Statin Use and Diabetes Mellitus Among HIV Outpatients
Statin Use and Diabetes Mellitus Among HIV Outpatients
In our large and sociodemographically diverse cohort of aging HIV-infected patients, we found that each year of statin use was associated with 14% increase in the rate of incident DM. The rates of DM were also increased among older patients, Hispanic/Latino patients, those coinfected with hepatitis C at baseline, and those who were obese, the recognized epidemiologic risk factors for DM. By contrast, we did not detect an association between antiretroviral use history, including use of PIs, and incident DM, although such association has been suggested by some prior studies and of concern because of adverse effects on lipids of some PI agents.
The aging of HIV-infected individuals in the United States is the result of improved survival afforded by the use of increasingly less complex, better tolerated, and more effective combination antiretroviral therapies. In addition to aging of HIV-infected patients, prolonged exposure to chronic inflammation resulting from HIV infection, exposure to some antiretroviral medications that adversely affect lipids, and some behavioral risk factors (e.g., prevalent tobacco use) appear to contribute to increased rates of comorbidities among these patients, as compared with the general population. CVD is one such comorbidity, and current guidelines recommend obtaining fasting lipid panels before and during treatment with ART. Consequently, increasing numbers of HIV-infected patients are prescribed statins for primary prevention of CVD. Statin therapy has been shown to reduce incident myocardial infarctions in at-risk populations with or without previous cardiovascular events. Because CVD risk is higher in the HIV-infected population, strict attention to appropriate statin therapy is warranted.
DM has been found to be more frequent among HIV-infected patients than matched controls in some but not all studies. Our analysis did not include an HIV-uninfected comparison group, but studies to date point to the association between HIV infection and/or its treatments and higher rates of DM. Tien et al found that HIV infection was associated with doubling in incidence of DM in women participating in the Women's Interagency HIV Study (WIHS); older age, higher BMI, and family history of DM, but not Hispanic/Latino or black ethnicity, were other leading factors. Previously, Brown et al found that the rate of DM in HIV-infected Multicenter AIDS Cohort Study (MACS) participants with combination antiretroviral therapy (cART) exposure was 4 times as high as that of HIV-seronegative MACS participants, whereas HIV-infected participants who were not prescribed cART had DM rates similar to those of HIV-negative controls, which appeared in part explained by the increased risk for DM with the use of ritonavir-containing cART in this study. By contrast, Butt et al found that after adjustment for known risk factors, HIV-infected veterans had a lower risk of diabetes (odds ratio: 0.84, 95% CI: 0.72 to 0.97), whereas hepatitis C virus coinfection and exposure to nucleoside and non-nucleoside reverse transcriptase inhibitors were associated with higher risk for DM. Hepatitis C has been associated with incident diabetes in other studies, as well.
In prior analyses of data from 2 CDC-funded HIV cohorts (2003–2006), we found that among HIV-infected women prescribed cART, over 10% in total and over 20% of Hispanics/Latinos had prevalent DM. Traditional risk factors such as older age, Hispanic/Latino race/ethnicity, obesity, hepatitis C virus infection, and to a lesser extent, cumulative PI use were associated with DM in these HIV-infected women. PI use may reflect the effects of both cART-associated "return to health" and PI-associated metabolic toxicities. In analyses standardized for demographics, HIV-infected women were more likely to have hyperglycemia and less likely to be obese than counterparts as captured in the National Health and Nutrition Examination Survey.
The finding in our HIV-infected cohort of a 14% increase (95% CI: 2 to 28) in the rate of incident DM per year of statin use is on par with the estimates from the general population. Sattar et al conducted a large meta-analysis of statin use and incident DM and found that the odds of incident DM over a mean period of 4 years were 9% higher in patients prescribed statins compared with those not prescribed statins (odds ratio: 1.09, 95% CI: 1.02 to 1.17), which was also the finding from another meta-analysis by Mills et al including some of the same studies (odds ratio: 1.09, 95% CI: 1.02 to 1.16). We also found associations of incident DM with the previously documented risk factors in the general population: older age, Hispanic/Latino race/ethnicity, prevalent hepatitis C coinfection, and higher BMI. Culver et al found a negative association with increasing BMI in HIV-uninfected postmenopausal women. Other studies have demonstrated a higher risk of incident DM in specific populations such as the elderly, postmenopausal women, and Asians. Incident DM has also been associated with higher statin dose, the degree of lowering of low-density lipoprotein cholesterol levels, and use of specific statins. We found that the risk of incident DM in our study was comparable or possibly slightly higher than the risk seen in studies in the general population, suggesting that HIV-infected individuals treated with statins are at modestly increased risk for incident DM. The biological mechanisms underlying the relationship between statin use and incident diabetes observed in this and other cohorts are not yet well understood.
There are several limitations to our observational study. We analyzed data abstracted from medical charts that were obtained in the course of routine HIV care. Not all patients had regular glucose measurements, which might result in underdiagnosis of DM. However, the frequency of glucose monitoring was not statistically higher for patients when they were being prescribed statins vs. not (data not shown), so the association between statin use and increased rate of DM is unlikely to result from surveillance bias. We cannot rule out that residual bias persisted because patients placed on statins may have been at higher risk for CVD and possibly at higher risk for DM, but we attempted to account for potential confounding by indication through a propensity score adjustment. The relatively small size of our study population and incident DM outcomes was another limitation. The relatively small size of our study population and incident DM outcomes (n=355) was another limitation. DM prevalence in the HOPS was previously estimated at 19.3% for women and 12.2% for men with at least 6 months of antiretroviral medication exposure. Because of sample size constraints, we did not have sufficient statistical power to examine different statins and statin doses and their relative associations with incident DM, including a potential dose–response relationship.
In summary, consistent with prior meta-analyses, the association between statin use and incident DM for HIV-infected patients was similar in magnitude to that found in the general population. The benefits of statin therapy outweigh the risk of incident DM in the primary prevention of CVD in non–HIV-infected adults, and statin use should be indicated by the guidelines for CVD prevention until further studies suggest otherwise. Likewise, patients should be monitored for glucose intolerance consistent with the guidelines recommended for the general population when receiving statin therapy and treated per standard of care if glucose intolerance arises.
Discussion
In our large and sociodemographically diverse cohort of aging HIV-infected patients, we found that each year of statin use was associated with 14% increase in the rate of incident DM. The rates of DM were also increased among older patients, Hispanic/Latino patients, those coinfected with hepatitis C at baseline, and those who were obese, the recognized epidemiologic risk factors for DM. By contrast, we did not detect an association between antiretroviral use history, including use of PIs, and incident DM, although such association has been suggested by some prior studies and of concern because of adverse effects on lipids of some PI agents.
The aging of HIV-infected individuals in the United States is the result of improved survival afforded by the use of increasingly less complex, better tolerated, and more effective combination antiretroviral therapies. In addition to aging of HIV-infected patients, prolonged exposure to chronic inflammation resulting from HIV infection, exposure to some antiretroviral medications that adversely affect lipids, and some behavioral risk factors (e.g., prevalent tobacco use) appear to contribute to increased rates of comorbidities among these patients, as compared with the general population. CVD is one such comorbidity, and current guidelines recommend obtaining fasting lipid panels before and during treatment with ART. Consequently, increasing numbers of HIV-infected patients are prescribed statins for primary prevention of CVD. Statin therapy has been shown to reduce incident myocardial infarctions in at-risk populations with or without previous cardiovascular events. Because CVD risk is higher in the HIV-infected population, strict attention to appropriate statin therapy is warranted.
DM has been found to be more frequent among HIV-infected patients than matched controls in some but not all studies. Our analysis did not include an HIV-uninfected comparison group, but studies to date point to the association between HIV infection and/or its treatments and higher rates of DM. Tien et al found that HIV infection was associated with doubling in incidence of DM in women participating in the Women's Interagency HIV Study (WIHS); older age, higher BMI, and family history of DM, but not Hispanic/Latino or black ethnicity, were other leading factors. Previously, Brown et al found that the rate of DM in HIV-infected Multicenter AIDS Cohort Study (MACS) participants with combination antiretroviral therapy (cART) exposure was 4 times as high as that of HIV-seronegative MACS participants, whereas HIV-infected participants who were not prescribed cART had DM rates similar to those of HIV-negative controls, which appeared in part explained by the increased risk for DM with the use of ritonavir-containing cART in this study. By contrast, Butt et al found that after adjustment for known risk factors, HIV-infected veterans had a lower risk of diabetes (odds ratio: 0.84, 95% CI: 0.72 to 0.97), whereas hepatitis C virus coinfection and exposure to nucleoside and non-nucleoside reverse transcriptase inhibitors were associated with higher risk for DM. Hepatitis C has been associated with incident diabetes in other studies, as well.
In prior analyses of data from 2 CDC-funded HIV cohorts (2003–2006), we found that among HIV-infected women prescribed cART, over 10% in total and over 20% of Hispanics/Latinos had prevalent DM. Traditional risk factors such as older age, Hispanic/Latino race/ethnicity, obesity, hepatitis C virus infection, and to a lesser extent, cumulative PI use were associated with DM in these HIV-infected women. PI use may reflect the effects of both cART-associated "return to health" and PI-associated metabolic toxicities. In analyses standardized for demographics, HIV-infected women were more likely to have hyperglycemia and less likely to be obese than counterparts as captured in the National Health and Nutrition Examination Survey.
The finding in our HIV-infected cohort of a 14% increase (95% CI: 2 to 28) in the rate of incident DM per year of statin use is on par with the estimates from the general population. Sattar et al conducted a large meta-analysis of statin use and incident DM and found that the odds of incident DM over a mean period of 4 years were 9% higher in patients prescribed statins compared with those not prescribed statins (odds ratio: 1.09, 95% CI: 1.02 to 1.17), which was also the finding from another meta-analysis by Mills et al including some of the same studies (odds ratio: 1.09, 95% CI: 1.02 to 1.16). We also found associations of incident DM with the previously documented risk factors in the general population: older age, Hispanic/Latino race/ethnicity, prevalent hepatitis C coinfection, and higher BMI. Culver et al found a negative association with increasing BMI in HIV-uninfected postmenopausal women. Other studies have demonstrated a higher risk of incident DM in specific populations such as the elderly, postmenopausal women, and Asians. Incident DM has also been associated with higher statin dose, the degree of lowering of low-density lipoprotein cholesterol levels, and use of specific statins. We found that the risk of incident DM in our study was comparable or possibly slightly higher than the risk seen in studies in the general population, suggesting that HIV-infected individuals treated with statins are at modestly increased risk for incident DM. The biological mechanisms underlying the relationship between statin use and incident diabetes observed in this and other cohorts are not yet well understood.
There are several limitations to our observational study. We analyzed data abstracted from medical charts that were obtained in the course of routine HIV care. Not all patients had regular glucose measurements, which might result in underdiagnosis of DM. However, the frequency of glucose monitoring was not statistically higher for patients when they were being prescribed statins vs. not (data not shown), so the association between statin use and increased rate of DM is unlikely to result from surveillance bias. We cannot rule out that residual bias persisted because patients placed on statins may have been at higher risk for CVD and possibly at higher risk for DM, but we attempted to account for potential confounding by indication through a propensity score adjustment. The relatively small size of our study population and incident DM outcomes was another limitation. The relatively small size of our study population and incident DM outcomes (n=355) was another limitation. DM prevalence in the HOPS was previously estimated at 19.3% for women and 12.2% for men with at least 6 months of antiretroviral medication exposure. Because of sample size constraints, we did not have sufficient statistical power to examine different statins and statin doses and their relative associations with incident DM, including a potential dose–response relationship.
In summary, consistent with prior meta-analyses, the association between statin use and incident DM for HIV-infected patients was similar in magnitude to that found in the general population. The benefits of statin therapy outweigh the risk of incident DM in the primary prevention of CVD in non–HIV-infected adults, and statin use should be indicated by the guidelines for CVD prevention until further studies suggest otherwise. Likewise, patients should be monitored for glucose intolerance consistent with the guidelines recommended for the general population when receiving statin therapy and treated per standard of care if glucose intolerance arises.
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