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Do Plentiful Diabetes Risk Factors Include HIV?

June 19, 2015

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The Milan investigators took a snapshot of diabetes prevalence in their study populations in 2008.10 A Danish study of similar size had the advantage of tracking diabetes incidence through more than a decade, from 1996 through 2010, in people with HIV and the general population.19 Denmark provides a unique platform for HIV research because everyone diagnosed with HIV in this country of 5.6 million people receives care at one of eight government HIV centers and gets tracked in a national database. The country also keeps detailed health records of the entire population that facilitate comparisons of HIV-positive and negative people.

For the diabetes study, researchers identified 4984 Danish-born people with HIV and matched them by age and gender to 19,936 people in the general population.19 Median age in the two groups stood at 38.7, 84% were men, and 97.5% were white. Through 8 years of follow-up in the HIV group and 11.2 years in the comparison group, incidence of type 2 diabetes measured 2.7% in people with HIV and 3.6% in the control group.

From 1996 through 1998, the early years of combination ART, diabetes incidence proved significantly higher in people with HIV both before they started ART (adjusted incidence rate ratio [aIRR] 2.40, 95% CI 1.03 to 5.62) and after they started therapy (aIRR 3.24, 95% CI 1.42 to 7.39). From 1999 through 2010, diabetes incidence was 55% lower in the HIV group before ART began (aIRR 0.45, 95% CI 0.21 to 0.96) and equivalent in the two groups after HIV-positive people started ART (aIRR 1.00, 95% CI 0.79 to 1.28).

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Thus the Danish team discerned a marked shift in diabetes risk among HIV-positive people relative to the general population starting in 1999.19 What happened? One factor must be dwindling prescriptions of antiretrovirals that bollix glucose metabolism. This study also linked heightened diabetes risk to stavudine, didanosine, indinavir, and saquinavir. But that can't be the whole story because diabetes risk was higher in HIV-positive people before 1999 even if they had not started antiretrovirals. The Danish investigators noted that a large DAD analysis of HIV-positive people charted waning diabetes risk as combination ART got safer (1999-2006).24 (The DAD study also implicated stavudine and didanosine -- as well as zidovudine -- in diabetes risk.)

The Danish researchers suggested that in these earlier years people with HIV were generally sicker than in later years and so perhaps more prone to metabolic upheavals.19 At the same time they got treated with toxic nucleoside monotherapy and with diabetogenic drugs like pentamidine. They could have also mentioned corticosteroids, thiazides, statins, certain antipsychotics, niacin, and megestrol acetate -- and among illicit drugs, opiates. The lower diabetes risk with than without HIV starting in 1999, the authors noted, could partly reflect lower obesity prevalence documented in the HIV-positive Danish population than in the general population, a finding mirrored in the United States.8

HIV did not emerge as a new-onset diabetes risk factor in a comparison of 222 HIV-positive and 155 HIV-negative but at-risk people in the Bronx, New York, with diabetes rates of 5% in the HIV group and 8% in the comparison group.22 New-onset diabetes or prediabetes combined proved significantly less likely with than without HIV (15% versus 26%, P = 0.038).

A 2006 WIHS analysis of 1524 women with HIV and 564 at risk for HIV infection found a new-onset diabetes rate of 1.96 per 100 person-years in HIV-negative women, slightly but nonsignificantly more than the 1.53 per 100 person-years in HIV-positive women without recent antiretroviral therapy and slightly but nonsignificantly less than in women taking a PI regimen (2.50 per 100) or women taking a non-PI regimen (2.89 per 100).20

A comparison of 6816 HIV-positive adults in South Carolina matched by age, race, gender, and total months of enrollment to 6816 HIV-negative Medicaid recipients also discovered differing diabetes risks with and without HIV depending on whether the HIV group was taking antiretroviral therapy.21 This analysis of people in care at some point from January 1994 through December 2011 found that antiretroviral-naive people with HIV did not differ from the HIV-negative group in diabetes incidence (aHR 0.82, 95% CI 0.63 to 1.07). But people taking combination antiretroviral therapy had a 45% lower risk of new-onset diabetes than did HIV-negative controls (aHR 0.55, 95% CI 0.46 to 0.65).

Finally, analysis of diabetes prevalence in 3227 HIV-positive and 3240 HIV-negative members of the Veterans Aging Cohort Study (VACS) in care after 2002 found a significantly lower diabetes rate in the HIV group (14.9% versus 21.4%, P < 0.0001).23 Logistic regression analysis adjusted for pertinent risk factors determined that veterans with HIV had 16% lower odds of prevalent diabetes (aOR 0.84, 95% CI 0.72 to 0.97). Most of this difference reflected lower BMI in the HIV group (43.5% with HIV overweight or obese versus 48% without HIV). Within the HIV group, however, overweight doubled the odds of prevalent diabetes (aOR 2.02, 95% CI 1.30 to 3.13) and obesity quadrupled the odds (aOR 4.10, 95% CI 2.57 to 6.53).

Together these findings suggest that in most populations studied, people with HIV run an equivalent or lower risk of diabetes than comparable cohorts without HIV -- perhaps because HIV groups (especially those dominated by men) tend to be leaner than their general-population counterparts, and perhaps because more routine care and monitoring of people with HIV catches rising glucose early and lets clinicians reverse or at least stall the surge. As awareness of glucose abnormalities in people with HIV grew, keener monitoring probably grew apace. Among people with HIV, though, greater weight certainly boosts diabetes risk, as discussed above9,10 and confirmed in other studies.19,21,23,25 At the same time, Todd Brown argues in this interview, "HIV patients have several diabetes risk factors that HIV-uninfected patients don't have," and people with multiple classical risk factors "may be at higher risk for diabetes." Brown also notes that HIV-positive people with an undetectable viral load have residual inflammation, which can contribute to diabetes risk.


Ten Nobel Prizes for Research on Diabetes
Nobel Prize

In an article on diabetes history, the University of Chicago's Kenneth Polonsky notes that 10 Nobel Prizes have gone to scientists working on some aspect of diabetes:

  • 1923: Frederick G. Banting, John J.R. Macleod: Discovery of insulin
  • 1947: Carl F. Cori, Gerty T. Cori: Course of catalytic conversion of glycogen
  • 1947: Bernardo A. Houssay: Role of hormones released by anterior pituitary lobe in sugar metabolism
  • 1958: Frederick Sanger: Structure of proteins, especially insulin
  • 1971: Earl W. Sutherland: Mechanisms of action of hormones
  • 1977: Rosalyn Yalow: Radioimmunoassays for peptide hormones
  • 1992: Edmond H. Fischer, Edwin G. Krebs: Reversible protein phosphorylation as biologic regulatory mechanism

Source: Polonsky KS. The past 200 years in diabetes. N Engl J Med. 2012;367:1332-1340.


Risk With Antiretrovirals and Other Drugs

The 2014 edition of HRSA guidelines for HIV care do not count HIV infection as a diabetes risk factor.1 They do stress that rarely used antiretrovirals -- indinavir and stavudine -- induced insulin resistance in short-term studies of healthy volunteers and that other antiretrovirals "also perturb glucose metabolism."1 The 1994-2011 population-based comparison of people with and without HIV in South Carolina found a similar new-onset diabetes risk in antiretroviral-naive people and the HIV-negative group, a lower diabetes risk in antiretroviral-treated people with HIV than in the HIV-negative group, but a one third higher risk with cumulative PI use than in people without HIV (aHR 1.35, 95% CI 1.03 to 1.78).21

The latest (2013) Infectious Diseases Society of America HIV guidelines say "previously reported adverse effects" of antiretroviral therapy -- including diabetes -- "are much less frequent with the use of the newer agents,"27 an opinion endorsed by Todd Brown in the interview. Indeed, a 4-week placebo-controlled trial of atazanavir or lopinavir/ritonavir in healthy HIV-negative adults found that neither affected insulin sensitivity.28 And a 48-week comparison of first-line atazanavir/ritonavir and darunavir/ritonavir found no clinically relevant differences between these PIs in fasting glucose or insulin sensitivity.29 But lopinavir/ritonavir prescribing information warns that people taking these PIs may experience new-onset or worsening diabetes mellitus. And in a recent review article, Brown and two colleagues suggest the only antiretrovirals clinicians may want to switch to manage glucose upsets are lopinavir/ritonavir, stavudine, and zidovudine.30 In light of findings on currently preferred PIs, it may be time for HSRA HIV guidelines to reconsider the blanket caveat that PIs raise diabetes risk.1

Two studies in people with HIV have linked efavirenz to abnormal glucose,31,32 although the impact was small (4 mg/dL).31 In the Veterans Aging Cohort Study, every year of nonnucleoside therapy hoisted diabetes risk 9%.23 But a 33,389-person DAD Study analysis linked nevirapine use to lower risk of new diabetes.24 Prescribing information for rilpivirine, the newest nonnucleoside, does not mention insulin resistance, glucose, or diabetes.

As for current nucleosides/nucleotides, tenofovir did not affect insulin sensitivity in HIV-negative volunteers.33 Prescribing information for coformulated tenofovir/emtricitabine (Truvada) includes no warnings on insulin resistance, glucose abnormalities, or diabetes mellitus. Elevated blood glucose is listed as a lab abnormality seen in people taking abacavir in clinical trials. But neither insulin resistance nor diabetes appears in prescribing information as an abacavir or abacavir/lamivudine (Epzicom) side effect. Alone among diabetes risk studies, a 2000-2006 WIHS analysis linked more than 1 year of lamivudine therapy to an almost tripled risk of diabetes, while finding no such association for stavudine, zidovudine, or abacavir.20 Since this study also tied cumulative nucleoside use to higher diabetes risk, longer lamivudine use could be a surrogate for longer nucleoside use.

Prescribing information for three licensed integrase inhibitors -- dolutegravir, elvitegravir, and raltegravir -- does not list insulin resistance, glucose abnormalities, or diabetes mellitus as side effects.

Research links several non-HIV drugs to glucose abnormalities, including corticosteroids, thiazides, statins, atypical antipsychotics, niacin, and illicit opiates. Because of their wide use in people with HIV, statins deserve special attention, but research so far has yielded mixed results on how these anti-lipid agents affect diabetes risk. HIV/diabetes mavens Anne Monroe, Marshall Glesby, and Todd Brown note that statins can increase insulin resistance.30 But "given the cardiovascular event reduction benefit from statins," they suggest, "increases in insulin resistance/diabetes mellitus likely do not outweigh the benefit of statin therapy in the general population or in HIV-infected patients."30

Opiate use boosted diabetes incidence in a study of 1713 HIV-positive women and 652 HIV-negative women in the Women's Interagency HIV Study.34 In an analysis adjusted for HCV infection, HIV status, antiretroviral status, and classic diabetes risk factors, current opiate use raised the risk of new-onset diabetes about 60% (aRH 1.61, 95% CI 1.02 to 2.52).

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This article was provided by The Center for AIDS Information & Advocacy. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.
 

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