Characteristics Of The Study Participants
Of all 5518 participants, 5340 performed LDL_C measurement on at least 3 visits during the study and were included in this analysis. The 5340 participants included 1632 women (30.6%), and had mean age was 62.8 (±6.6) years old. Key baseline characteristics were similar in the two therapy groups (Table 1).
Table 1
Characteristics of the Patients at Baseline or during follow-up
| | All patients (n=5340) | | Therapy Statusa | | LDL variabilityb |
Fenofibrate(n=2673) | Placebo (n=2667) | VIM <13.2 (n=2665) | VIM ≥13.2 (n=2675) | P |
At baseline | | | | | | | | | |
Age | | 62.8±6.6 | | 62.8±6.5 | 62.8±6.7 | | 62.9±6.6 | 62.6±6.5 | 0.06 |
Female sex (n, %) | | 1632 (30.6) | | 817 (30.6) | 815 (30.6) | | 770 (28.9) | 862 (32.2) | 0.008 |
Weight | | 94.9±18.3 | | 94.6±18.2 | 95.2±18.5 | | 95.6±17.9 | 94.3±18.7 | 0.009 |
Body-mass index | | 32.3±5.3 | | 32.2±5.3 | 32.4±5.3 | | 32.4±5.3 | 32.2±5.4 | 0.28 |
Waist circumference (cm) | | 107.7±13.5 | | 107.5±13.3 | 107.8±13.7 | | 108.1±13.4 | 107.2±13.6 | 0.02 |
Systolic blood pressure (mmHg) | | 133.9±17.7 | | 133.8±17.6 | 133.9±17.9 | | 132.2±17.2 | 135.5±18.1 | <0.0001 |
Diastolic blood pressure (mmHg) | | 74.0±10.8 | | 73.8±10.6 | 74.1±10.9 | | 73.1±10.6 | 74.8±10.9 | <0.0001 |
Fasting serum glucose (mg/dl) | | 175.8±54.6 | | 176.3±54.1 | 175.3±55.1 | | 170.7±51.8 | 180.8±56.8 | <0.0001 |
Total cholesterol (mg/dl) | | 175.3±37.4 | | 174.9±36.8 | 175.7±38.0 | | 162.8±28.2 | 187.8±41.1 | <0.0001 |
LDL cholesterol (mg/dl) | | 100.6±30.7 | | 100.0±30.2 | 101.2±31.0 | | 91.5±24 | 109.6±33.8 | <0.0001 |
HDL cholesterol (mg/dl) | | 38.1±7.8 | | 38.0±7.8 | 38.2±7.7 | | 38.5±7.7 | 37.7±7.8 | 0.0005 |
Plasma triglyceride (mg/dl) | | 188.0±113 | | 189.7±111,5 | 186.3±114.6 | | 167±91.1 | 208.9±127.9 | <0.0001 |
Serum creatinine (mg/dl) | | 0.92±0.22 | | 0.93±0.23 | 0.93±0.22 | | 0.92±0.23 | 0.93±0.21 | 0.04 |
Lipids during follow-up | | | | | | | | | |
Mean total cholesterol (mg/dl) | | 160.6±26.8 | | 158.3±26.2 | 162.9±27.2* | | 156.9±23.6 | 164.3±29.1 | <0.0001 |
Mean plasma triglyceride (mg/dl) | | 165.5±88.5 | | 152.5±80.6 | 178.6±94.0* | | 151.4±72.6 | 179.5±100 | <0.0001 |
Mean HDL cholesterol (mg/dl) | | 39.9±8.2 | | 40.2±8.7 | 39.5±7.8* | | 40.5±8.3 | 39.2±8.1 | <0.0001 |
Mean LDL cholesterol (mg/dl) | | 88.4±19.8 | | 88.2±19.9 | 88.6±19.7 | | 86.6±18.4 | 90.1±21.0 | <0.0001 |
Maximum LDL cholesterol (mg/dl) | | 120.1±29.6 | | 119.0±29.6 | 121.3±29.5* | | 107.4±22.7 | 132.8±30.2 | <0.0001 |
Minimum LDL cholesterol (mg/dl) | | 64.2±17.8 | | 64.7±17.5 | 63.7±18.0‡ | | 68.2±17.1 | 60.1±17.5 | <0.0001 |
LDL SD | | 19.3±8.8 | | 18.7±8.8 | 19.9±8.8* | | 13.5±4.8 | 25.1±8.1 | <0.0001 |
LDL CV (%) | | 22.1±9.2 | | 21.4±9.0 | 22.7±9.4* | | 15.8±5.3 | 28.3±8.0 | <0.0001 |
LDL VIM | | 13.9±6.0 | | 13.8±6.0 | 14.1±5.9 | | 9.3±2.5 | 18.5±4.8 | <0.0001 |
LDL ARV | | 18.4±9.6 | | 17.7±9.5 | 19.0±9.6* | | 13.7±5.8 | 23.0±10.3 | <0.0001 |
Values were means (SD) or median (quartile). VIM indicates variability independent of the mean; ARV, average real variability; and MMD, the difference of maximum minus minimum LDL. aThe Fenofibrate vs Placebo group, *P<0.001; †P<0.01; and ‡P<0.05. bHigh vs Low VIM, and the P value is given. |
Compared with the placebo group, the Fenofibrate group had significantly (P<0.001) lower total cholesterol (158.3 vs. 162.9 mg/dl) and triglyceride levels (152.5 vs. 178.6 mg/dl), but higher HDL levels (40.2 vs. 39.5 mg/dl). For LDL_C levels, the Fenofibrate group showed similar mean LDL_C, higher maximum LDL_C (120.1 vs. 119.0 mg/dl), but lower minimum LDL_C (63.7 vs. 64.7 mg/dl). For LDL_C variability indices, the Fenofibrate group showed no difference in mean LDL level and LDL VIM, but lower SD and ARV (all P<0.001, Table 1).
Compared with low LDL_C variability (VIM<13.2), high LDL_C variability (VIM≥13.2) group had significantly greater baseline body weight and waist circumference, and significantly (P<0.0001) higher baseline systolic and diastolic blood pressure, fasting serum glucose, and total, HDL and LDL cholesterol, but lower triglyceride levels. Increased LDL_C variability group had significantly (P<0.0001) higher total and LDL cholesterol and triglyceride, but lower HDL cholesterol. As expected, increased LDL_C variability group had significantly (P<0.0001) higher various LDL_C variability indices, including SD, VIM, and ARV (Table 1).
Variability Indices And Outcomes
During the trial, the primary outcome, all-cause deaths and cardiovascular deaths occurred in 276, 179 and 87 subjects in the Fenofibrate, respectively, and in 294, 201 and 102 subjects in the placebo group, respectively. In multiple C ox regression analyses adjusted for sex and age, education, waist circumference, body mass index, systolic and diastolic blood pressure, and fasting plasma glucose at baseline, and additionally mean LDL_C during follow-up, all three LDL_C variability indices were significantly (P<0.001) associated with primary outcome, and all-cause and cardiovascular deaths in total population and the Fenofibrate group. However, in the placebo group, only LDL_C ARV was significantly associated with total and cardiovascular deaths (Table 2).
Table 2
Association of mean and variability indexes of LDL cholesterol during follow-up with Outcomes
Outcomes | Model | | Total population (n=5340) | | Fenofibrate(n=2673) | | Placebo (n=2667) |
| HR (95%CI) | P | | HR (95%CI) | P | | HR (95%CI) | P |
Primary outcome | | | | | | | | | | |
Mean (+20 mg/dl) | Nonea | | 1.33 (1.22-1.45) | <0.0001 | | 1.33 (1.17-1.51) | <0.0001 | | 1.34 (1.19-1.51) | <0.0001 |
CV (+9.2%) | Nonea | | 0.93 (0.85-1.02) | 0.13 | | 1.05 (0.92-1.20) | 0.44 | | 0.83 (0.73-0.94) | 0.004 |
| Meanb | | 0.97 (0.88-1.06) | 0.47 | | 1.09 (0.95-1.24) | 0.21 | | 0.86 (0.75-0.98) | 0.023 |
VIM (+6 U) | Nonea | | 0.88 (0.71-1.09) | 0.24 | | 1.16 (0.87-1.56) | 0.31 | | 0.67 (0.50-0.90) | 0.008 |
| Meanb | | 0.92 (0.74-1.14) | 0.44 | | 1.21 (0.89-1.62) | 0.22 | | 0.70 (0.52-0.95) | 0.02 |
ARV (+10 mg/dl) | Nonea | | 1.51 (1.31-1.75) | <0.0001 | | 1.64 (1.36-1.97) | <0.0001 | | 1.35 (1.09-1.68) | 0.006 |
| Meanb | | 1.27 (1.07-1.49) | 0.005 | | 1.20 (1.04-1.39) | 0.01 | | 1.32 (1.16-1.50) | <0.0001 |
Total mortality | | | | | | | | | | |
Mean (+20 mg/dl) | Nonea | | 1.32 (1.19-1.46) | <0.0001 | | 1.25 (1.07-1.46) | 0.004 | | 1.37 (1.20-1.56) | <0.0001 |
CV (+9.2%) | Nonea | | 1.07 (0.97-1.18) | 0.19 | | 1.26 (1.10-1.44) | 0.001 | | 0.93 (0.81-1.07) | 0.29 |
| Mean | | 1.12 (1.01-1.23) | 0.03 | | 1.29 (1.13-1.49) | 0.0003 | | 0.98 (0.85-1.13) | 0.77 |
VIM (+6 U) | Nonea | | 1.15 (1.05-1.27) | 0.004 | | 1.26 (1.12-1.43) | 0.0003 | | 1.06 (0.92-1.22) | 0.45 |
| Meanb | | 1.13 (1.03-1.25) | 0.01 | | 1.25 (1.10-1.42) | 0.0007 | | 1.04 (0.90-1.19) | 0.63 |
ARV (+10 mg/dl) | Nonea | | 1.37 (1.26-1.49) | <0.0001 | | 1.35 (1.21-1.52) | <0.0001 | | 1.40 (1.24-1.59) | <0.0001 |
| Meanb | | 1.29 (1.17-1.42) | <0.0001 | | 1.31 (1.15-1.51) | <0.0001 | | 1.29 (1.12-1.48) | 0.0006 |
Cardiovascular mortality | | | | | | | | | | |
Mean (+20 mg/dl) | Nonea | | 1.34 (1.16-1.54) | <0.0001 | | 1.30 (1.05-1.62) | 0.018 | | 1.36 (1.13-1.64) | 0.001 |
CV (+9.2%) | Nonea | | 1.04 (0.90-1.20) | 0.59 | | 1.33 (1.10-1.61) | 0.003 | | 0.83 (0.67-1.01) | 0.07 |
| Meanb | | 1.09 (0.94-1.26) | 0.27 | | 1.37 (1.13-1.66) | 0.001 | | 0.86 (0.70-1.07) | 0.17 |
VIM (+6 U) | Nonea | | 1.17 (1.02-1.34) | 0.02 | | 1.38 (1.18-1.61) | <0.0001 | | 0.96 (0.78-1.18) | 0.68 |
| Meanb | | 1.15 (1.00-1.31) | 0.047 | | 1.35 (1.16-1.59) | 0.0002 | | 0.94 (0.76-1.15) | 0.53 |
ARV (+10 mg/dl) | Nonea | | 1.37 (1.22-1.55) | <0.0001 | | 1.44 (1.24-1.68) | <0.0001 | | 1.29 (1.07-1.55) | 0.008 |
| Meanb | | 1.28 (1.11-1.47) | 0.0006 | | 1.40 (1.17-1.68) | 0.0003 | | 1.15 (0.93-1.42) | 0.19 |
Model indicates which LDL index was entered into the models in addition to the predictor variable per se. VIM indicates variability independent of the mean; ARV, average real variability; and MMD, the difference of maximum minus minimum LDL. All models were adjusted for mean of lipid during visits, therapy group (if applicable), sex, and baseline age, education, body mass index, systolic and diastolic blood pressure, smoking, drinking, and fasting plasma glucose. aNone indicates that no LDL cholesterol index was entered in the model. bMean indicates that the mean of LDL_C during visits was additionally entered in the model. |
To allow for nonlinearity, all three LDL_C variability indices were split into deciles and HRs calculated in relation to the first decile in the placebo group. For the primary outcome, only the 10th decile of LDL_C VIM and ARV in both groups had significantly higher risk (Figure 1B). For all-cause deaths, only the 10th decile of LDL_C CV in the intensive-therapy group had marginally significantly higher risk (Figure 1C). For cardiovascular deaths, some deciles of LDL_C variability indices had significantly lower risk but not higher risk.
Maximum And Minimum Ldl_c During Follow-up And Outcomes
In multiple Cox regression analyses, the mean LDL_C during follow-up was significantly associated with primary outcome, total mortality, and cardiovascular mortality in total population, the Fenofibrate group, and the placebo group (Table 2). We further investigated the prognostic variability of maximum and minimum LDL_C during follow-up to look at the most benefits in the way of lipid control. In multivariate analysis adjusted for other covariates and mean LDL_C during follow-up, the minimum but not the maximum LDL_C were more frequently significantly associated with the primary outcome, and total and cardiovascular deaths in total population, as well as in the Fenofibrate and placebo groups analyzed separately. The hazard ratios of the 1-SD increase in minimum LDL_C were 1.54 (95%CI, 1.41-1.67), 1.41 (1.28-1.56), and 1.54 (1.34-1.77) for primary outcome, all-cause deaths and cardiovascular deaths, respectively in the total population (Table 3).
Table 3
Hazard ratios for top decile of maximum and minimum LDL cholesterol during follow-up for Outcomes
| | Total population (n=5340) | | Fenofibrate(n=2673) | | Placebo (n=2667) |
| | HR (95%CI) | P | | HR (95%CI) | P | | HR (95%CI) | P |
Maximum LDL_C | | | | | | | | | |
+1 SD (30 mg/dL) | | | | | | | | | |
Primary outcome | | 1.10 (1.01-1.20) | 0.04 | | 1.15 (1.01-1.31) | 0.03 | | 1.15 (1.01-1.31) | 0.03 |
All-cause deaths | | 1.12 (1.01-1.23) | 0.04 | | 1.16 (0.99-1.34) | 0.06 | | 1.08 (0.94-1.24) | 0.30 |
Cardiovascular deaths | | 1.15 (0.99-1.33) | 0.054 | | 1.26 (1.02-1.56) | 0.03 | | 1.05 (0.87-1.28) | 0.60 |
≥70 vs. <70 mg/dL | | | | | | | | | |
Primary outcome | | 0.85 (0.48-1.52) | 0.59 | | 0.75 (0.33-1.69) | 0.49 | | 0.98 (0.43-2.20) | 0.95 |
All-cause deaths | | 0.61 (0.34-1.12) | 0.11 | | 0.50 (0.21-1.24) | 0.13 | | 0.70 (0.31-1.61) | 0.40 |
Cardiovascular deaths | | 0.48 (0.23-1.03) | 0.06 | | 0.62 (0.15-2.56) | 0.51 | | 0.43 (0.17-1.07) | 0.07 |
Minimum LDL_C | | | | | | | | | |
+1 SD (18 mg/dL) | | | | | | | | | |
Primary outcome | | 1.54 (1.41-1.67) | <0.0001 | | 1.48 (1.31-1.68) | <0.0001 | | 1.60 (1.42-1.80) | <0.0001 |
All-cause deaths | | 1.41 (1.28-1.56) | <0.0001 | | 1.31 (1.13-1.53) | 0.0005 | | 1.50 (1.31-1.70) | <0.0001 |
Cardiovascular deaths | | 1.54 (1.34-1.77) | <0.0001 | | 1.43 (1.15-1.78) | 0.001 | | 1.63 (1.36-1.96) | <0.0001 |
≥70 vs. <70 mg/dL | | | | | | | | | |
Primary outcome | | 2.11 (1.77-2.52) | <0.0001 | | 1.95 (1.51-2.52) | <0.0001 | | 2.30 (1.79-2.94) | <0.0001 |
All-cause deaths | | 1.60 (1.31-1.97) | <0.0001 | | 1.48 (1.10-1.99) | 0.01 | | 1.73 (1.30-2.28) | 0.0001 |
Cardiovascular deaths | | 2.03 (1.52-2.70) | <0.0001 | | 1.70 (1.11-2.60) | 0.02 | | 2.39 (1.61-3.53) | <0.0001 |
All models were adjusted for therapy group (if applicable), sex, and baseline age, education, body mass index, systolic and diastolic blood pressure, smoking, drinking, and fasting plasma glucose. |
We further looked into the maximum and minimum LDL_C exceed 70 mg/dl, the threshold recommended by recent guideline, in relation to various outcomes. In similar adjusted analysis, the minimum but not the maximum LDL_C exceeded 70 mg/dl were significantly (P≤0.01) associated with the primary outcome, and total and cardiovascular deaths in total population, as well as in the Fenofibrate and placebo groups analyzed separately. The hazard ratios of minimum LDL_C≥ 70 mg/dl were 2.11 (95%CI, 1.77-2.52), 1.60 (1.31-1.97), and 2.03 (1.52-2.70) for primary outcome, all-cause deaths and cardiovascular deaths, respectively in the total population (Table 3).