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Is diabetes prevalence higher among HIV-infected individuals compared
with the general population? Evidence from MMP and NHANES 2009-2010
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Jan 2017 BMC
We presented the first nationally representative estimate of DM prevalence among HIV-infected adults receiving medical care in the USA in 2009-2010 where 1 in 10 HIV-infected adults had a diagnosis of DM. Although obesity is a risk factor for prevalent DM among HIV-infected adults, when compared with the general US adult population, HIV-infected adults may have higher DM prevalence at younger ages and in the absence of obesity. Healthcare providers caring for HIV-infected patients should follow existing DM screening guidelines. Given the large burden of DM among HIV-infected adults, additional research would help to determine whether DM screening guidelines should be modified to include HIV infection as a risk factor for DM and to identify optimal management strategies in this population.
Taken together, our results highlight the need for more nuanced measures of chronic inflammation present in HIV infection and their interaction with traditional risk factors such as obesity.
Beyond the effect of ART on insulin resistance and development of DM, chronic inflammation during HIV infection may accelerate the development of comorbid conditions such as DM.32 Although this chronic inflammatory state may explain the development of DM among HIV-infected adults at younger ages and among the non-obese, there is a continued need for research assessing other important risk factors for DM among HIV-infected individuals, including diet and exercise, as well as a deeper understanding of insulin and glucose homeostasis in the setting of HIV infection.
The aPD [adjusted prevalence difference] of DM between HIV-infected adults and the general US adult population was heterogeneous by subpopulation. HIV-infected women had a 5% higher prevalence than their counterparts in the general population, an effect that was independent of obesity. There is evidence that the use of ART may increase conversion to DM among women with high-risk genetic polymorphisms;33 however, sex-specific differences in insulin resistance, particularly the role of sex hormones in the setting of HIV infection, remain understudied.
Time since HIV diagnosis was significantly associated with a higher DM prevalenceT...it may serve as a proxy for older age, exposure to chronic inflammation due to HIV infection, as well as cumulative exposure to ART, all of which have been linked to insulin resistance.24 ,26-30....Similar to previous studies, we observed a strong association between both increasing age and obesity and prevalent DM among HIV-infected individuals...suggesting that these traditional risk factors play a major role in the development of DM among HIV-infected adults. Despite evidence suggesting a link between ART and DM, ART prescription in the past year was not associated with prevalent DM in our study...This may be due to our inability to assess cumulative exposure to ART in MMP. The ARTs indinavir, zidovudine, saquinavir, stavudine, and didanosine have been associated with a higher prevalence of DM;9 ,24 ,25 only a small percentage of HIV-infected adults in MMP were currently prescribed these agents (0.4% indinavir, 11.2% zidovudine, 1.0% saquinavir, 1.2% stavudine, and 2.4% didanosine), which may also account for the null association between ART exposure and DM...Another surrogate marker for systemic inflammation, CD4 count nadir, was not associated with increased prevalence of DM after adjusting for other covariates.
Finally, although HCV has been described as a risk factor for DM in the general population, our findings indicate that HIV may compound the deleterious effects of HCV, putting HIV/HCV coinfected individuals at even higher risk of DM.34 Observed differences could be due to a lower engagement in medical care by HCV-infected adults in the general population and suboptimal screening practices.35Nevertheless, this finding is particularly relevant, given the availability of directly acting antiviral agents as curative HCV therapy and highlights a potential additional benefit of HCV treatment for coinfected patients.36
The unadjusted prevalence of DM (CI) among HIV-infected adults was 10.3% (9.1% to 11.5%), and was higher compared with the general US adult population (8.3% (7.2% to 9.4%)) as well as the general US adult population having received care in the previous 12 months (9.7% (8.4% to 11.1%)) (data not shown). Among HIV-infected adults with diagnosed DM, 3.9% (95% CI 2.9% to 5.2%) had DM type 1, 52.3% (CI 46.7% to 57.8%) had DM type 2, and 43.9% (CI 38.1% to 49.8%) had unspecified DM. After adjusting for differences in distributions of sex, age, race/ethnicity, education, poverty, obesity, and HCV infection prevalence, the adjusted PD (aPD) of DM in HIV-infected adults versus the general US adult population was 3.8% (table 2) [11.8 vs 8.0, among whites 11.4 vs 6.5, among blacks 13.1 vs 11.8]. The largest difference in DM prevalence among HIV-infected adults relative to their counterparts in the general US adult population occurred among those with HCV infection (6.3%), those with a high school or equivalent education (5.1%), women (5.0%), non-Hispanics whites (4.9%), individuals living at or below the poverty line (4.6%), obese individuals (4.4%) and ages 20-44 years (4.1%). After restricting the NHANES population to adults who had received care in the previous 12 months, associations were similar to those described above with a slight decrease in the magnitude of DM PD (table 3).
Among HIV-infected adults, DM prevalence varied by selected characteristics (table 4). The adjusted DM prevalence was lowest among those aged 20-44 years (6.7%) and highest among those aged ≥60 years (19.6%), and obese (18.9%) (table 4). Factors independently associated with total DM among HIV-infected adults included increasing age, obesity, increasing time since HIV diagnosis, and geometric mean CD4.
In table 3 among non-obese HIV+ diabetes adjusted prevalence was 8.1 vs 5.14 among general population. Among HCV Pos + HIV+ 14.0 vs 8.22 in general population, among those >60 22.2 in HIV+ vs 20.54 in general population.
Based on our findings, as well as current literature regarding DM among HIV-infected individuals, there are several important implications. First, HIV-care providers should follow existing DM screening guidelines, which recommend FBG and HbA1c be obtained prior to and after starting ART.37 Second, existing data from prospective studies should be examined to determine if screening guidelines should be modified, given the increased prevalence of DM among younger and non-obese HIV-infected persons. Third, improved tests for DM diagnosis and monitoring among HIV-infected persons should be explored, given studies that have demonstrated the diagnostic limitations of HbA1c in this population.10 ,14 ,15 Finally, additional research will be important to identify optimal DM management strategies among HIV-infected persons as traditional strategies to improve insulin sensitivity such as weight loss and diabetic medical therapy have been shown to be less effective among HIV-infected individuals.38 ,39
Measures
The primary outcome variable was DM. In MMP, DM was defined using the following criteria documented in the medical record: (1) physician-diagnosed DM listed on a problem list or in the assessment/plan portion of a progress note; or (2) prescription of insulin or oral hypoglycemic medications (excluding metformin monotherapy). In NHANES, DM was defined using the following criteria: (1) answered 'Yes' to the question: 'Other than during pregnancy, have you ever been told by a doctor or health professional that you have diabetes or sugar diabetes?'; or (2) answered 'Yes' to any of the following questions: (a) 'Are you now taking insulin?'; or (b) 'Are you now taking diabetic pills to lower your blood sugar? These are sometimes called oral agents and oral hypoglycemic agents'. Prescription medication data available in NHANES were used to exclude individuals treated with metformin monotherapy who had responded 'Yes' to question 2b. Exclusion of patients on metformin monotherapy who were not classified as having DM in MMP or answered 'No' to question 1 in NHANES were excluded due to the use of this medication for pre-diabetes and polycystic ovarian syndrome. Laboratory criteria to establish the diagnosis of DM were available for MMP and NHANES; however, they were not used because the fasting nature of blood glucose measurements from laboratory data abstracted from medical charts was unknown, and HbA1c measurements have not been validated for the diagnosis of DM among HIV-infected individuals.10 ,14 ,15 Our analyses of DM prevalence were therefore restricted to comparisons of diagnosed DM, as described above.
Discussion
Among a nationally representative US sample of HIV-infected adults receiving medical care in 2009 and 2010, the DM prevalence was 10.3%; increasing age, obesity, longer duration of HIV infection, and geometric mean CD4 were independently associated with a higher DM prevalence. When compared with the general US adult population, HIV-infected individuals had a 3.8% higher prevalence of DM after adjusting for age, sex, race/ethnicity, education, poverty-level, obesity, and HCV infection. This analysis provides the first nationally representative estimate of DM burden among HIV-infected adults and suggests that HIV-infected persons may be more likely to have DM at younger ages and in the absence of obesity compared with the general US adult population.
Our estimates of DM prevalence among HIV-infected adults are lower compared with previous US studies. The Multicenter AIDS Cohort Study reported 14% DM prevalence among 411 men who have sex with men recruited from 1999 to 2003.8 The Veterans Aging Cohort Study Virtual Cohort observed a similar baseline prevalence (14%) in a cohort of 27 350 HIV-infected veterans recruited from 2003 to 2009.23 These differences may reflect the burden of undiagnosed diabetes measured with fasting blood glucose and HbA1c. The HIV Outpatient Study (HOPS) reported a higher DM prevalence among HIV-infected women (19%) compared with HIV-infected men (12%), a finding that although not statistically significant was observed in our sample.24 Conversely, DM prevalence among HIV-infected individuals in non-US cohorts is significantly lower than our estimate, ranging from 2.7% to 3.3%.9 ,25 ,26
Similar to previous studies, we observed a strong association between both increasing age and obesity and prevalent DM among HIV-infected individuals,8 ,10 ,11 ,24 ,26 ,27 suggesting that these traditional risk factors play a major role in the development of DM among HIV-infected adults. Despite evidence suggesting a link between ART and DM, ART prescription in the past year was not associated with prevalent DM in our study.9 ,24 ,26 This may be due to our inability to assess cumulative exposure to ART in MMP. The ARTs indinavir, zidovudine, saquinavir, stavudine, and didanosine have been associated with a higher prevalence of DM;9 ,24 ,25 only a small percentage of HIV-infected adults in MMP were currently prescribed these agents (0.4% indinavir, 11.2% zidovudine, 1.0% saquinavir, 1.2% stavudine, and 2.4% didanosine), which may also account for the null association between ART exposure and DM. Time since HIV diagnosis was significantly associated with a higher DM prevalence. Although the exact mechanistic pathways measured by this variable are hard to elucidate, it may serve as a proxy for older age, exposure to chronic inflammation due to HIV infection, as well as cumulative exposure to ART, all of which have been linked to insulin resistance.24 ,26-30 Another surrogate marker for systemic inflammation, CD4 count nadir, was not associated with increased prevalence of DM after adjusting for other covariates. This is contrary to previous studies which have linked CD4+ nadir <200 cells/μL with increased levels of interleukin 6, high-sensitivity C reactive protein, and soluble tumor necrosis receptors.26 ,31 ,32 In addition, geometric mean CD4 count was associated with a higher prevalence of DM in our sample; however, the lack of clear directionality makes it hard to interpret. Taken together, our results highlight the need for more nuanced measures of chronic inflammation present in HIV infection and their interaction with traditional risk factors such as obesity.
The aPD of DM between HIV-infected adults and the general US adult population was heterogeneous by subpopulation. HIV-infected women had a 5% higher prevalence than their counterparts in the general population, an effect that was independent of obesity. There is evidence that the use of ART may increase conversion to DM among women with high-risk genetic polymorphisms;33 however, sex-specific differences in insulin resistance, particularly the role of sex hormones in the setting of HIV infection, remain understudied. Beyond the effect of ART on insulin resistance and development of DM, chronic inflammation during HIV infection may accelerate the development of comorbid conditions such as DM.32 Although this chronic inflammatory state may explain the development of DM among HIV-infected adults at younger ages and among the non-obese, there is a continued need for research assessing other important risk factors for DM among HIV-infected individuals, including diet and exercise, as well as a deeper understanding of insulin and glucose homeostasis in the setting of HIV infection.
Finally, although HCV has been described as a risk factor for DM in the general population, our findings indicate that HIV may compound the deleterious effects of HCV, putting HIV/HCV coinfected individuals at even higher risk of DM.34 Observed differences could be due to a lower engagement in medical care by HCV-infected adults in the general population and suboptimal screening practices.35 Nevertheless, this finding is particularly relevant, given the availability of directly acting antiviral agents as curative HCV therapy and highlights a potential additional benefit of HCV treatment for coinfected patients.36
Based on our findings, as well as current literature regarding DM among HIV-infected individuals, there are several important implications. First, HIV-care providers should follow existing DM screening guidelines, which recommend FBG and HbA1c be obtained prior to and after starting ART.37 Second, existing data from prospective studies should be examined to determine if screening guidelines should be modified, given the increased prevalence of DM among younger and non-obese HIV-infected persons. Third, improved tests for DM diagnosis and monitoring among HIV-infected persons should be explored, given studies that have demonstrated the diagnostic limitations of HbA1c in this population.10 ,14 ,15 Finally, additional research will be important to identify optimal DM management strategies among HIV-infected persons as traditional strategies to improve insulin sensitivity such as weight loss and diabetic medical therapy have been shown to be less effective among HIV-infected individuals.38 ,39
This analysis is subject to several limitations. First, the definition of diagnosed DM was different between MMP (medical record abstraction) and NHANES (self-reported) and may be a source of bias. A recent cohort-based validation of prevalence of DM based on self-report showed a specificity and negative predictive value >95%, with a sensitivity and positive predictive value between 60% and 70%.40 This indicates that were there a bias introduced by self-reporting of DM, it would be towards and increased prevalence of DM with self-report. Furthermore, comparisons between self-reported and medical record-based estimates of DM have shown substantial agreement between both measures, and in some cases, an underestimation of DM prevalence in medical records relative to self-report.41-43 Second, there is a risk of observer bias in our sample, given differences in engagement in care between our samples. We addressed this by performing a sensitivity analysis restricting the NHANES sample to adults having received care in the previous 12 months. Although we observed only slight changes in the magnitude of the associations, there is a possibility of overestimation of the PD between MMP and NHANES. Third, risk factors for DM, such as family history/genetics, diet, and exercise, were not included in this analysis and could explain some of the excess prevalence observed among HIV-infected adults. However, the inclusion of patients with type 1 diabetes is unlikely to have resulted in the excess diabetes prevalence observed in our study as the prevalence of type 1 diabetes in NHANES has been estimated to range between 3.6% and 4.8%.44 Fourth, the measurement of BMI and HCV were standardized for the NHANES population and not for MMP participants resulting in a biased association between these variables and DM when comparing NHANES and MMP participants. Fifth, MMP data are representative of HIV-infected persons receiving medical care and do not necessarily reflect DM prevalence among HIV-infected persons not diagnosed or not receiving care. Sixth, the increased prevalence of DM among HIV-infected women relative to the general US adult population may be due to misclassification bias; although we excluded pregnant women and diagnoses labeled gestational diabetes in the medical record of MMP participants, female patients with gestational diabetes may have been mislabeled and included in our sample. Finally, the NHANES population included HIV-infected adults who may or may not have received medical care. However, the prevalence of HIV-infected individuals in the NHANES population is negligible (0.21%).45 Although diabetes rates were standardized to the combined population of MMP and NHANES, given the very small percentage represented by MMP in the general US adult population, the bias introduced should be minimal.
Conclusion
We presented the first nationally representative estimate of DM prevalence among HIV-infected adults receiving medical care in the USA in 2009-2010 where 1 in 10 HIV-infected adults had a diagnosis of DM. Although obesity is a risk factor for prevalent DM among HIV-infected adults, when compared with the general US adult population, HIV-infected adults may have higher DM prevalence at younger ages and in the absence of obesity. Healthcare providers caring for HIV-infected patients should follow existing DM screening guidelines. Given the large burden of DM among HIV-infected adults, additional research would help to determine whether DM screening guidelines should be modified to include HIV infection as a risk factor for DM and to identify optimal management strategies in this population.
Is diabetes prevalence higher among HIV-infected individuals compared with the general population? Evidence from MMP and NHANES 2009-2010
http://drc.bmj.com/content/5/1/e000304
Abstract
Background Nationally representative estimates of diabetes mellitus (DM) prevalence among HIV-infected adults in the USA are lacking, and whether HIV-infected adults are at increased risk of DM compared with the general adult population remains controversial.
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