

Another group of drugs called protease inhibitors is generally associated with increased levels of lipids (fatty substances)—cholesterol and triglycerides— in the blood. If left untreated, this increase in lipids leads to a heightened risk for cardiovascular disease.

Now researchers involved with a very large database called DAD suggest that the use of d4T or AZT is associated with an increased risk of diabetes. However, there are some issues with DAD that make drawing firm conclusions problematic. These issues are explored further in this report.

Study details

The study team analysed health-related information collected from clinics mostly in Europe but also from the United States, Australia and Argentina. At the time participants entered the study their average profile was as follows:

26% female, 74% male
age – 38 years
34% were smoking tobacco
CD4+ count – 410 cells
24% had previously experienced a life-threatening infection

The study team focused on the time between April 2001 and January 2005.

Results—focus on fat

At the start of the study, 952 out of a total of 32,437 participants had diabetes. Over the course of the study, 742 more participants (3%) developed diabetes.

Taking into account many possible factors, the study team found that the following had an impact on the development of diabetes:

total cholesterol: an increase of 1 mmol/L raised the risk of diabetes by 9%
triglycerides: a doubling of triglyceride levels increased the risk of diabetes by 81%
an increase in body fat content was associated with a 57% increase in the risk of diabetes
a decrease in body fat content was associated with a 28% increase in the risk of diabetes

These changes in body fat are likely related to the HIV lipodystrophy syndrome. In people with lipodystrophy, some parts of the body, such as the belly and breasts (in women) gain fat while other parts, such as the limbs and face, lose fat. In HIV negative people, changes in body fat content can increase the risk of diabetes, so it is not surprising that a link between changes in body fat in the DAD study were also associated with an increased risk of diabetes.

Results—treatment

For each year of d4T use, the risk of diabetes increased by 20%. The drugs AZT and ddI (Videx EC, didanosine) were also associated with a heightened risk of developing diabetes (but lesser so than the risk with d4T).

Results—other factors

In addition to the factors mentioned above, the study team also found that several other risk factors were linked to developing diabetes in the DAD study, as follows:

older age
being male
being overweight or obese
being heterosexual
being a person of colour

Nukes and diabetes

Insulin is a hormone produced by the pancreas gland. Insulin helps move sugar (glucose) from the blood into cells where it can be burned as a source of energy. It is possible that d4T and other nukes might trigger insulin resistance, a condition whereby cells grow increasingly insensitive to the effects of insulin. The body tries to compensate for this by producing ever-increasing amounts of insulin but eventually the pancreas becomes exhausted and diabetes develops. Researchers are not sure exactly how d4T might cause insulin resistance, but they suspect that it damages the energy-producing parts of cells (mitochondria), causing them to malfunction.

A large randomized trial has confirmed that d4T and ddI are associated with the development of insulin resistance in HIV positive people. Results from a small study suggest that AZT may also cause similar problems. The good news is that two commonly used nukes—abacavir (Ziagen and in Kivexa and Trizivir) and tenofovir (Viread and in Truvada and Atripla) —are not linked to insulin resistance.

Protease inhibitors and diabetes

Experiments with cells, animals and people suggest that exposure to the protease inhibitor ritonavir (Norvir and in Kaletra) increases the risk of insulin resistance. Yet the DAD researchers found that exposure to ritonavir in their study was linked to a reduced risk for diabetes. How their study found such a link is puzzling. Concerned by this finding, the DAD team noted that this result about ritonavir “should be viewed cautiously.”

Non-nukes and diabetes

The DAD analysis suggests that use of the non-nuke nevirapine (Viramune) is associated with a reduced risk of developing diabetes.

Points to consider

In addition to the findings mentioned above, there are some important issues brought about by the way DAD conducted its data-capture and analysis that readers may wish to note. Here are some of these points:

Design flaw

Perhaps the most important point is this: DAD was an observational study. Such studies can find associations. However, because they are not randomized, observational studies cannot entirely rule out the possibility of bias when interpreting their findings. Therefore, the DAD study cannot be certain about its findings.

Missing in action

While the DAD researchers tried to collect as much data as possible, their analysis may have been affected by the lack of important information. For instance, there appears to be little or no information, certainly in the published paper, about participants with close family members who had a history of diabetes. At least one other study of HIV positive people found that participants who had family members with diabetes were themselves at high risk for developing this complication.

Still useful

Perhaps the good news from the DAD study is that the proportion of participants who developed diabetes after starting treatment was small—only 2%. Another useful outcome of the DAD study is that it may remind both physicians and HIV positive people that diabetes is a potential complication. Therefore, regular monitoring of fasting blood samples for glucose levels is important.

Developing good dietary habits is equally important (eating more fibre, whole grains and colourful fruit and vegetables, and much less food containing refined flour and sugar). This can be done with advice from a nutritionist or dietician. Regular exercise is also helpful for reducing weight and staying healthy.

For tips about healthy eating, see the Spring 2008 issue of The Positive Side at:

http://www.positiveside.ca/e/V10I1/Conquerthekitchen_e.htm

All about diabetes

For more information about diabetes and how to prevent, manage and live with it, visit this link:

http://www.diabetes.ca/section_about/index.asp

—Sean R. Hosein

REFERENCES:

Fleischman A, Johnsen S, Systrom DM, et al. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. American Journal of Physiology. Endocrinology and Metabolism. 2007 Jun;292(6):E1666-73
Blümer RM, van Vonderen MG, Sutinen J, et al. Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy. AIDS. 2008 Jan 11;22(2):227-36.
Carper MJ, Cade WT, Cam M, et al. HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus. American journal of physiology. Endocrinology and metabolism. 2008 Mar;294(3):E558-67.
Hruz PW, Yan Q, Struthers H, et al. HIV protease inhibitors that block GLUT4 precipitate acute, decompensated heart failure in a mouse model of dilated cardiomyopathy. FASEB J. 2008; in press.
Caumo A, Guffanti M, Perseghin G, et al. Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity. AIDS. 2007 Nov 12;21(17):2366-7.
Blass SC, Ellinger S, Vogel M, et al. Overweight HIV Patients with Abdominal Fat Distribution Treated with Protease Inhibitors are at High Risk for Abnormalities in Glucose Metabolism - A Reason for Glycemic Control. European Journal of Medical Research. 2008 May 26;13(5):209-14.
De Wit S, Sabin CA, Weber R, et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care. 2008 Jun;31(6):1224-9.
Dagogo-Jack S. HIV therapy and diabetes risk. Diabetes Care. 2008 Jun;31(6):1267-8.

Created on: 07/14/2008

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