The relation between insulin resistance (IR) and coronary artery disease in patients with human immunodeficiency virus (HIV) infection remains incompletely defined. Fasting serum insulin and glucose measurements from 448 HIV-infected and 306 uninfected men enrolled in the Multicenter AIDS Cohort Study were collected at semiannual visits from 2003 to 2013 and used to compute the homeostatic model assessment of IR (HOMA-IR). Coronary computed tomographic angiography (CTA) was performed at the end of the study period to characterize coronary pathology. Associations between HOMA-IR (categorized into tertiles and assessed near the time of the CTA and over the 10-year study period) and the prevalence of coronary plaque or stenosis ≥50% were assessed with multivariate logistic regression. HOMA-IR was higher in HIV-infected men than HIV-uninfected men when measured near the time of CTA (3.2 vs 2.7, p = 0.002) and when averaged over the study period (3.4 vs 3.0, p <0.001). The prevalence of coronary stenosis ≥50% was similar between both groups (17% vs 15%, p = 0.41). Both measurements of HOMA-IR were associated with greater odds of coronary stenosis ≥50% in models comparing men with values in the highest versus the lowest tertiles, although the effect of mean HOMA-IR was stronger than the single measurement of HOMA-IR before CTA (odds ratio 2.46, 95% CI 1.95 to 3.11, vs odds ratio 1.43, 1.20 to 1.70). This effect was not significantly modified by HIV serostatus. In conclusion, IR over nearly a decade was greater in HIV-infected men than HIV-uninfected men, and in both groups, was associated with significant coronary artery stenosis.
Independent of the deleterious effects of hyperglycemia, insulin resistance (IR) is believed to promote atherosclerosis by impairing normal endothelial cell function and altering macrophage function in arterial plaques. Despite the well-known associations between IR and coronary artery disease (CAD) in the general population, relatively few studies have examined this association in human immunodeficiency virus (HIV)–infected populations. We sought to investigate the relation between HIV infection, IR, and subclinical CAD using a well-established marker of IR (homeostatic model assessment of IR [HOMA-IR]) and a highly accurate imaging technique (coronary computed tomographic angiography [CTA]) to detect atherosclerotic disease and characterize it more specifically than with coronary artery calcium (CAC) scores or carotid intima-media thickness (cIMT) alone, as other studies have done previously. Taking advantage of the longitudinal data from the Multicenter AIDS Cohort Study (MACS), we measured HOMA-IR at the study visit closest to the CTA and also averaged HOMA-IR measurements over a 10-year period before the CTA to capture any cumulative effect of IR on CAD. We hypothesized that HOMA-IR was greater in HIV-infected than uninfected men and, consequently, the presence and extent of CAD would be amplified in men with more IR.
Methods
The MACS is an ongoing, prospective observational study investigating the sequela of HIV infection in men who have sex with men (MSM) in 4 large metropolitan areas in the United States: Baltimore, Maryland/Washington DC; Chicago, Illinois; Los Angeles, California; and Pittsburgh, Pennsylvania. Data from these men, including a clinical evaluation and laboratory testing, are obtained semiannually. Men enrolled in the MACS were entered into an ancillary investigation focusing on the cardiovascular effects of HIV infection if they were 40-to 70-years old, weighed <300 lbs., and had no history of cardiac surgery or percutaneous transluminal coronary angioplasty. All participants underwent coronary CTA if they had no iodinated contrast allergy, atrial fibrillation, or renal insufficiency (defined as an estimated glomerular filtration rate under 60 ml/min/1.73 m 2 ). This analysis was restricted to men who participated in the ancillary investigation and underwent CTA. Each individual provided informed consent, and the institutional review board at each site approved the study protocol.
At each semiannual visit, study participants underwent a physical examination and submitted fasting blood samples. Data regarding demographic information, co-morbidities, and medication use (including antiretroviral therapy [ART], antihypertensives, and lipid-lowering agents) were collected through standardized questionnaires. Anthropometric data, including weight, waist circumference, waist-to-hip ratio, and body mass index (BMI), were measured using a standardized protocol at each visit, as previously described. Fasting lipid profiles, comprising total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, and triglycerides, were obtained according to a prespecified protocol, and low-density lipoprotein was directly measured if triglycerides exceeded 400 mg/dl and the Friedewald equation could not be used. Co-morbidities such as hypertension were defined as a systolic blood pressure (SBP) >140 mm Hg, diastolic blood pressure >90 mm Hg, or antihypertensive medication use. Diabetes mellitus was defined as a fasting glucose level ≥126 mg/dl, nonfasting glucose level ≥200 mg/dl, hemoglobin A1c ≥6.5%, or the use of medications to treat diabetes at >1 follow-up visit at any point during the study period. HIV disease activity was assessed through laboratory data (i.e., CD4 + T-cell count, CD4 + T-cell count nadir, plasma HIV RNA levels) or through the participant’s medical records and questionnaire responses (i.e., a history of AIDS, duration of ART, including protease inhibitor use). Hepatitis C virus (HCV) infection was identified by enzyme immunoassay (anti-HCV; ADVIA Centaur HCV assay; Siemens Healthcare Diagnostics, Tarrytown, New York) followed by quantitative real-time PCR (COBAS AmpliPrep COBAS TaqMan HCV assay; Roche Molecular Systems, Pleasanton, California). The aforementioned data were collected before CTA acquisition.
The median duration between the date of the CTA and the date of the closest MACS visit with fasting glucose and insulin data, which were measured at each semiannual visit, was 2.6 months (interquartile range [IQR] 1.0 to 5.3). The 10 years of longitudinal data before the CTA included a median of 14 study visits in HIV-uninfected men (range 1 to 21 visits) and 13 visits in HIV-infected men (range 1 to 22 visits). Fasting glucose levels were measured using the combined hexokinase/glucose-6-phosphate dehydrogenase method (coefficient of variation 1.8%), and fasting insulin levels were measured using a radioimmunoassay technique (coefficient of variation 2.6%; Lincoln Research, St. Charles, Missouri) at a centralized laboratory (Heinz Laboratory, Pittsburgh, Pennsylvania). These measurements were used to calculate the HOMA-IR with the following equation: (fasting glucose [mg/dl] × fasting insulin [mU/L])/405. The mean HOMA-IR was calculated from all semiannual visits from 2003 to 2013 before the CTA was performed.
The protocol for measurement of coronary atherosclerosis with CTA has been described previously. In brief, all men underwent an electrocardiogram-gated coronary CTA using multidetector scanners (64-slice multidetector at 3 sites and 320-row multidetector at 1 site) to characterize coronary lesions. Plaques were localized according to the American Heart Associations’ 15-segment classification of coronary anatomy. Plaque size in a given segment was graded semiquantitatively on a 0-to-3 scale using the following scoring: plaque absent, 0; mild plaque, 1; moderate plaque, 2; and severe plaque, 3. Plaque composition was also categorized as calcified (≥50% of the plaque density exceeding 130 Hounsfield units), mixed (<50% of the plaque exceeding 130 Hounsfield units), and noncalcified. Stenoses measuring ≥50% of the prelesion vessel diameter were also identified. Each participant was assigned a calcified plaque score (CPS), mixed plaque score (MPS), and non-CPS (NCPS) by summing the scores from the 15 coronary artery segments. Total plaque score, a reflection of the extent of plaque burden, was then calculated as the combination of the CPS, MPS, and NCPS. Two blinded readers in a central location (Los Angeles Biomedical Research Institute at Harbor-University of California-Los Angeles Medical Center) used 3-dimensional image analysis workstations (GE Advantage Workstations; GE Healthcare, Bethesda, Maryland) to interpret the CTAs, and this method of image analysis is reliable and highly reproducible.
Demographic and metabolic parameters at the time of the CTA were compared by HIV serostatus using the Wilcoxon rank-sum and Pearson chi-square tests for continuous and categorical variables, respectively. Using the longitudinal HOMA-IR measurements, we used a mixed-effects multinomial logistic regression model to evaluate the associations between HOMA-IR tertiles as the dependent variable and concurrent measurements of HIV and HCV serostatus, demographic parameters (age and race [non-Hispanic white vs nonwhite]), and traditional cardiovascular disease (CVD) risk factors (BMI, SBP, the use of antihypertension medications, total cholesterol concentrations, HDL cholesterol concentrations, the use of lipid-lowering medications, and smoking status [current vs former vs never]). All measurements available from 2003 to the time of a participant’s CTA were included, and the mixed-effects model accounted for correlation between the repeated measures within individual subjects. To evaluate whether HOMA-IR was associated with the plaque presence or severity, we performed multivariate regression analyses (both logistic and linear) with the different plaque measurements as the dependent variables and HOMA-IR as the primary independent variable, adjusting for HIV and HCV serostatus as well as the demographic parameters and CVD risk factors specified previously. One set of models used the HOMA-IR measure at a time most proximally but before the CTA, whereas the second set used the mean of all HOMA-IR measurements available from 2003 to the time the CTA was performed. Both HOMA-IR variables were modeled as tertiles and compared the effect of the highest versus lowest tertile and the effect of the middle versus the lowest tertile. Tertiles were chosen to categorize the data given the absence of well-established cutoffs for HOMA-IR measurements that correspond to clinically meaningful end points. Logistic models were used to assess the relation of HOMA-IR with the presence of each plaque type and coronary artery stenosis ≥50% and linear regression to assess the association with plaque extent in men with plaque present. To assess whether the associations between HOMA-IR and the CTA findings differed by HIV serostatus, an HIV-serostatus × HOMA-IR tertile interaction term was added to the multivariate models. We also examined the associations between HOMA-IR and the CTA findings in multivariate models restricted to the HIV-infected population with additional adjustment for CD4 + T-cell count and undetectable plasma HIV RNA (defined as <50 copies/ml). A small proportion of participants were missing data, so for the analyses between HOMA-IR and plaque, missing data were imputed 10 times based on the distribution of covariates using a Markov chain Monte Carlo method, assuming multivariate normality. All statistical analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina). Statistical significance was established with a p value <0.05.
Results
Data from 754 men who underwent CTA were included in this analysis ( Table 1 ). Median follow-up time between the first HOMA-IR calculation and when CTA was performed was 8.4 years (IQR of 7.8 to 9.3 years). HIV-infected patients had higher fasting glucose and insulin concentrations compared with HIV-uninfected men at measurements from the study visit closest to the CTA, resulting in a higher median HOMA-IR. Similarly, mean HOMA-IR over a nearly 10-year period was greater in the HIV-infected versus HIV-uninfected men.
| Variable | HIV-uninfected (n =306) | HIV-infected (n = 448) | P-value ∗ |
|---|---|---|---|
| Age (years) | 54 (50-61) | 51 (47-57) | <0.001 |
| White | 69% | 50% | |
| Hispanic | 6% | 15% | <0.001 |
| Black | 24% | 34% | |
| Other | 2% | <1% | |
| BMI (kg/m 2 ) | 26.6 (24.0-29.8) | 25.6 (23.3-28.4) | <0.01 |
| Diabetes mellitus | 9% | 12% | 0.21 |
| Hypertension | 42% | 45% | 0.43 |
| Antihypertensive medication use | 29% | 32% | 0.41 |
| Lipid-lowering therapy use | 31% | 33% | 0.55 |
| Anti-diabetic therapy use | 6% | 8% | 0.31 |
| Smoker | |||
| Current | 22% | 30% | |
| Former | 54% | 43% | <0.01 |
| Never | 23% | 26% | |
| Cumulative cigarette pack years | 3.3 (0-22.3) | 5.4 (0-21.3) | 0.36 |
| Current HOMA-IR | 2.7 (2.0-3.9) | 3.2 (2.2-4.5) | <0.01 |
| Mean HOMA-IR over study period † | 3.0 (2.2-4.1) | 3.4 (2.5-5.0) | <0.001 |
| Fasting glucose (mg/dL) | 96 (89-104) | 98 (90-107) | 0.04 |
| Fasting insulin (μU/mL) | 11.5 (8.9-16.0) | 12.9 (9.8-17.6) | <0.01 |
| Hemoglobin A1c (%) | 5.6 (5.4-5.8) | 5.5 (5.3-5.8) | 0.01 |
| Total cholesterol (mg/dL) | 194 (168-218) | 185 (159-212) | <0.01 |
| LDL cholesterol (mg/dL) | 114 (91-139) | 103 (82-133) | <0.001 |
| HDL cholesterol (mg/dL) | 52 (43-62) | 45 (38-55) | <0.001 |
| Triglycerides (mg/dL) | 106 (74-147) | 127 (93-193) | <0.001 |
| Serum creatinine (mg/dL) | 1.00 (0.89-1.07) | 0.99 (0.85-1.10) | 0.69 |
| HCV infection | 2.8% | 10.6% | <0.001 |
| Viral load undetectable ‡ | – | 79% | – |
| CD4 + T-cell count (cells/mm 3 ) | – | 599 (426-774) | – |
| CD4 + T-cell count nadir (cells/mm 3 ) | – | 287 (176-413) | – |
| Time on HAART (years) | – | 12.3 (8.5-14.0) | – |
| Protease inhibitor use | – | 42% | – |
| History of AIDS | – | 11% | – |
∗ Demographic and metabolic parameters at the time of the CTA were compared by HIV serostatus using the Wilcoxon rank-sum and Pearson chi-square tests for continuous and categorical variables, respectively.
† Mean HOMA-IR averages all HOMA-IR measurements over the 10 years before the participant’s CTA.
HIV infection demonstrated a graded association with HOMA-IR in the multivariate analysis ( Figure 1 ), with 1.5-fold greater odds of having a HOMA-IR value in the middle compared to the lowest tertile and 2.5-fold greater odds of having a HOMA-IR value in the highest compared to the lowest tertile. Greater HOMA-IR was also associated with advancing age, and the association between age and HOMA-IR did not differ by HIV serostatus (data for interaction not shown). In addition, increased HOMA-IR was associated with variables such as greater BMI, SBP, the use of antihypertensive medications, higher total cholesterol levels, the use of lipid-lowering agents, and lower HDL-c levels ( Table 2 ). Over the 10-year study interval, HOMA-IR did not significantly change in the HIV-infected or HIV-uninfected men after multivariate adjustment ( Figure 2 ).
| Effect | Middle Tertile of HOMA-IR | Highest Tertile of HOMA-IR | ||
|---|---|---|---|---|
| Odds Ratio (95% CI) | P-value | Odds Ratio (95% CI) | P-value | |
| HIV-infection | 1.49 (1.23-1.81) | <0.001 | 2.46 (1.89-3.21) | <0.001 |
| HCV-infection | 1.27 (0.85-1.92) | 0.24 | 2.20 (1.34-3.64) | 0.002 |
| Age (per 1 year change) | 1.02 (1.01-1.03) | 0.003 | 1.02 (1.01-1.04) | 0.003 |
| Race (Non-Hispanic White vs. Other) | 0.93 (0.75-1.15) | 0.51 | 0.67 (0.50-0.89) | 0.006 |
| Current vs. never smoking | 0.96 (0.76-1.22) | 0.75 | 0.95 (0.70-1.30) | 0.76 |
| Former vs. never smoking | 0.97 (0.78-1.21) | 0.79 | 0.95 (0.72-1.27) | 0.75 |
| BMI (per 1 kg/m 2 change) | 1.16 (1.13-1.19) | <0.001 | 1.33 (1.29-1.37) | <0.001 |
| Systolic blood pressure (per 10 mmHg) | 1.08 (1.02-1.14) | 0.006 | 1.11 (1.04-1.19) | 0.001 |
| Anti-hypertensive use | 1.24 (1.02-1.51) | 0.029 | 1.47 (1.18-1.84) | <0.001 |
| Total cholesterol (per 5mg/dL) | 1.01 (1.00-1.02) | 0.047 | 1.01 (1.00-1.02) | 0.14 |
| HDL cholesterol (per 5mg/dL) | 0.89 (0.87-0.92) | <0.001 | 0.88 (0.84-0.91) | <0.001 |
| Lipid-lowering therapy use | 1.31 (1.08-1.58) | 0.005 | 1.43 (1.14-1.78) | 0.002 |
Coronary plaque was present in a majority of men: 78% of HIV-infected men and 75% of HIV-uninfected men ( Table 3 ). HIV-infected men had a higher prevalence of noncalcified plaque and a higher NCPS. However, the CPS and MPS were not statistically different between infected and uninfected subjects, nor was the prevalence of a stenosis ≥50%.
| Parameter | HIV-uninfected (n = 306) | HIV-infected (n = 448) | P-value |
|---|---|---|---|
| Presence of coronary plaque | 75% | 78% | 0.29 |
| Presence of calcified coronary plaque | 41% | 35% | 0.11 |
| Presence of non-calcified plaque | 53% | 64% | <0.01 |
| Presence of mixed coronary plaque | 32% | 35% | 0.41 |
| Presence of coronary stenosis ≥ 50% | 15% | 17% | 0.41 |
| Total plaque score, median (IQR) | 2 (0-5) | 2 (1-5) | 0.35 |
| Calcified plaque score, median (IQR) | 0 (0-2) | 0 (0-1) | 0.04 |
| Non-calcified plaque score, median (IQR) | 1 (0-2) | 1 (0-3) | 0.001 |
| Mixed plaque score, median (IQR) | 0 (0-1) | 0 (0-1) | 0.27 |
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