Clinical and demographic characteristics
The sample’s clinical and demographic characteristics are summarized in Table 1. A total of 2,448 patients were included in our study, 524 (21.4%) of whom were in the DPN group. The mean age of participants was 64.0 ± 12.9 years at the time of the investigation. 1409 (57.6%) of the sample were male and 1039 (42.4%) were female. The mean duration of diabetes was 10.3 ± 8.4 years, and the mean serum HbA1c level was 7.4 ± 1.4% (57 ± 15.3 mmol/mol). The majority of patients (96.2%) had received at least one form of pharmacological treatment for diabetes.
Table 1
Clinical and sociodemographic characteristics of the study
Variable | Total (n = 2448) | Without neuropathy (n = 1,924) | With neuropathy (n = 524) | P value |
N | % | N | % | N | % |
Sociodemographic factors |
Age, years | 64.0 ± 12.9 | 62.1 ± 12.4 | 71.1 ± 12.4 | < 0.001 |
≧ 65 | 1149 | 46.9 | 777 | 40.4 | 372 | 71.0 | < 0.001 |
Male Gender | 1409 | 57.6 | 1090 | 56.7 | 319 | 60.9 | 0.083 |
BMI, kg/m2 | 25.7 ± 4.1 | 25.8 ± 4.1 | 25.4 ± 4.1 | 0.071 |
Waist circumference, cm | 90.9 ± 10.5 | 90.4 ± 10.4 | 92.6 ± 10.4 | 0.030 |
SBP ≧ 130 mmHg or DBP ≧ 85 mmHg | 1389 | 57.4 | 1075 | 56.5 | 314 | 39.4 | 0.095 |
Smoker | 236 | 9.6 | 201 | 10.4 | 35 | 6.7 | 0.010 |
Alcohol drinker | 86 | 3.5 | 66 | 3.4 | 20 | 3.8 | 0.666 |
Diabetes-related factors |
Fasting plasma glucose, mg/dL | 143.2 ± 46.3 | 143.4 ± 45.9 | 142.6 ± 48 | 0.745 |
HbA1c, % (mmol/mol) | 7.4 ± 1.4 | 7.4 ± 1.4 | 7.5 ± 1.5 | 0.589 |
Duration of diabetes, years | 10.3 ± 8.4 | 9.3 ± 7.9 | 13.9 ± 9.4 | < 0.001 |
Type of diabetes treatment | | | | | | | < 0.001 |
No medication | 77 | 3.8 | 59 | 3.7 | 18 | 4.0 |
OHA only | 1430 | 69.8 | 1163 | 72.6 | 267 | 59.9 |
Insulin only | 156 | 7.6 | 100 | 6.2 | 56 | 12.6 |
Insulin + OHA | 385 | 18.8 | 280 | 17.5 | 105 | 23.5 |
Lipid-lowering drugs | | | | | | | 0.148 |
No medication | 396 | 16.2 | 298 | 15.5 | 98 | 18.7 |
statin only | 1654 | 67.6 | 1305 | 67.8 | 349 | 66.6 |
fibrate only | 63 | 2.6 | 47 | 2.4 | 16 | 3.1 |
statin + fibrate | 335 | 13.7 | 274 | 14.2 | 61 | 11.6 |
Biochemical factors |
Baseline TC, mg/dL | 191.7 ± 41.6 | 193.4 ± 42.3 | 185.6 ± 38.6 | < 0.001 |
≧ 200 | 878 | 36.3 | 709 | 37.3 | 169 | 32.5 | 0.042 |
Baseline TG, mg/dL | 199.7 ± 228.6 | 198.6 ± 223.1 | 204.5 ± 252.5 | 0.795 |
≧ 200 | 207 | 30.0 | 168 | 29.8 | 39 | 31.0 | 0.796 |
Baseline HDL-C, mg/dL | 50.3 ± 13.2 | 50.3 ± 12.9 | 50.2 ± 14.1 | 0.833 |
Female < 50; male < 40 | 749 | 31.5 | 582 | 31.2 | 167 | 32.7 | 0.508 |
Baseline LDL-C, mg/dL | 118.0 ± 31.3 | 119 ± 30.8 | 114.6 ± 32.7 | 0.019 |
≧ 130 | 524 | 31.5 | 423 | 32.7 | 101 | 27.5 | 0.060 |
Follow-up TC, mg/dL | 161.0 ± 28.3 | 162.4 ± 28.1 | 155.7 ± 28.2 | < 0.001 |
≧ 200 | 187 | 7.8 | 154 | 8.2 | 33 | 6.5 | 0.212 |
Follow-up TG, mg/dL | 151.1 ± 118.6 | 153.2 ± 123.4 | 143.1 ± 97.6 | 0.147 |
≧ 200 | 240 | 17.9 | 189 | 17.7 | 51 | 18.5 | 0.767 |
Follow-up HDL-C, mg/dL | 50.2 ± 12.6 | 50.4 ± 12.5 | 49.8 ± 13.2 | 0.344 |
Female < 50; male < 40 | 742 | 31.1 | 587 | 31.2 | 155 | 30.6 | 0.804 |
Follow-up LDL-C, mg/dL | 93.7 ± 23.7 | 94.8 ± 23.7 | 89.7 ± 23.1 | < 0.001 |
≧ 130 | 150 | 6.3 | 125 | 6.7 | 25 | 4.9 | 0.154 |
eGFR | 77.9 ± 30.9 | 81.5 ± 29.8 | 65.1 ± 31.6 | < 0.001 |
< 60 ml/min/1.73m2 | 603 | 27.8 | 388 | 22.8 | 215 | 45.7 | < 0.001 |
Comorbidities |
Heart disease (CVD or IHD) | 482 | 19.7 | 297 | 15.4 | 185 | 35.3 | < 0.001 |
Liver disease | 48 | 2.0 | 36 | 1.9 | 12 | 2.3 | 0.540 |
Data are expressed as mean ± SD for continuous variables and frequency (%) for categorical variables. Differences in continuous variables by ANOVA; differences in categorical variables by Fisher’s exact or chi-squared test. |
BMI, body mass index; kg, kilograms; cm, centimeters; HbA1c, glycated hemoglobin; OHA, oral hypoglycemic agent; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; CVD, cardiovascular disease; IHD, ischemic heart disease. |
The patients with DPN were significantly older than the patients without DPN (71.1 ± 12.4 years vs 62.1 ± 12.4 years, P < 0.001). Compared to those without DPN, patients with DPN tended to have a larger waist circumference (92.6 ± 10.4 cm vs 90.4 ± 10.4 cm, P = 0.030), were more likely to smoke (P = 0.010), and had a longer duration of diabetes (13.9 ± 9.4 years vs 9.3 ± 7.9 years, P < 0.001), fewer prescriptions for oral hypoglycemic medication, more insulin prescriptions, lower eGFR levels (65.1 ± 31.6 vs 81.5 ± 29.8 mL/min/1.73m2, P < 0.001), and higher rates of co-morbid heart disease (35.3% vs 15.4%, P < 0.001). No differences were found between DPN patients and controls with respect to gender, BMI, history of alcohol consumption, systolic and diastolic blood pressure, fasting plasma glucose, HbA1c levels, number of lipid-lowering drug prescriptions, and co-morbid liver disease.
In respect to the plasma lipid levels, the patients with DPN had not only lower baseline and follow-up TC values (baseline: 185.6 ± 38.6 vs 193.4 ± 42.3 mg/dL, P < 0.001; follow-up: 155.7 ± 28.2 vs 162.4 ± 28.1 mg/dL, P < 0.001), but also lower baseline and follow-up LDL-C levels (baseline: 114.6 ± 32.7 vs 119 ± 30.8 mg/dL, P = 0.019; follow-up: 89.7 ± 23.1 vs 94.8 ± 23.7 mg/dL, P < 0.001). No differences were found in plasma HDL-C or TGs levels.
Comparison of DPN risks between NL-N, NL-D, and HL-D
As mentioned, the 2,448 patients were allocated to one of three groups—NL-N, NL-D, or HL-D—depending on the lipidemic and prescription status of lipid-lowering drugs. The NL-N group comprised 396 patients (16.2%), 98 of whom had DPN; the NL-D group comprised 946 patients (38.6%), 213 of whom had DPN; and the HL-D group comprised 1106 individuals (45.2%), 213 of whom had DPN. To determine whether hyperlipidemia or lipid-lowering drugs were associated with DPN, multivariate logistic regression analysis was performed, revealing no differences in the risk of DPN between the NL-N and NL-D group (OR: 1.10; 95%CI: 0.58–2.09; Table 2). These results indicate that in patients without hyperlipidemia, intake of lipid-lowering medication did not impact the risk of DPN. Furthermore, the risk of DPN in the HL-D group did not significantly differ from those in the NL-N or NL-D group, suggesting that neither hyperlipidemia nor lipid-lowering drugs significantly influenced the risk of DPN in patients with T2D.
Table 2
Adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for DPN, according to lipidemic status and lipid-lowering drug use condition
Variables | Adjusted ORa | 95% CI | P-value |
Sub-analysis |
NL-N | 1.00 | ─ | ─ |
NL-D | 1.10 | 0.58–2.09 | 0.771 |
HL-D | 0.89 | 0.45–1.76 | 0.734 |
Sub-analysis |
NL-D | 1.00 | ─ | ─ |
NL-N | 0.91 | 0.48–1.72 | 0.771 |
HL-D | 0.81 | 0.49–1.34 | 0.410 |
NL-N, normolipidemic non-lipid-lowering drug users; NL-D, normolipidemic lipid-lowering drug users; HL-D, hyperlipidemic lipid-lowering drug users. |
aAdjusted for age, sex, waist, smoking, duration of diabetes, type of diabetes treatment, eGFR, heart disease. |
Differential impacts of LDL-C or TC on DPN in NL-N, NL-D, and HL-D
Significantly lower baseline and follow-up LDL-C and TC were found in the DPN population in our study. To explore whether plasma LDL-C or TC concentrations differentially affected risk of DPN, the HL group was subcategorized into two groups on the basis of plasma LDL-C and TC values. Patients with high plasma LDL-C levels (> 130 mg/dL) were allocated to the HLDL group, whereas those with low levels (< 130 mg/dL) were assigned to the NLDL group. Meanwhile, individuals with high plasma TC (> 200 mg/dL) and normal plasma TC (< 200 mg/dL) levels were assigned to the HTC and NTC group, respectively.
Multivariate logistic regression analysis was performed to determine whether baseline plasma LDL-C or TC levels were independently correlated with DPN. Relative to the NTC-N group, no significant differences were found with regard to DPN in either the NTC-D or HTC-D group (Table 3). The corresponding adjusted ORs of DPN were 1.09 (95% CI: 0.58–2.05, P = 0.781) and 0.85 (95% CI: 0.42–1.74, P = 0.661), respectively. Similarly, no differences in DPN risk were found between the NLDL-N, NLDL-D (OR: 1.42, 95%CI: 0.72–2.8; P = 0.308), and HLDL-D (OR: 1.37, 95% CI: 0.61–3.07; P = 0.447) groups.
Table 3
Adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for DPN, according to classification of lipid profiles
Variables | Adjusted ORa | 95% CI | P-value |
Sub-analysis – Baseline TC |
Baseline NTC-N | 1.00 | ─ | ─ |
Baseline NTC-D | 1.09 | 0.58–2.05 | 0.781 |
Baseline HTC-D | 0.85 | 0.42–1.74 | 0.661 |
Sub-analysis – Baseline LDL-C |
Baseline NLDL-N | 1.00 | ─ | ─ |
Baseline NLDL-D | 1.42 | 0.72–2.8 | 0.308 |
Baseline HLDL-D | 1.37 | 0.61–3.07 | 0.447 |
Sub-analysis – Follow-up TC |
Follow-up NTC-N | 1.00 | ─ | ─ |
Follow-up NTC-D | 1.10 | 0.59–2.05 | 0.770 |
Follow-up HTC-D | 0.72 | 0.2–2.62 | 0.617 |
Sub-analysis – Follow-up LDLC |
Follow-up NLDL-N | 1.00 | ─ | ─ |
Follow-up NLDL-D | 1.09 | 0.58–2.03 | 0.790 |
Follow-up HLDL-D | 0.75 | 0.2–2.79 | 0.668 |
NTC-N, normocholesterolemic non-lipid-lowering drug users; NTC-D, normocholesterolemic lipid-lowering drug users; HTC-D, hypercholesterolemic lipid-lowering drug users; NLDL-N, normal LDL-C non-lipid-lowering drug users; NLDL-D: normal LDL-C lipid-lowering drug users; HLDL-D: hyper-LDL-C lipid-lowering drug users. |
aAdjusted for age, sex, waist, smoking, duration of diabetes, type of diabetes treatment, eGFR, heart disease. |
Regarding follow-up plasma TC and LDL-C levels, similar results were found. Multivariate analysis revealed no differences in the DPN risk between the NTC-N, NTC-D (OR: 1.10, 95% CI: 0.59–2.05), and HTC-D (OR: 0.72, 95% CI: 0.2–2.62) group. Lastly, compared with the NLDL-N group, neither the NLDL-D nor HLDL-D group showed significant differences in the risk of DPN, with corresponding adjusted ORs of 1.09 (95% CI: 0.58–2.03) and 0.75 (95% CI: 0.2–2.79), respectively. These results suggest that plasma LDL-C and TC levels were not associated with DPN in our study.
Differential impacts of statin or fibrate on DPN in NL-N, NL-D, and HL-D
Finally, to determine whether different classes of lipid-lowering drugs had diverse effects on the risk of DPN, we categorized the patients who received medication intervention into two subgroups: the statin (S) and the fibrate (F) group. The results of the multivariate logistic regression analysis are shown in Table 4.
Table 4
Adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for DPN, according to different classes of lipid-lowering drugs use
Variables | Adjusted ORa | 95% CI | P-value |
Sub-analysis – Statin |
NL-N | 1.00 | ─ | ─ |
NL-S | 1.09 | 0.59–2.03 | 0.776 |
HL-S | 0.89 | 0.46–1.71 | 0.720 |
Sub-analysis – Fibrate |
NL-N | 1.00 | ─ | ─ |
NL-F | 0.73 | 0.33–1.61 | 0.431 |
HL-F | 0.50 | 0.16–1.6 | 0.245 |
NL-N, normolipidemic non-lipid-lowering drug users; NL-S, normolipidemic statin users; HL-S, hyperlipidemic statin users; NL-F, normolipidemic fibrate users; HL-F, hyperlipidemic fibrate users |
aAdjusted for age, sex, waist, smoking, duration of diabetes, type of diabetes treatment, eGFR, heart disease. |
First, relative to the NL-N group, no significant differences in the risk of DPN were found in the NL-S and HL-S groups. The corresponding adjusted ORs were 1.09 (95% CI: 0.59–2.03) and 0.89 (95% CI: 0.46–1.71) in the NL-S and HL-S group, respectively. As concerns fibrate use, no group was significantly associated with DPN. Our results suggest that neither statin nor fibrate are significant risk factors for DPN.