Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes
Abstract
:1. Introduction
2. Research Design and Method
2.1. Data Source
2.2. Ethics Statement
2.3. Study Population
2.4. Measurements
2.5. Surrogate Measurement of NAFLD and Probability of Advanced Fibrosis
× BMI + 0.718 × ln GGT + 0.053 × WC − 15.745) × 100
2.6. Outcome Variable
2.7. Statistical Analysis
3. Results
3.1. Characteristics of Study Population
3.2. Risk of CVD According to NAFLD and CKD
3.3. Stratified Analyses
3.4. Subgroup Analysis in Subjects with NAFLD
3.5. Subgroup Analysis in Subjects with CKD
4. Discussion
5. Strengths and Limitations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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No CKD /No NAFLD | No CKD/NAFLD | CKD/No NAFLD | CKD/NAFLD | p-Value | |
---|---|---|---|---|---|
Number of subjects | 1,065,190 | 379,638 | 124,507 | 37,879 | |
Age, years | 56.5 ± 12.1 | 51.9 ± 11.5 | 65.3 ± 11.2 | 62.0 ± 11.5 | <0.0001 |
Male (%) | 567,790 (53.3) | 283,075 (75.6) | 49,682 (39.9) | 21,439 (56.6) | <0.0001 |
Smoking status | <0.0001 | ||||
Never-smoker (%) | 657,597 (61.7) | 164,527 (43.3) | 90,663 (72.8) | 22,810 (60.2) | |
Ex-smoker (%) | 170,467 (16.0) | 78,392 (20.7) | 18,091 (14.5) | 7351 (19.4) | |
Current smoker (%) | 237,126 (22.3) | 136,719 (36.0) | 15,753 (12.7) | 7736 (20.4) | |
Alcohol consumption | <0.0001 | ||||
None (%) | 680,576 (63.9) | 168,735 (44.5) | 97,478 (78.3) | 24,336 (64.2) | |
Mild-to-moderate (%) | 384,614 (36.1) | 210,903 (55.6) | 27,032 (21.7) | 13,561 (35.8) | |
Regular physical activity (%) | 229,673 (21.6) | 66,218 (17.4) | 25,657 (20.6) | 6911 (18.2) | <0.0001 |
BMI, kg/m2 | 23.9 ± 2.7 | 28.2 ± 3.4 | 24.1 ± 2.7 | 28.4 ± 3.5 | <0.0001 |
Waist circumference (cm) | 82.0 ± 7.2 | 93.0 ± 8.6 | 83.0 ± 7.3 | 94.2 ± 8.3 | <0.0001 |
SBP (mmHg) | 127.1 ± 15.5 | 132.1 ± 15.4 | 129.8 ± 16.6 | 132.9 ± 16.4 | <0.0001 |
DBP (mmHg) | 77.9 ± 9.9 | 82.3 ± 10.3 | 77.6 ± 10.3 | 80.9 ± 10.5 | <0.0001 |
Hypertension (%) | 498,952 (46.8) | 221,449 (58.3) | 86,834 (69.7) | 29,484 (77.8) | <0.0001 |
Dyslipidemia (%) | 380,152 (35.7) | 173,055 (45.6) | 58,176 (46.7) | 21,034 (55.5) | <0.0001 |
DM duration ≥ 5 years (%) | 306,461 (28.8) | 65,192 (17.2) | 55,941 (44.9) | 12,921 (34.1) | <0.0001 |
Insulin use (%) | 71,954 (6.8) | 16,580 (4.4) | 16,953 (13.6) | 4135 (10.9) | <0.0001 |
OHA ≥ 3 (%) | 143,862 (13.5) | 39,644 (10.4) | 23,172 (18.6) | 6274 (16.6) | <0.0001 |
Statin use (%) | 277,520 (26.1) | 102,071 (26.9) | 44,274 (35.6) | 14,639 (38.6) | <0.0001 |
Laboratory results | |||||
Fasting glucose (mg/dL) | 144.1 ± 45.8 | 152.9 ± 47.1 | 138.9 ± 48.6 | 147.8 ± 52.3 | <0.0001 |
Total cholesterol (mg/dL) | 195.3 ± 43.6 | 211.9 ± 47.4 | 194.8 ± 45.1 | 209.1 ± 50.8 | <0.0001 |
Triglyceride (mg/dL) † | 122.2 (122.1, 122.3) | 232.7 (232.3, 233.0) | 131.6 (131.3, 132.0) | 231.7 (230.5, 233.0) | <0.0001 |
HDL-cholesterol (mg/dL) | 53.1 ± 23.8 | 49.1 ± 32.1 | 53.1 ± 40.0 | 55.7 ± 62.4 | <0.0001 |
Urine Protein | |||||
Negative | 983,624 (92.3) | 335,195 (88.3) | 103,959 (83.5) | 30,280 (79.9) | <0.0001 |
Trace | 32,872 (3.1) | 15,754 (4.2) | 5174 (4.2) | 1808 (4.8) | |
1+ | 30,976 (2.9) | 17,327 (4.6) | 7274 (5.8) | 2732 (7.2) | |
2+ | 13,212 (1.2) | 8457 (2.2) | 5212 (4.2) | 1985 (5.2) | |
3,4+ | 3728 (0.4) | 2432 (0.6) | 2354 (1.9) | 893 (2.4) |
Number of Subjects | Number of Events | Incidence Rate (1000 p-y) | Model 1 | Model 2 | Model 3 | After IPTW | |
---|---|---|---|---|---|---|---|
Adjusted HR (95% CI) | |||||||
Myocardial Infarction | |||||||
No CKD/No NAFLD | 1,065,190 | 24,759 | 3.35 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
No CKD/NAFLD | 379,638 | 8617 | 3.28 | 1.18 (1.15–1.21) | 1.16 (1.13–1.19) | 1.21 (1.18–1.25) | 1.27 (1.24–1.31) |
CKD/No NAFLD | 124,507 | 5752 | 6.85 | 1.45 (1.40–1.49) | 1.33 (1.29–1.37) | 1.33 (1.30–1.37) | 1.18 (1.24–1.31) |
CKD/NAFLD | 37,897 | 1735 | 6.68 | 1.56 (1.49–1.64) | 1.43 (1.36–1.50) | 1.49 (1.42–1.57) | 1.58 (1.50–1.67) |
Stroke | |||||||
No CKD/No NAFLD | 1,065,190 | 36,027 | 4.90 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
No CKD/NAFLD | 379,638 | 11,468 | 4.39 | 1.18 (1.15–1.20) | 1.14 (1.11–1.16) | 1.21 (1.18–1.24) | 1.33 (1.30–1.11) |
CKD/No NAFLD | 124,507 | 8340 | 10.04 | 1.28 (1.25–1.31) | 1.19 (1.16–1.22) | 1.19 (1.16–1.22) | 1.08 (1.05–1.11) |
CKD/NAFLD | 37,897 | 2592 | 10.10 | 1.51 (1.45–1.57) | 1.37 (1.32-1.43) | 1.48 (1.41–1.54) | 1.54 (1.47–1.62) |
Overall mortality | |||||||
No CKD/No NAFLD | 1,065,190 | 70,966 | 9.51 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
No CKD/NAFLD | 379,638 | 19,468 | 7.35 | 1.09 (1.07–1.11) | 1.10 (1.08–1.11) | 1.54 (1.52–1.57) | 1.69 (1.66–1.72) |
CKD/No NAFLD | 124,507 | 21,250 | 24.90 | 1.46 (1.44–1.48) | 1.39 (1.37–1.42) | 1.41 (1.39–1.43) | 1.17 (1.15–1.19) |
CKD/NAFLD | 37,897 | 5293 | 20.04 | 1.41 (1.37–1.45) | 1.37 (1.33–1.40) | 2.00 (1.94–2.06) | 2.13 (2.06–2.21) |
Cardiovascular mortality | |||||||
No CKD/No NAFLD | 1,065,190 | 12,490 | 1.67 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
No CKD/NAFLD | 379,638 | 3349 | 1.26 | 1.14 (1.10–1.19) | 1.09 (1.05–1.14) | 1.47 (1.41–1.54) | 1.57 (1.51–1.63) |
CKD/No NAFLD | 124,507 | 4659 | 5.46 | 1.67 (1.62–1.73) | 1.55 (1.50–1.61) | 1.57 (1.51–1.62) | 1.34 (1.29–1.40) |
CKD/NAFLD | 37,897 | 1190 | 4.50 | 1.75 (1.65–1.85) | 1.58 (1.49–1.68) | 2.20 (2.07–2.35) | 2.31 (2.15–2.49) |
AAR | Number of Subjects | Number of Events | Incidence of Event (1000 Person-Years) | Model 1 | Model 2 | |
---|---|---|---|---|---|---|
Adjusted HR (95% CI) | ||||||
Myocardial Infarction | ||||||
Non-CKD | <0.8 | 180,271 | 3576 | 2.85 | 1 (reference) | 1 (reference) |
<1.4 | 173,116 | 4266 | 3.56 | 0.96 (0.91,1.00) | 1.01 (0.96, 1.05) | |
≥1.4 | 26,251 | 775 | 4.42 | 1.08 (1.00, 1.17) | 1.13 (1.04, 1.23) | |
CKD | <0.8 | 11,787 | 444 | 5.34 | 1.30 (1.18, 1.44) | 1.21 (1.09, 1.34) |
<1.4 | 21,347 | 1047 | 7.18 | 1.41 (1.31, 1.51) | 1.35 (1.26, 1.46) | |
≥1.4 | 4763 | 244 | 7.93 | 1.43 (1.25,1.63) | 1.38 (1.21, 1.58) | |
Stroke | ||||||
Non-CKD | <0.8 | 180,271 | 3889 | 3.11 | 1 (reference) | 1 (reference) |
<1.4 | 173,116 | 6332 | 5.32 | 1.13 (1.08, 1.17) | 1.14 (1.09, 1.19) | |
≥1.4 | 26,251 | 1247 | 7.18 | 1.30 (1.22, 1.39) | 1.29 (1.20, 1.37) | |
CKD | <0.8 | 11,787 | 564 | 6.82 | 1.25 (1.14, 1.37) | 1.15 (1.05, 1.26) |
<1.4 | 21,347 | 1600 | 11.13 | 1.45 (1.36, 1.54) | 1.38 (1.29, 1.46) | |
≥1.4 | 4763 | 428 | 14.14 | 1.57 (1.42, 1.74) | 1.50 (1.36, 1.67) | |
Overall mortality | ||||||
Non-CKD | <0.8 | 180,271 | 5452 | 4.32 | 1 (reference) | 1 (reference) |
<1.4 | 173,116 | 10,646 | 8.81 | 1.24 (1.20, 1.29) | 1.26 (1.22, 1.31) | |
≥1.4 | 26,251 | 3370 | 19.02 | 2.22 (2.12, 2.32) | 2.16 (2.06, 2.25) | |
CKD | <0.8 | 11,787 | 1015 | 12.03 | 1.40 (1.31,1.50) | 1.32 (1.23, 1.41) |
<1.4 | 21,347 | 3185 | 21.46 | 1.75 (1.67, 1.84) | 1.71 (1.63, 1.79) | |
≥1.4 | 4763 | 1093 | 34.87 | 2.44 (2.28, 2.61) | 2.36 (2.20, 2.52) | |
Cardiovascular mortality | ||||||
Non-CKD | <0.8 | 180,271 | 949 | 0.75 | 1 (reference) | 1 (reference) |
<1.4 | 173,116 | 1864 | 1.54 | 1.19 (1.10, 1.29) | 1.23 (1.14, 1.34) | |
≥1.4 | 26,251 | 536 | 3.02 | 1.92 (1.72,2.14) | 1.93 (1.73, 2.15) | |
CKD | <0.8 | 11,787 | 226 | 2.68 | 1.70 (1.47, 1.97) | 1.56 (1.35, 1.81) |
<1.4 | 21,347 | 729 | 4.91 | 2.08 (1.88, 2.31) | 2.00 (1.81, 2.22) | |
≥1.4 | 4763 | 235 | 7.50 | 2.65 (2.28, 3.07) | 2.57 (2.21, 2.98) |
Urine Protein | Number of Subjects | Number of Events | Incidence of Event (1000 p-y) | Multivariate Model HR (95% CI) | After IPTW HR (95% CI) | |
---|---|---|---|---|---|---|
Myocardial Infarction | ||||||
Non-NAFLD | Negative | 103,959 | 4286 | 6.04 | 1 (reference) | 1 (reference) |
Trace | 5174 | 258 | 7.45 | 1.17 (1.04–1.33) | 1.14 (1.00–1.29) | |
1+ | 7274 | 496 | 10.68 | 1.59 (1.44–1.75) | 1.50 (1.36–1.65) | |
2+ | 5212 | 438 | 13.64 | 2.01 (1.82–2.22) | 1.77 (1.60–1.96) | |
3,4+ | 2888 | 274 | 15.74 | 2.34 (2.06–2.65) | 1.93 (1.70–2.19) | |
NAFLD | Negative | 30,280 | 1219 | 5.82 | 1.19 (1.11–1.28) | 1.23 (1.15–1.32) |
Trace | 1808 | 81 | 6.51 | 1.29 (1.03–1.61) | 1.30 (1.05–1.61) | |
1+ | 2732 | 162 | 8.84 | 1.64 (1.40–1.93) | 1.55 (1.32–1.82) | |
2+ | 1985 | 169 | 13.20 | 2.43 (2.08–2.85) | 2.29 (1.96–2.68) | |
3,4+ | 1092 | 104 | 15.44 | 2.91 (2.38–3.55) | 2.57 (2.11–3.13) | |
Stroke | ||||||
Non-NAFLD | Negative | 103,959 | 6401 | 9.12 | 1 (reference) | 1 (reference) |
Trace | 5174 | 406 | 11.88 | 1.25 (1.13–1.38) | 1.21 (1.09–1.34) | |
1+ | 7274 | 644 | 14.01 | 1.40 (1.29–1.52) | 1.30 (1.20–1.42) | |
2+ | 5212 | 521 | 16.37 | 1.66 (1.52–1.82) | 1.47 (1.34–1.61) | |
3,4+ | 2888 | 368 | 21.65 | 2.33 (2.09–2.59) | 1.92 (1.73–2.14) | |
NAFLD | Negative | 30,280 | 18,979 | 9.16 | 1.25 (1.18–1.33) | 1.30 (1.22–1.37) |
Trace | 1808 | 138 | 11.25 | 1.49 (1.25–1.77) | 1.57 (1.34–1.85) | |
1+ | 2732 | 239 | 13.25 | 1.66 (1.46–1.90) | 1.62 (1.42–1.85) | |
2+ | 1985 | 182 | 14.36 | 1.81 (1.56–2.11) | 1.68 (1.45–1.95) | |
3,4+ | 1092 | 136 | 20.59 | 2.74 (2.30–3.25) | 2.40 (2.04–2.84) | |
Overall mortality | ||||||
Non-NAFLD | Negative | 103,959 | 16,002 | 22.24 | 1 (reference) | 1 (reference) |
Trace | 5174 | 1027 | 29.14 | 1.25 (1.29–1.34) | 1.20 (1.23–1.28) | |
1+ | 7274 | 1788 | 37.60 | 1.55 (1.48–1.63) | 1.41 (1.34–1.48) | |
2+ | 5212 | 1492 | 45.02 | 1.98 (1.87–2.09) | 1.63 (1.54–1.72) | |
3,4+ | 2888 | 941 | 52.43 | 2.59 (2.42–2.76) | 1.92 (1.80–2.05) | |
NAFLD | Negative | 30,280 | 3783 | 17.79 | 1.38 (1.32–1.43) | 1.47 (1.41–1.53) |
Trace | 1808 | 284 | 22.49 | 1.85 (1.68–2.03) | 1.84 (1.64–2.05) | |
1+ | 2732 | 482 | 25.74 | 1.33 (1.30–1.37) | 1.89 (1.73–2.07) | |
2+ | 1985 | 453 | 34.40 | 2.56 (2.32–2.81) | 2.45 (2.24–2.69) | |
3,4+ | 1092 | 291 | 41.76 | 3.53 (3.14–3.98) | 3.09 (2.77–3.45) | |
Cardiovascular mortality | ||||||
Non-NAFLD | Negative | 103,959 | 3469 | 4.82 | 1 (reference) | 1 (reference) |
Trace | 5174 | 235 | 6.67 | 1.34 (1.17–1.53) | 1.28 (1.12–1.47) | |
1+ | 7274 | 429 | 9.02 | 1.77 (1.60–1.96) | 1.59 (1.43–1.76) | |
2+ | 5212 | 321 | 9.69 | 2.07 (1.84–2.33) | 1.69 (1.50–1.89) | |
3,4+ | 2888 | 205 | 11.42 | 2.81 (2.44–3.25) | 2.07 (1.80–2.38) | |
NAFLD | Negative | 30,280 | 836 | 3.93 | 1.36 (1.24–1.48) | 1.41 (1.30–1.53) |
Trace | 1808 | 69 | 5.46 | 1.86 (1.46–2.37) | 2.05 (1.65–2.54) | |
1+ | 2732 | 120 | 6.41 | 2.09 (1.73–2.52) | 2.04 (1.70–2.43) | |
2+ | 1985 | 99 | 7.52 | 2.60 (2.12–3.19) | 2.49 (2.06–3.00) | |
3,4+ | 1092 | 66 | 9.47 | 3.77 (2.94–4.83) | 3.30 (2.64–4.13) |
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Chung, G.-E.; Han, K.; Lee, K.-N.; Cho, E.-J.; Bae, J.-H.; Yang, S.-Y.; Yu, S.-J.; Choi, S.-H.; Yim, J.-Y.; Heo, N.-J. Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes. Biomedicines 2022, 10, 1245. https://doi.org/10.3390/biomedicines10061245
Chung G-E, Han K, Lee K-N, Cho E-J, Bae J-H, Yang S-Y, Yu S-J, Choi S-H, Yim J-Y, Heo N-J. Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes. Biomedicines. 2022; 10(6):1245. https://doi.org/10.3390/biomedicines10061245
Chicago/Turabian StyleChung, Goh-Eun, Kyungdo Han, Kyu-Na Lee, Eun-Ju Cho, Jung-Ho Bae, Sun-Young Yang, Su-Jong Yu, Seung-Ho Choi, Jeong-Yoon Yim, and Nam-Ju Heo. 2022. "Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes" Biomedicines 10, no. 6: 1245. https://doi.org/10.3390/biomedicines10061245
APA StyleChung, G. -E., Han, K., Lee, K. -N., Cho, E. -J., Bae, J. -H., Yang, S. -Y., Yu, S. -J., Choi, S. -H., Yim, J. -Y., & Heo, N. -J. (2022). Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes. Biomedicines, 10(6), 1245. https://doi.org/10.3390/biomedicines10061245