Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 1 Online Appendix for the following JACC article TITLE: Impact of Non–Insulin-Dependent Type 2 Diabetes on Carotid Wall 18FFluorodeoxyglucose Positron Emission Tomography Uptake AUTHORS: Jan Bucerius, MD, Venkatesh Mani, PHD, Colin Moncrieff, James H. F. Rudd, MD, PHD, Josef Machac, MD, Valentin Fuster, MD, PHD, Michael E. Farkouh, MD, MSC, Zahi A. Fayad, PHD APPENDIX Supplementary Table 2b. Multiple Linear Regression Analyses in the Whole Study Population Using Uncorrected FDG Uptake Parameters 95% Uncorrected FDG Uptake Standardized Confidence Adjusted Parameters Coefficient Interval R2 Significance 0.104 0.002 meanSUV p value BMI ≥ 30 kg/m2 0.277 0.080 - 0.325 0.001 Diabetes -0.159 -0.242 - 0.005 0.06 Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 2 Male 0.162 -0.004 - 0.253 0.058 Hypertension 0.152 -0.010 - 0.234 0.072 meanTBR 0.119 < 0.0001 Smoking 0.267 0.094 - 0.408 0.002 Male 0.216 0.037 - 0.273 0.011 Hypertension 0.166 0.000 - 0.230 0.052 Age > 65 years 0.158 -0.007 - 0.221 0.065 SHS 0.107 0.001 BMI ≥ 30 kg/m2 0.215 0.044 - 0.355 0.012 Smoking 0.212 0.056 - 0.487 0.014 Male 0.194 0.026 - 0.354 0.023 Age > 65 years 0.179 0.011 - 0.318 0.036 Multiple linear regression analyses with backward elimination to identify clinical risk factors of carotid vessel wall inflammation in the whole study population as depicted by uncorrected FDG uptake parameters. Mean standardized uptake value (meanSUV), mean target-to-background ratio (meanTBR), and single hottest segment (SHS), respectively, were the response variables and the cardiovascular risk factors age >65 years, male sex, body mass index (BMI) ≥30 kg/m2, statin medication, history of cardiovascular disease, smoking, alcohol use, exercise, hypertension, diabetes, and family history of cardiovascular disease were the explanatory variables. Variables were retained in the model when p < 0.10. is the standardized regression coefficient. In contrast to the glucose-corrected FDG uptake parameters, diabetes could only be shown to be associated with meanSUV. Male sex Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 3 was the only clinical risk factor to be associated with all of the uncorrected FDG uptake values. Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 4 Supplementary Table 3b. Multiple Linear Regression Analyses in Subjects With and Without Diabetic Disease (Uncorrected FDG Uptake Parameters) 95% Uncorrected FDG Standardized Confidence Adjusted Uptake Parameters Coefficient R2 Significance p value 0.126 0.012 Interval meanSUV Diabetic Subjects Smoking 0.384 0.099 - 0.763 Nondiabetic Subjects 0.012 0.115 0.004 BMI ≥ 30 kg/m2 0.268 0.050 - 0.374 0.011 Hypertension 0.217 0.011 - 0.321 0.036 Exercising 0.178 -0.019 - 0.288 0.085 meanTBR Diabetic Subjects 0.304 < 0.0001 Smoking 0.587 0.370 - 1.001 < 0.0001 Age > 65 years 0.228 -0.026 - 0.309 0.096 Nondiabetic Subjects 0.098 0.004 Hypertension 0.245 0.029 - 0.309 0.018 Male 0.215 0.009 - 0.301 0.038 SHS Diabetic Subjects 0.32 < 0.0001 Smoking 0.512 0.455 - 1.417 < 0.0001 BMI ≥ 30 kg/m2 0.235 -0.027 - 0.478 0.079 Type 2 Diabetes and Carotid Wall FDG Uptake Nondiabetic Subjects Bucerius et al. 5 0.081 0.01 Male 0.214 0.009 - 0.387 0.040 Hypertension 0.212 0.006 - 0.368 0.043 Multiple linear regression analyses with backward elimination to identify clinical risk factors of carotid vessel wall inflammation as depicted by uncorrected FDG uptake parameters in diabetic and nondiabetic subjects. meanSUV, mean target-to-background ratio (meanTBR) and single hottest segment (SHS), were the response variables and the cardiovascular risk factors age > 65 years, male sex, body mass index (BMI) ≥ 30 kg/m2, statin medication, history of cardiovascular disease, smoking, alcohol use, exercise, hypertension, and family history of cardiovascular disease were the explanatory variables. Variables were retained in the model when p < 0.05. The best model is shown. is the standardized regression coefficient. Similar to the glucose-corrected FDG uptake parameters, smoking was a clinical risk factor for carotid wall inflammation as depicted by all uncorrected FDG uptake parameters in diabetic patients. This was the same with regard to hypertension, which was found to be significantly associated with all uncorrected FDG uptake parameters as also seen with the glucose-corrected uptake values in nondiabetic subjects. Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 6 Supplementary Table 4. Clinical Variables Stratified by Tertiles of meanSUVgluc, meanTBRgluc, and SHSgluc n = 131 1st Tertile meanSUVgluc 2nd Tertile 3rd Tertile 0.96 - 2.14 2.15 - 3.34 3.35 - 4.54 n (%) n (%) n (%) p value 40 (30) 78 (60) 13 (10) Age > 65 years 11 (28) 34 (44) 1 (8) 0.021 Male sex 24 (60) 61 (78) 9 (69) 0.11 BMI ≥ 30 kg/m2 7 (18) 30 (39) 8 (62) 0.007 Smoking 7 (18) 9 (12) 2 (15) 0.66 Alcohol 12 (30) 33 (42) 5 (39) 0.43 Exercise 22 (55) 46 (59) 2 (15) 0.014 History of Cardiovascular Disease 27 (68) 49 (63) 7 (54) 0.67 Family History of Cardiovascular 28 (70) 45 (58) 6 (46) 0.24 Characteristics Lifestyle Medical History Disease Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 7 Hypertension 19 (48) 61 (78) 8 (62) 0.003 Diabetes 7 (18) 26 (33) 9 (69) 0.002 Statin Medication 31 (38) 60 (77) 10 (77) 1.0 meanTBRgluc 0.95 - 2.08 2.09 - 3.22 3.23 - 4.37 n (%) n (%) n (%) p value 51 (39) 72 (55) 8 (6) Age > 65 years 14 (28) 31 (43) 1 (13) 0.078 Male 32 (63) 57 (79) 5 (63) 0.12 BMI ≥ 30 kg/m2 12 (24) 27 (38) 6 (75) 0.012 Smoking 7 (14) 9 (13) 2 (25) 0.62 Alcohol 16 (31) 30 (42) 4 (50) 0.4 Exercise 28 (55) 40 (56) 2 (25) 0.25 History of Cardiovascular Disease 31 (61) 47 (65) 5 (63) 0.88 Family History of Cardiovascular 37 (73) 39 (54) 3 (38) 0.048 Hypertension 24 (47) 61 (85) 3 (38) < 0.0001 Diabetes 8 (16) 27 (38) 7 (88) < 0.0001 Statin Medication 36 (71) 60 (83) 5 (63) 0.15 Characteristics Lifestyle Medical History Disease Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 8 SHSgluc n (%) n (%) n (%) p value 84 (64) 43 (33) 4 (3) Age > 65 years 28 (33) 18 (42) 0 (0) 0.21 Male 56 (67) 37 (86) 1 (25) 0.008 BMI ≥ 30 kg/m2 21 (25) 21 (49) 3 (75) 0.006 Smoking 11 (13) 5 (12) 2 (50) 0.1 Alcohol 28 (33) 20 (47) 2 (50) 0.31 Exercise 48 (57) 21 (49) 1 (25) 0.35 History of Cardiovascular Disease 52 (62) 28 (65) 3 (75) 0.83 Family History of Cardiovascular 57 (68) 20 (47) 2 (50) 0.061 Hypertension 52 (62) 33 (77) 3 (75) 0.23 Diabetes 19 (23) 20 (47) 3 (75) 0.004 Statin Medication 63 (75) 35 (81) 3 (75) 0.72 Characteristics Lifestyle Medical History Disease Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 9 Clinical variables stratified by tertiles of glucose-corrected FDG uptake parameters (meanSUVgluc, meanTBRgluc, and SHSgluc). Data are presented as absolute numbers and percentages. The p values represent overall differences across the groups. For all FDG uptake parameters, incidence of diabetes increased with increments of carotid wall inflammation as depicted by FDG-PET uptake. Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 10 Type 2 Diabetes and Carotid Wall FDG Uptake Bucerius et al. 11 Figure 4. Mean Standardized Uptake Value (meanSUVgluc [upper panel], Mean Targetto-Background Ratio (meanTBRgluc [middle panel], and Single Hottest Segment (SHSgluc [lower panel]) in Diabetic Patients Classified According to Fasting Glucose Levels (mmol/l). Data are presented as median (bolded line), 25th to 75th percentile (box), and 5th to 95th percentile (whiskers). Circles represent outliers. A one-way ANOVA was performed to test for between-group differences. Linear trend across categories was executed by using oneway ANOVA linear contrasts: meanSUVgluc Unweighted: p < 0.0001 Weighted: p < 0.0001 meanTBRgluc Unweighted: p < 0.0001 Weighted: p < 0.0001 SHSgluc Unweighted: p < 0.0001 Weighted: p < 0.0001 For all FDG uptake parameters in diabetic subjects, increasing values are observed with increments of fasting pre-scan glucose values.