Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
Article Figures & Tables
Tables
- Table 1
DCCT baseline characteristics of participants according to the presence or absence of any DPN over the duration of the DCCT/EDIC study, through EDIC year 13/14
Overall No Yes Per unit change OR (95% CI) P value N 1,386 931 455 Design Treatment group (% conventional) 51 48 57 Conventional vs. intensive 1.56 (1.26, 1.93) 0.0001 Cohort (% secondary) 51 45 61 Secondary vs. primary 1.90 (1.53, 2.36) <0.0001 Physical Sex (% men) 52 49 60 Men vs. women 1.51 (1.21, 1.88) 0.0002 Age (years) 27 (22, 32) 26 (21, 32) 29 (24, 34) 5 years 1.30 (1.21, 1.41) <0.0001 Adult (% ≥18 years) 87 84 91 ≥18 vs. <18 years 1.83 (1.28, 2.63) 0.0009 Height (cm) 171 (164, 179) 170 (163, 177) 174 (167, 182) 5 cm 1.20 (1.13, 1.27) <0.0001 Weight men (kg) 74 (67, 82) 73 (66, 80) 78 (70, 85) 5 kg 1.19 (1.11, 1.27) <0.0001 Weight women (kg) 62 (56, 69) 61 (55, 68) 64 (58, 70) 5 kg 1.20 (1.10, 1.32) <0.0001 BMI men (kg/m2) 24 (22, 25) 23 (21, 25) 24 (22, 26) 1 kg/m2 1.08 (1.02, 1.14) 0.0052 BMI women (kg/m2) 23 (21, 25) 23 (21, 25) 23 (22, 25) 1 kg/m2 1.09 (1.03, 1.15) 0.0021 Behavioral Cigarette smoker (%) 18 18 20 Yes vs. no 1.23 (0.94, 1.60) 0.1358 Occasional or regular alcohol use (%) 22 20 24 Yes vs. none 1.23 (0.95, 1.59) 0.1107 Moderate or strenuous activity (%) 70 68 74 Yes vs. sedentary 1.31 (1.03, 1.66) 0.0264 Family history Hypertension (%) 56 54 58 Yes vs. no 1.16 (0.93, 1.44) 0.1872 Myocardial infarction (%) 49 47 52 Yes vs. no 1.18 (0.95, 1.46) 0.1366 Type 1 diabetes (%) 14 14 15 Yes vs. no 1.22 (0.90, 1.66) 0.2041 Type 2 diabetes (%) 9 8 12 Yes vs. no 1.44 (1.04, 2.00) 0.0292 Blood pressure SBP (mmHg) 114 (106, 122) 112 (106, 120) 116 (110,124) 5 mmHg 1.11 (1.06, 1.17) <0.0001 DBP (mmHg) 72 (68, 80) 70 (66, 78) 76 (68, 80) 5 mmHg 1.16 (1.09, 1.24) <0.0001 Pulse pressure (mmHg) 40 (34, 48) 40 (34, 48) 40 (36, 48) 5 mmHg 1.03 (0.98, 1.09) 0.2658 Pulse rate (bpm) 76 (68, 84) 76 (68, 82) 76 (70, 84) 1 bpm 1.02 (1.01, 1.03) <0.0001 Lipids Total cholesterol (mg/dL) 174 (152, 196) 172 (152, 194) 176 (155, 202) 10 mg/dL 1.05 (1.02, 1.08) 0.0038 Triglycerides (mg/dL) 70 (55, 93) 69 (54, 92) 73 (57, 98) 10 mg/dL 1.03 (1.01, 1.05) 0.0032 HDL cholesterol (mg/dL) 49 (42, 57) 50 (42, 58) 47 (41, 56) 10 mg/dL 0.92 (0.84, 1.00) 0.0614 LDL cholesterol (mg/dL) 106 (90, 127) 104 (89, 125) 110 (92, 131) 10 mg/dL 1.06 (1.02, 1.10) 0.0011 History of diabetes Duration of type 1 diabetes (years) 4 (2, 9) 4 (2, 8) 6 (3, 10) 1 year 1.08 (1.06, 1.11) <0.0001 Stimulated C-peptide (nmol/L⋅100) Duration <5 years 12 (4, 25) 12 (4, 26) 13 (4, 24) 1 year 0.99 (0.98, 1.01) 0.3172 Duration ≥5 years 3 (3, 4) 3 (3, 4) 3 (3, 3) 1 year 1.01 (0.97, 1.05) 0.6864 Insulin dose (units/kg/day) 0.64 (0.50, 0.80) 0.64 (0.50, 0.81) 0.63 (0.49, 0.77) 1 unit/kg/day 0.88 (0.57, 1.35) 0.5552 HbA1c (%) 8.80 (7.84, 10.08) 8.63 (7.70, 9.74) 9.20 (8.23, 10.60) 1% 1.31 (1.22, 1.40) <0.0001 HbA1c (mmol/mol) 72.7 (62.2, 86.7) 70.8 (60.7, 83.0) 77.1 (66.5, 92.4) 1 mmol/mol 1.31 (1.22, 1.40) <0.0001 Data are based on 1,386 participants with at least two DPN assessments during DCCT/EDIC. Medians (first quartile, third quartile) or % are presented. ORs and P values were generated using GEE models with no adjustment for other factors.
- Table 2
DCCT baseline characteristics of participants according to the presence or absence of any CAN over the course of the DCCT/EDIC study, through EDIC year 16/17
Overall No Yes Per unit change OR (95% CI) P value N 1,434 803 631 Design Treatment group (% conventional) 51 49 53 Conventional vs. intensive 1.36 (1.11, 1.66) 0.0025 Cohort (% secondary) 50 44 57 Secondary vs. primary 1.72 (1.41, 2.10) <0.0001 Physical Sex (% men) 53 54 52 Men vs. women 0.92 (0.75, 1.13) 0.4286 Age (years) 27 (22, 32) 26 (21, 31) 29 (23, 34) 5 years 1.39 (1.29, 1.50) <0.0001 Adult (% ≥18 years) 86 83 91 ≥18 vs. <18 years 2.03 (1.45, 2.85) <0.0001 Height (cm) 171 (164, 179) 171 (164, 178) 171 (164, 180) 5 cm 1.02 (0.97, 1.07) 0.4951 Weight men (kg) 74 (67, 82) 73 (66, 81) 76 (69, 84) 5 kg 1.14 (1.07, 1.21) <0.0001 Weight women (kg) 62 (56, 69) 61 (55, 68) 63 (57, 69) 5 kg 1.09 (1.01, 1.18) 0.0251 BMI men (kg/m2) 24 (22, 25) 23 (21, 25) 24 (22, 26) 1 kg/m2 1.10 (1.04, 1.15) 0.0004 BMI women (kg/m2) 23 (21, 25) 23 (21, 25) 23 (21, 25) 1 kg/m2 1.07 (1.02, 1.12) 0.0107 Behavioral Cigarette smoker (%) 18 16 21 Yes vs. no 1.77 (1.38, 2.28) <0.0001 Occasional or regular alcohol use (%) 22 19 24 Yes vs. none 1.31 (1.03, 1.65) 0.0261 Moderate or strenuous activity (%) 70 67 73 Yes vs. sedentary 1.23 (0.98, 1.53) 0.0698 Family history Hypertension (%) 56 55 58 Yes vs. no 1.22 (1.00, 1.50) 0.0528 Myocardial infarction (%) 49 49 49 Yes vs. no 1.00 (0.81, 1.22) 0.9666 Type 1 diabetes (%) 14 14 15 Yes vs. no 1.07 (0.80, 1.43) 0.6297 Type 2 diabetes (%) 9 8 11 Yes vs. no 1.54 (1.12, 2.11) 0.0073 Blood pressure SBP (mmHg) 114 (106, 122) 112 (106, 120) 116 (108, 122) 5 mmHg 1.07 (1.03, 1.12) 0.0021 DBP (mmHg) 72 (68, 80) 72 (66, 80) 74 (68, 80) 5 mmHg 1.13 (1.07, 1.20) <0.0001 Pulse pressure (mmHg) 40 (34, 48) 40 (35, 48) 40 (34, 48) 5 mmHg 1.00 (0.95, 1.05) 0.9673 Pulse rate (bpm) 76 (68, 84) 74 (68, 80) 78 (72, 84) 1 bpm 1.03 (1.02, 1.04) <0.0001 Lipids Total cholesterol (mg/dL) 174 (152, 196) 171 (150, 195) 177 (156, 201) 10 mg/dL 1.09 (1.06, 1.12) <0.0001 Triglycerides (mg/dL) 70 (55, 94) 68 (54, 90) 72 (56, 98) 10 mg/dL 1.04 (1.02, 1.06) 0.0002 HDL cholesterol (mg/dL) 49 (42, 58) 50 (42, 58) 48 (42, 57) 10 mg/dL 0.99 (0.91, 1.07) 0.7660 LDL cholesterol (mg/dL) 107 (91, 127) 104 (88, 125) 110 (92, 130) 10 mg/dL 1.10 (1.06, 1.13) <0.0001 History of diabetes Duration of type 1 diabetes (years) 4 (2, 9) 4 (2, 8) 5 (2, 10) 1 year 1.07 (1.05, 1.10) <0.0001 Stimulated C-peptide (nmol/L⋅100) Duration <5 years 12 (4, 25) 12 (4, 24) 13 (5, 27) 1 year 1.00 (0.99, 1.01) 0.4487 Duration ≥5 years 3 (3, 4) 3 (3, 4) 3 (3,3) 1 year 0.99 (0.95, 1.03) 0.6122 Insulin dose (units/kg/day) 0.64 (0.50, 0.80) 0.65 (0.50, 0.82) 0.63 (0.50, 0.79) 1 unit/kg/day 0.79 (0.52, 1.20) 0.2679 HbA1c (%) 8.80 (7.82, 10.10) 8.64 (7.70, 9.81) 9.00 (8.01, 10.30) 1% 1.25 (1.18, 1.33) <0.0001 HbA1c (mmol/mol) 72.7 (62.0, 86.9) 70.9 (60.7, 83.7) 74.9 (64.7, 89.1) 1 mmol/mol 1.25 (1.18, 1.33) <0.0001 Data are based on 1,434 participants with at least two CAN assessments during DCCT/EDIC. Medians (first quartile, third quartile) or % are presented. ORs and P values were generated using GEE models with no adjustment for other factors.
- Table 3
ORs for DPN and CAN per unit change in each baseline or time-dependent covariate in separate longitudinal GEE models, minimally adjusted for age and updated mean HbA1c
DPN CAN * OR (95% CI) P value OR (95% CI) P value Design Treatment group (conventional vs. intensive) B 1.05 (0.83, 1.32) 0.7022 1.12 (0.91, 1.38) 0.2883 Cohort (secondary vs. primary) B 2.07 (1.66, 2.57) <0.0001 1.81 (1.49, 2.21) <0.0001 Physical Sex (men vs. women) B 1.51 (1.21, 1.88) 0.0003 0.85 (0.70, 1.04) 0.1164 Adult (≥18 vs. <18 years) B 1.05 (0.66, 1.67) 0.8291 0.76 (0.50, 1.16) 0.1997 Height (per 5 cm) C 1.21 (1.14, 1.28) <0.0001 0.96 (0.91, 1.01) 0.1134 Weight (per 5 kg) C 1.09 (1.06, 1.13) <0.0001 1.02 (0.99, 1.05) 0.1299 Mean weight (per 5 kg) M 1.12 (1.08, 1.17) <0.0001 1.02 (0.98, 1.06) 0.2686 BMI (per 1 kg/m2) C 1.02 (1.00, 1.05) 0.0612 1.03 (1.01, 1.04) 0.0079 Mean BMI (per 1 kg/m2) M 1.04 (1.01, 1.07) 0.0090 1.03 (1.01, 0.106) 0.0174 Behavioral Cigarette smoker (yes vs. no) C 0.98 (0.75, 1.29) 0.8932 1.39 (1.10, 1.76) 0.0057 Occasional or regular alcohol use (yes vs. none) C 1.14 (0.93, 1.41) 0.2158 0.85 (0.72, 1.00) 0.0462 Moderate or strenuous activity (yes vs. sedentary) C 1.08 (0.89, 1.31) 0.4471 0.86 (0.74, 1.00) 0.0543 Family history Hypertension (yes vs. no) B 1.17 (0.94, 1.46) 0.1514 1.25 (1.03, 1.53) 0.0276 Myocardial infarction (yes vs. no) B 1.17 (0.94, 1.45) 0.1503 0.97 (0.80, 1.19) 0.7897 Type 1 diabetes (yes vs. no) B 1.15 (0.83, 1.57) 0.4048 0.95 (0.71, 1.28) 0.7468 Type 2 diabetes (yes vs. no) B 1.22 (0.87, 1.73) 0.2544 1.22 (0.89, 1.66) 0.2164 Blood pressure SBP (per 5 mmHg) C 1.08 (1.04, 1.12) 0.0003 1.09 (1.06, 1.13) <0.0001 Mean SBP (per 5 mmHg) M 1.17 (1.10, 1.24) <0.0001 1.24 (1.17, 1.30) <0.0001 DBP (per 5 mmHg) C 1.07 (1.01, 1.13) 0.0184 1.05 (1.00, 1.09) 0.0462 Mean DBP (per 5 mmHg) M 1.21 (1.11, 1.32) <0.0001 1.21 (1.11, 1.31) <0.0001 Pulse pressure (per 5 mmHg) C 1.07 (1.02, 1.12) 0.0035 1.11 (1.07, 1.14) <0.0001 Pulse rate (per 1 bpm) C 1.01 (1.00, 1.02) 0.0048 1.03 (1.03, 1.04) <0.0001 Mean pulse rate (per 1 bpm) M 1.03 (1.02, 1.04) <0.0001 1.07 (1.06, 1.09) <0.0001 Hypertension (yes vs. no) C 2.03 (1.56, 2.64) <0.0001 1.94 (1.61, 2.34) <0.0001 Medications ACE inhibitor use (yes vs. no) C 1.54 (1.20, 1.97) 0.0008 1.51 (1.25, 1.82) <0.0001 ARB use (yes vs. no) C 1.24 (0.87, 1.77) 0.2438 1.45 (1.13, 1.87) 0.0038 β-Blocker use (yes vs. no) C 2.88 (1.79, 4.64) <0.0001 2.77 (1.95, 3.92) <0.0001 Calcium channel blocker use (yes vs. no) C 1.41 (0.88, 2.26) 0.1524 1.70 (1.21, 2.40) 0.0022 Lipid-lowering agent use (yes vs. no) C 1.15 (0.89, 1.48) 0.2740 1.36 (1.12, 1.65) 0.0020 Lipids Total cholesterol (per 10 mg/dL) C 0.98 (0.95, 1.01) 0.1607 1.00 (0.98, 1.02) 0.9612 Mean total cholesterol (per 10 mg/dL) M 1.02 (0.98, 1.05) 0.4334 1.06 (1.02, 1.10) 0.0027 Triglycerides (per 20% increase mg/dL) C 1.06 (1.02, 1.10) 0.0054 1.07 (104, 1.10) <0.0001 Mean triglycerides (per 20% increase mg/dL) M 1.09 (1.04, 1.15) <0.0001 1.14 (1.09, 1.18) <0.0001 HDL cholesterol (per 10 mg/dL) C 0.89 (0.83, 0.93) 0.0034 0.96 (0.91, 1.01) 0.1113 Mean HDL cholesterol (per 10 mg/dL) M 0.88 (0.81, 0.96) 0.0052 0.95 (0.88, 1.03) 0.2238 LDL cholesterol (per 10 mg/dL) C 0.98 (0.95, 1.01) 0.1804 0.99 (0.96, 1.02) 0.4320 Mean LDL cholesterol (per 10 mg/dL) M 1.02 (0.98, 1.06) 0.4137 1.04 (1.00, 1.08) 0.0719 Hyperlipidemia (yes vs. no) C 1.02 (0.83, 1.26) 0.8568 1.27 (1.08, 1.51) 0.0052 History of diabetes Duration of type 1 diabetes (per 1 year) B 1.11 (1.08, 1.13) <0.0001 1.09 (1.06, 1.12) <0.0001 Stimulated C-peptide (per 1 nmol/L*100) Duration <5 years B 0.99 (0.98, 1.00) 0.1345 1.00 (0.98, 1.01) 0.7650 Duration ≥5 years B 1.00 (0.96, 1.05) 0.8726 0.98 (0.94, 1.02) 0.3685 Insulin dose (per 1 unit/kg/day) C 1.19 (0.82, 1.73) 0.3718 1.26 (0.99, 1.62) 0.0648 Mean insulin dose (per 1 unit/kg/day) M 2.07 (1.25, 3.43) 0.0046 1.88 (1.18, 3.00) 0.0083 Kidney disease eGFR (per 5 mL/min/1.73 m2) C 0.93 (0.90, 0.97) <0.0001 0.92 (0.90, 0.95) <0.0001 eGFR <60 mL/min/1.73 m2 (yes vs. no) C 2.56 (1.36, 4.80) 0.0034 5.95 (3.36, 10.52) <0.0001 Any eGFR <60 mL/min/1.73 m2 (yes vs. no) A 2.44 (1.45, 4.10) 0.0007 3.24 (2.12, 4.99) <0.0001 AER (per 20% increase mg/24 h) C 1.06 (1.04, 1.07) <0.0001 1.06 (1.04, 1.07) <0.0001 Sustained AER ≥30 mg/24 h (yes vs. no) C 2.45 (1.89, 3.17) <0.0001 2.36 (1.86, 3.00) <0.0001 Any sustained AER ≥30 mg/24 h (yes vs. no) A 2.50 (1.98, 3.15) <0.0001 2.87 (2.32, 3.53) <0.0001 AER ≥300 mg/24 h (yes vs. no) C 3.81 (2.42, 6.01) <0.0001 3.25 (2.17, 4.87) <0.0001 Any AER ≥300 mg/24 h (yes vs. no) A 4.02 (2.81, 5.75) <0.0001 3.30 (2.36, 4.59) <0.0001 Hypoglycemia Coma and/or seizure (yes vs. no) C 1.09 (0.61, 1.97) 0.7636 1.03 (0.73, 1.45) 0.8697 Requiring assistance (yes vs. no) C 1.36 (0.96, 1.92) 0.0837 1.13 (0.88, 1.45) 0.3264 Data are based on 1,386 participants with at least two DPN assessments or 1,434 participants with at least two CAN assessments during DCCT/EDIC. ORs and P values were generated using GEE models, adjusting for age and updated mean HbA1c. Triglyceride and AER values were log transformed, and the ORs are presented per 20% increase in the covariate (1.2β). ARB, angiotensin II receptor blocker.
* B, baseline value; C, current value; M, updated mean value; A, cumulative incidence (e.g., any use). Covariates classified as C, M, and A enter into the analyses as time-dependent covariates.
- Table 4
Final multivariable GEE models for DPN and CAN as a function of baseline and time-dependent covariates
DPN OR (95% CI) Z-test value P value Mean HbA1c (per 1%) 1.63 (1.51, 1.77) 11.81 <0.0001 Age (per 5 years) 1.42 (1.30, 1.55) 8.05 <0.0001 Duration of type 1 diabetes (per 1 year) 1.10 (1.08, 1.13) 7.66 <0.0001 Height (per 5 cm) 1.27 (1.19, 1.35) 7.31 <0.0001 Any AER ≥300 mg/24 h (yes vs. no) 2.44 (1.60, 3.73) 4.12 <0.0001 Mean pulse rate (per 1 bpm) 1.03 (1.01, 1.04) 3.92 <0.0001 β-Blocker use (yes vs. no) 2.50 (1.47, 4.24) 3.38 0.0007 Any sustained AER ≥30 mg/24 h (yes vs. no) 1.48 (1.12, 1.96) 2.76 0.0058 CAN OR (95% CI) Z-test value P value Age (per 5 years) 1.50 (1.39, 1.62) 10.43 <0.0001 Mean HbA1c (per 1%) 1.27 (1.17, 1.37) 6.04 <0.0001 Any sustained AER ≥30 mg/24 h (yes vs. no) 1.95 (1.57, 2.43) 5.96 <0.0001 Duration of type 1 diabetes (per 1 year) 1.07 (1.05, 1.10) 5.73 <0.0001 Mean pulse rate (per 1 bpm) 1.04 (1.02, 1.06) 4.62 <0.0001 Mean SBP (per 5 mmHg) 1.11 (1.05, 1.17) 3.75 0.0002 β-Blocker use (yes vs. no) 2.01 (1.37, 2.93) 3.60 0.0003 eGFR <60 mL/min/1.73 m2 (yes vs. no) 2.88 (1.59, 5.19) 3.51 0.0005 Pulse rate (per 1 bpm) 1.02 (1.00, 1.03) 2.84 0.0045 Cigarette smoker (yes vs. no) 1.31 (1.04, 1.66) 2.28 0.0226 Data are based on 1,386 participants with at least two DPN assessments or 1,434 participants with at least two CAN assessments during DCCT/EDIC. Odds ratios and P values were generated using GEE models. Covariates are listed in the order of significance as indicated by the Z-test value.
In this Issue
May 2020, 69(5)
Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
