Introduction
Blood samples for measurements of triglyceride levels are typically obtained in the fasting state, and increased levels of fasting triglycerides have been associated with increased risk of cardiovascular disease (CVD) in a number of studies [
1‐
4]. Atherosclerosis is suggested to be a postprandial phenomenon [
5,
6]. Recent prospective cohort studies suggest that the association with coronary heart disease (CHD) is stronger for nonfasting than fasting triglycerides [
7,
8], and possibly also for stroke [
9]. In the Women’s Health Study, nonfasting triglycerides were associated with incident cardiovascular events, independent of other risk factors, lipids, and markers of insulin resistance, whereas weaker associations were found for fasting levels [
7]. The associations were particularly strong for samples drawn 2–4 h after meals. This corresponds to peak levels of triglycerides and remnant particles at 4 h after meal consumption, with a gradually decline thereafter [
8]. Elevated levels of postprandial triglycerides may indicate a high content of remnant lipoproteins derived from triglyceride rich chylomicrons [
5]. Remnant lipoproteins can enter the arterial wall, and contribute to the formation of foam cells and thus cause atherosclerosis [
10]. Measurements in the postprandial state include these remnant lipoproteins.
The associations between triglycerides and cardiovascular risk have been reported to be stronger in women than in men in both fasting and nonfasting states [
1,
8]. The Norwegian Counties Study is a prospective cohort study comprising three consecutive cardiovascular screenings performed between 1974 and 1988 in three Norwegian counties including over 90,000 individuals. Two earlier papers from this cohort study (in 1989 and 1993), found nonfasting triglycerides to be an independent risk factor for cardiovascular death in women [
11], but not in men [
12]. These papers had short follow-up, and used data only from the first screening. With additional data from the two latter screenings and a substantially longer follow-up, we study the association between nonfasting levels of triglycerides and cardiovascular mortality risk, including stroke, in this large cohort of women and men. In a subsample from the second screening, we also study the effect of adjustment for HDL-cholesterol and Framingham risk score.
Results
The study included 42,600 women and 43,641 men aged 20–50 years at inclusion, with a mean follow-up of 27.0 years (range 0.01–33.8). Women had lower levels of triglycerides compared to men, medians (range) triglycerides were 1.13 (0.21–18.72) mmol/l and 1.69 (0.21–19.35) mmol/l, respectively (Table
1). Mean age, total cholesterol, systolic and diastolic blood pressure, BMI, the proportions of smokers and physically inactive individuals increased over the quintiles for both women and men. The proportion of post-menopausal women also increased with increasing quintiles of triglycerides. The majority of the blood samples (98.2%) were drawn less than 8 h after the last meal (data not shown), and can therefore be considered nonfasting samples. The levels of triglycerides were highest in the category measured less than 1 h after meal with a gradual decline thereafter (data not shown).
Table 1
Baseline [Baseline values are data from first attendance for individuals participating in at least one of the screenings] characteristics of 86,241 participants (42,600 women and 43,641 men) from the Norwegian Counties Study by quintiles of triglycerides in the main study sample (age 20–50 at baseline)
Women Triglycerides, median (range), (mmol/l) | | 0.66 (0.21–0.79) | 0.90 (0.80–1.01) | 1.13 (1.02–1.27) | 1.46 (1.28–1.70) | 2.16 (1.71–18.72) | 1.13 (0.21–18.72) |
No. of participants | 8,585 | 8,303 | 8,576 | 8,654 | 8,482 | 42,600 |
Age, mean (SD), year | 37.8 (7.1) | 39.2 (6.9) | 39.7 (6.8) | 40.0 (6.9) | 40.1 (6.7) | 39.5 (6.9) |
Total cholesterol, mean (SD), (mmol/l) | 5.37 (0.96) | 5.76 (1.01) | 5.98 (1.10) | 6.19 (1.14) | 6.66 (1.34) | 5.99 (1.20) |
Systolic blood pressure, mean (SD), (mm Hg) | 125 (15) | 126 (15) | 127 (16) | 129 (16) | 132 (18) | 128 (16) |
Diastolic blood pressure, mean (SD), (mm Hg) | 77 (8) | 78 (10) | 78 (10) | 79 (11) | 81 (11) | 79 (11) |
BMI, mean (SD), (kg/m2) | 22.8 (3.0) | 23.4 (3.3) | 23.9 (3.6) | 24.4 (3.9) | 26.0 (4.7) | 24.1 (3.9) |
Post-menopausal (%) | 4.1 | 6.3 | 7.5 | 8.9 | 12.3 | 7.8 |
Smoking (%) | 31.8 | 36.9 | 40.5 | 43.0 | 48.4 | 40.1 |
Physical inactivity (%) | 18.1 | 20.3 | 20.5 | 22.2 | 24.8 | 21.8 |
Time since meal, mean (SD) | 2.75 (0.99) | 2.61 (0.98) | 2.56 (0.97) | 2.45 (0.95) | 2.42 (0.93) | 2.56 (0.97) |
Men Triglycerides, median (range), (mmol/l) | | 0.89 (0.21–1.10) | 1.29 (1.11–1.47) | 1.69 (1.48–1.93) | 2.23 (1.94–2.64) | 3.41 (2.65–19.35) | 1.69 (0.21–19.35) |
No. of participants | 8,754 | 8,596 | 8,900 | 8,659 | 8,732 | 43,641 |
Age, mean (SD), year | 38.2 (7.5) | 39.1 (7.1) | 39.8 (6.8) | 40.2 (6.5) | 40.7 (6.1) | 39.6 (6.9) |
Total cholesterol, mean (SD), (mmol/l) | 5.56 (1.08) | 5.92 (1.14) | 6.13 (1.19) | 6.42 (1.23) | 6.86 (1.32) | 6.18 (1.27) |
Systolic blood pressure, mean (SD), (mm Hg) | 133 (15) | 134 (15) | 135 (15) | 136 (15) | 138 (15) | 135 (14.9) |
Diastolic blood pressure, mean (SD), (mm Hg) | 81 (11) | 82 (11) | 82 (11) | 83 (11) | 85 (11) | 82 (11) |
BMI, mean (SD), (kg/m2) | 23.8 (2.6) | 24.3 (2.6) | 24.7 (2.8) | 25.3 (2.9) | 26.5 (3.2) | 24.9 (3.0) |
Smoking (%) | 47.7 | 51.1 | 51.9 | 53.1 | 55.5 | 51.9 |
Physical inactivity (%) | 16.0 | 17.5 | 18.1 | 19.2 | 21.5 | 18.5 |
Time since meal, mean (SD) | 2.77 (1.10) | 2.51 (1.06) | 2.38 (1.02) | 2.29 (1.00) | 2.26 (0.98) | 2.44 (1.05) |
During follow-up, 5,267 women and 9,528 men died (Tables
2,
3). Of these, 1,296 women and 3,620 men died from CVD, 626 women and 2,408 men from IHD, and 360 women and 543 men from stroke. Mean age at death was 63.4 years (range 23.5–82.9). Mortality rates from all causes, CVD and IHD, increased over quintiles in both women and men, and from stroke in women only. In women the mortality rates were markedly higher in the fifth quintile. Significant interactions between triglycerides and gender were found for all endpoints, and all analyses were thus stratified by gender. In age-adjusted analyses, significant positive trends were found for all endpoints, except for stroke in men (Tables
2,
3). The estimated HRs were highest for CVD and IHD, and higher in women than men.
Table 2
Association between triglycerides and risk of death from all causes, CVD, IHD, and stroke in 41,317 women in the main study sample (age 20–50 at baseline)
No. of participants
| 8,343 | 8,082 | 8,350 | 8,385 | 8,157 | |
All cause deaths |
No. of cases | 663 | 842 | 1,056 | 1,202 | 1,504 | |
Mortality per 1,000 person years | 2.9 | 3.8 | 4.6 | 5.2 | 6.9 | |
Age-adjusted HR (95% CI) | 1.00 | 1.15 (1.04–1.27) | 1.34 (1.21–1.47) | 1.48 (1.34–1.63) | 1.87 (1.71–2.05) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 1.06 (0.96–1.18) | 1.17 (1.06–1.30) | 1.24 (1.13–1.37) | 1.42 (1.28–1.57) | <0.001 |
CVD deaths |
No. of cases | 110 | 204 | 233 | 280 | 469 | |
Mortality per 1,000 person years | 0.5 | 0.9 | 1.0 | 1.2 | 2.1 | |
Age-adjusted HR (95% CI) | 1.00 | 1.61 (1.28–2.03) | 1.69 (1.35–2.12) | 1.95 (1.56–2.43) | 3.27 (2.66–4.03) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 1.37 (1.09–1.73) | 1.28 (1.02–1.61) | 1.34 (1.07–1.68) | 1.77 (1.41–2.21) | <0.001 |
IHD deaths |
No. of cases | 47 | 92 | 97 | 136 | 254 | |
Mortality per 1,000 person years | 0.2 | 0.4 | 0.4 | 0.6 | 1.2 | |
Age-adjusted HR (95% CI) | 1.00 | 1.70 (1.20–2.42) | 1.65 (1.16–2.33) | 2.23 (1.60–3.10) | 4.17 (3.05–5.70) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 1.40 (0.99–2.00) | 1.19 (0.84–1.69) | 1.43 (1.02–2.01) | 2.02 (1.45–2.82) | <0.001 |
Stroke deaths |
No. of cases | 34 | 62 | 74 | 81 | 109 | |
Mortality per 1,000 person years | 0.1 | 0.3 | 0.3 | 0.4 | 0.5 | |
Age-adjusted HR (95% CI) | 1.00 | 1.63 (1.07–2.48) | 1.80 (1.20–2.70) | 1.90 (1.27–2.84) | 2.58 (1.75–3.79) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 1.47 (0.96–2.23) | 1.49 (0.99–2.25) | 1.49 (0.99–2.25) | 1.71 (1.13–2.59) | 0.03 |
Table 3
Association between triglycerides and risk of death from all causes, CVD, IHD, and stroke in 42,653 men in the main study sample (age 20–50 at baseline)
No. of participants
| 8,548 | 8,386 | 8,689 | 8,477 | 8,553 | |
All cause deaths | | | | | | |
No. of cases | 1,671 | 1,674 | 1,940 | 2,012 | 2,231 | |
Mortality per 1,000 person years | 7.3 | 7.4 | 8.4 | 9.1 | 10.2 | |
Age-adjusted HR (95% CI) | 1.0 | 0.95 (0.89–1.02) | 1.04 (0.97–1.11) | 1.12 (1.05–1.20) | 1.28 (1.20–1.36) | <0.001 |
Multivariable HR (95% CI)a
| 1.0 | 0.89 (0.83–0.96) | 0.94 (0.88–1.00) | 0.96 (0.90–1.03) | 0.99 (0.92–1.06) | 0.43 |
CVD deaths |
No. of cases | 533 | 582 | 703 | 801 | 1.001 | |
Mortality per 1.000 person years | 2.3 | 2.6 | 3.0 | 3.6 | 4.6 | |
Age-adjusted HR (95% CI) | 1.00 | 1.04 (0.92–1.16) | 1.17 (1.05–1.31) | 1.39 (1.25–1.55) | 1.78 (1.61–1.98) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 0.92 (0.82–1.03) | 0.96 (0.85–1.08) | 1.03 (0.92–1.15) | 1.07 (0.96–1.21) | 0.03 |
IHD deaths |
No. of cases | 311 | 373 | 474 | 561 | 689 | |
Mortality per 1,000 person years | 1.4 | 1.7 | 2.0 | 2.5 | 3.2 | |
Age-adjusted HR (95% CI) | 1.00 | 1.14 (0.98–1.33) | 1.37 (1.18–1.58) | 1.68 (1.46–1.93) | 2.11 (1.85–2.41) | <0.001 |
Multivariable HR (95% CI)a
| 1.00 | 1.00 (0.86–1.16) | 1.09 (0.94–1.26) | 1.20 (1.04–1.39) | 1.21 (1.05–1.40) | <0.001 |
Stroke deaths |
No. of cases | 102 | 99 | 113 | 105 | 124 | |
Mortality per 1,000 person years | 0.4 | 0.4 | 0.5 | 0.5 | 0.6 | |
Age-adjusted HR (95% CI) | 1.00 | 0.91 (0.69–1.19) | 0.97 (0.74–1.26) | 0.94 (0.71–1.23) | 1.15 (0.89–1.50) | 0.30 |
Multivariable HR (95% CI)a
| 1.00 | 0.85 (0.64–1.12) | 0.86 (0.66–1.13) | 0.79 (0.59–1.05) | 0.86 (0.65–1.15) | 0.30 |
In multivariable analyses, the associations were attenuated in both women and men (Tables
2,
3). Significantly elevated HRs were found in women in the fifth quintile for all cause, CVD, and IHD deaths (
P for trend <0.001) and for stroke (
P for trend 0.03). In men the positive trend disappeared for all cause deaths after multivariable adjustment, but was still significant for CVD and IHD deaths (
P for trend 0.03 and <0.001, respectively). No significant interactions were found between triglycerides and time since last meal, BMI, smoking, or cholesterol. No substantial deviations from the proportional hazards assumption were detected. The linearity assumption for triglycerides was met for most models, except in men for all cause and IHD deaths, and for CVD deaths in women.
Table
4 shows the change in the HR when adjusting individually for each of the three major risk factors, cholesterol, systolic blood pressure, and smoking. The relative increase in risk associated with an increase of 1 mmol/l triglyceride was higher in women than in men in both age-adjusted and multivariable analyses. Adjusting for confounders reduced the HRs, and in men cholesterol was the strongest confounder, whereas in women cholesterol, blood pressure and smoking similarly changed the estimates. Adjusting for regression dilution bias strengthens the effect estimates. For example for IHD in women, age-adjusted HR per 1 mmol/l triglyceride changes from 1.45 to 2.07 if we adjust for regression dilution bias. The estimates given in the tables are not adjusted for regression dilution bias.
Table 4
Risk of death from all causes, CVD, IHD, and stroke by a 1 mmol/l increase in nonfasting triglyceride levels in the main study sample (age 20–50 at baseline)
All cause deaths
| n = 5,267 | n = 9,528 |
None | 1.27 (1.24–1.30) | 1.10 (1.08–1.12) |
Total cholesterol (mmol/l) | 1.23 (1.20–1.27) | 1.05 (1.03–1.07) |
Systolic blood pressure (mm Hg) | 1.24 (1.21–1.27) | 1.08 (1.07–1.10) |
Smoking (yes/no) | 1.22 (1.19–1.25) | 1.09 (1.07–1.10) |
All three | 1.17 (1.13–1.20) | 1.03 (1.02–1.05) |
Full modelb
| 1.16 (1.13–1.20) | 1.03 (1.01–1.04) |
CVD deaths
| n = 1,296 | n = 3,620 |
None | 1.40 (1.35–1.45) | 1.17 (1.15–1.19) |
Total cholesterol (mmol/l) | 1.34 (1.28–1.39) | 1.08 (1.06–1.11) |
Systolic blood pressure (mm Hg) | 1.35 (1.30–1.40) | 1.14 (1.11–1.16) |
Smoking (yes/no) | 1.34 (1.29–1.39) | 1.16 (1.13–1.18) |
All three | 1.24 (1.18–1.30) | 1.05 (1.03–1.08) |
Full modelb
| 1.20 (1.14–1.27) | 1.03 (1.00–1.05) |
IHD deaths
| n = 626 | n = 2,408 |
None | 1.45 (1.40–1.52) | 1.19 (1.16–1.22) |
Total cholesterol (mmol/l) | 1.39 (1.32–1.46) | 1.09 (1.06–1.12) |
Systolic blood pressure (mm Hg) | 1.41 (1.35–1.47) | 1.15 (1.12–1.18) |
Smoking (yes/no) | 1.40 (1.34–1.46) | 1.17 (1.14–1.20) |
All three | 1.29 (1.22–1.36) | 1.05 (1.03–1.08) |
Full modelb
| 1.26 (1.19–1.34) | 1.03 (1.00–1.06) |
Stroke deaths
| n = 360 | n = 543 |
None | 1.27 (1.15–1.40) | 1.07 (1.00–1.14) |
Total cholesterol (mmol/l) | 1.22 (1.09–1.36) | 1.03 (0.96–1.11) |
Systolic blood pressure (mm Hg) | 1.22 (1.10–1.35) | 1.04 (0.98–1.11) |
Smoking (yes/no) | 1.21 (1.09–1.34) | 1.06 (1.00–1.13) |
All three | 1.12 (0.99–1.26) | 1.01 (0.94–1.08) |
Full modelb
| 1.09 (0.96–1.23) | 0.99 (0.92–1.07) |
The baseline characteristics of the sub-sample from screening II with HDL-measurements are given in Table
5. Mean follow-up was 24.8 years (range from 0.01 to 27.8). Due to the study design, mean age at screening (Table
5) and mean age at death was slightly higher in the sub-sample, i.e. 65.6 years (range 26.3–81.6). Women had higher HDL-cholesterol levels than men. Compared to the main study sample (Table
1), the subjects in the sub-sample smoked less and were more physically active. By comparing the different models with and without adjustment for HDL-cholesterol, we see that the effect of triglycerides is attenuated after adjustment, particularly in women (Table
6). Additionally, the previous differences between men and women were no longer present after inclusion of HDL-cholesterol in the models. There is still a significant effect of triglycerides on all cause mortality in both men and women, however, the association is considerably weaker after multivariable adjustment (Table
6), suggestion residual confounding. No significant interactions were found between triglycerides and HDL-cholesterol.
Table 5
Baseline [Baseline values are data from attendance at screening II] characteristics of the sub sample with HDL-cholesterol from screening II (age 20–55 at baseline)
Age, mean (SD) | 44.7 (7.3) | 44.6 (7.4) |
Triglycerides, mean (SD), (mmol/l) | 1.41 (0.78) | 2.07 (1.14) |
Total cholesterol, mean (SD), (mmol/l) | 6.02 (1.19) | 6.00 (1.11) |
HDL-cholesterol, mean (SD), (mmol/l) | 1.43 (0.34) | 1.18 (0.31) |
Systolic blood pressure, mean (SD), (mm Hg) | 131 (18) | 137 (16) |
BMI, mean (SD), (kg/m2) | 24.4 (3.8) | 25.2 (3.0) |
Post-menopausal (%) | 26.8 | – |
Smoking (%) | 33.6 | 44.7 |
Physical inactivity (%) | 14.9 | 13.7 |
Time since meal, mean (SD) | 2.56 (0.92) | 2.39 (1.01) |
Table 6
Risk of death from all causes, CVD, IHD, and stroke by a 1 mmol/l increase in nonfasting triglyceride levels in the sub sample with HDL-cholesterol from screening II (age 20–55 at baseline)
All cause deaths
| n = 2,827 | n = 4,747 |
None | 1.19 (1.15–1.24) | 1.10 (1.08–1.13) |
HDL-cholesterol (mmol/l) | 1.15 (1.10–1.20) | 1.11 (1.08–1.13) |
Cholesterol, systolic blood pressure, and smoking | 1.11 (1.06–1.16) | 1.06 (1.03–1.08) |
All four | 1.07 (1.02–1.12) | 1.06 (1.03–1.09) |
Full modelb
| 1.06 (1.01–1.12) | 1.06 (1.03–1.09) |
CVD deaths
| n = 709 | n = 1,734 |
None | 1.37 (1.28–1.46) | 1.21 (1.17–1.26) |
HDL-cholesterol (mmol/l) | 1.25 (1.16–1.35) | 1.18 (1.14–1.23) |
Cholesterol, systolic blood pressure, and smoking | 1.19 (1.10–1.28) | 1.12 (1.08–1.16) |
All four | 1.06 (0.97–1.16) | 1.07 (1.03–1.12) |
Full modelb
| 1.03 (0.94–1.13) | 1.06 (1.01–1.11) |
IHD deaths
| n = 344 | n = 1,143 |
None | 1.44 (1.32–1.57) | 1.24 (1.19–1.29) |
HDL-cholesterol (mmol/l) | 1.29 (1.16–1.43) | 1.18 (1.13–1.24) |
Cholesterol, systolic blood pressure, and smoking | 1.20 (1.09–1.33) | 1.12 (1.07–1.17) |
All four | 1.02 (0.90–1.15) | 1.04 (0.99–1.09) |
Full modelb
| 0.99 (0.88–1.13) | 1.03 (0.97–1.08) |
Stroke deaths
| n = 195 | n = 278 |
None | 1.33 (1.17–1.51) | 1.07 (0.97–1.19) |
HDL-cholesterol (mmol/l) | 1.19 (1.02–1.39) | 1.07 (0.96–1.19) |
Cholesterol, systolic blood pressure, and smoking | 1.23 (1.07–1.42) | 1.05 (0.95–1.17) |
All four | 1.10 (0.92–1.30) | 1.04 (0.93–1.17) |
Full modelb
| 1.10 (0.92–1.31) | 1.05 (0.93–1.18) |
The Framingham CHD risk scores were significantly associated with risk of death from CVD and IHD (Table
7). The hazard ratio was unchanged after adjustment for triglycerides, and triglycerides had no predictive value after inclusion of the Framingham score in the model.
Table 7
Risk of death from CVD and IHD in the sub sample with calculated Framingham risk score from screening II (age 40–55 at baseline)
Women (n = 16,805) | | |
CVD deaths (n = 691) | | |
Triglycerides (per 1 mmol/l) | 1.36 (1.28–1.46) | 0.97 (0.89–1.06) |
Framingham (per 1 unit) | 1.11 (1.10–1.12) | 1.11 (1.10–1.13) |
IHD deaths (n = 335) | | |
Triglycerides (per 1 mmol/l) | 1.43 (1.31–1.56) | 0.96 (0.85–1.08) |
Framingham (per 1 unit) | 1.13 (1.11–1.14) | 1.13 (1.11–1.15) |
Men (n = 16,318) | | |
CVD deaths (n = 1,657) | | |
Triglycerides (per 1 mmol/l) | 1.22 (1.18–1.26) | 1.02 (0.98–1.07) |
Framingham (per 1 unit) | 1.08 (1.07–1.08) | 1.08 (1.07–1.08) |
IHD deaths (n = 1,092) | | |
Triglycerides (per 1 mmol/l) | 1.25 (1.19–1.29) | 1.01 (0.96–1.07) |
Framingham (per 1 unit) | 1.09 (1.08–1.10) | 1.09 (1.08–1.10) |
Discussion
In the Norwegian Counties Study nonfasting triglycerides were positively associated with CVD death in both genders, with hazard ratios being higher in women than in men. After adjustment for cholesterol, systolic blood pressure and smoking, and in a sub sample also HDL-cholesterol, the associations were distinctly attenuated. After adjustment for the Framingham risk score, the positive association between triglycerides and mortality risk disappeared.
Recent reports from two prospective studies have described strong associations between postprandial triglycerides and risk of CVD and stroke [
7‐
9]. The Copenhagen City Heart Study showed an independent effect of nonfasting triglycerides on myocardial infarction, IHD, and stroke, particularly in women [
8,
9]. Accordingly, in the Women’s Health Study nonfasting, but not fasting, levels were associated with incident cardiovascular events in females [
7]. In the Copenhagen City Heart Study, the main analyses were not adjusted for HDL-cholesterol, and thus are comparable to our analyses on the total study sample. For example for all cause deaths in women the age-adjusted HRs per1 mmol/l increase in triglycerides were 1.27 and 1.26 in ours and the Danish study, respectively. After multivariable adjustment the corresponding HRs were 1.16 and 1.18. Comparable estimates were also found for IHD and CVD. In the Women’s Health Study, on the other hand, the association between triglycerides and risk still persisted after adjustment for additional risk factors including HDL-cholesterol [
7]. Discrepancies between univariate and multivariable analyses in studies on CVD risk and triglycerides have been reported in many studies [
4,
7,
8]. Due to the strong negative correlation between HDL-cholesterol and triglycerides, and to the differences in the measurement variability of these lipids, it has been shown theoretically that by adjusting for HDL-cholesterol, the triglyceride-disease association will be consistently underestimated [
4]. It is thus controversial whether HDL-cholesterol should be included in multivariable models, as also discussed in the two prospective studies described above [
7,
8].
It has been difficult to demonstrate a possible causal relationship between triglycerides and CVD by drug intervention studies, as drugs that reduce triglycerides also raise HDL-cholesterol [
20]. Interestingly, a recent paper addresses the question of causality by studying a genetic polymorphism regulating triglyceride concentration [
24]. The results from this collaborative analysis of 101 studies indicate a causal association between triglyceride-mediated pathways and coronary heart disease. Previous meta-analyses report an increase in CHD risk of about 70% comparing high triglyceride levels with low triglyceride levels [
2,
3]. However, it is probably not the nonfasting triglycerides per se that cause atherosclerosis, but rather the cholesterol content of remnant lipoproteins [
8,
21]. Remnant lipoproteins arise after lipolysis of chylomicrons and VLDL, the two classes of lipoproteins whose major lipid is triglyceride [
22]. The remnant particles are under normal conditions rapidly taken up by the liver [
22]. Hepatic removal of the remnant particles are, however, a complex process, and in people with a predisposition of producing remnant particles or small dense LDL and HDL particles, people with metabolic syndrome or type 2 diabetes, hepatic clearance of remnant particles can be delayed [
8,
22,
23]. Thus, prolonged exposure of increased levels of circulating remnant particles will enhance the possibility for the particles to be entrapped in the arterial wall. Accordingly, remnant lipoproteins have been shown to increase risk of atherosclerotic heart disease [
23]. A strong correlation between nonfasting triglycerides levels and remnant lipoprotein cholesterol has been shown [
8], and this may account for the stronger associations of nonfasting levels of triglycerides with CVD [
7]. One cannot exclude, however, that the association between nonfasting triglycerides levels and cardiovascular risk observed in our and previous studies in part could be a result of residual confounding by unmeasured confounders.
The finding of stronger effects of nonfasting triglycerides among women than men in our and previous studies [
8,
9,
11], are not easily explained. A gender dependent difference in risk has also been shown for fasting triglycerides [
1,
4,
25], however, data are not consistent [
2,
3].
The Framingham risk score includes HDL-cholesterol [
18], and adjusting for HDL-cholesterol or the Framingham risk score attenuated the effect of triglycerides in the present study. Accordingly, a recent study including data from 112 prospective studies concluded that lipid assessment could be simplified by measurement of nonfasting lipids, either total cholesterol and HDL-cholesterol or apolipoproteins, without regard to triglycerides [
26]. Thus the role for triglycerides as an independent risk factor is still controversial.
The Norwegian Counties Study has several strengths. First, the mortality in the three counties under study, were found to be similar to the national levels [
27], and as the attendance was high (84–88%), we argue that this study sample is representative of Norway. Our study sample is of considerable size, and has a long and complete follow-up. It is noted that the power to detect a hazard ratio of 1.06 at the 5% level, varies from >0.9 in men (all cause deaths) to 0.2 in women (stroke deaths). For IHD deaths the power is 0.6 in women and 0.9 in men. Thus, for some endpoints, we have sufficient power to reveal even small effects.
A major limitation is that we do not have data on exposure after 1988. Due to the long follow-up time, a considerable number of individuals might have started with medications affecting triglycerides levels. We could not adjust for alcohol or hormone therapy, however, no differences in CVD mortality between users and non-users of hormone therapy have previously been reported in women from screening III [
28].
In summary, we observed a stronger association between nonfasting triglycerides and risk of cardiovascular death in women than in men. The effect, was, however, attenuated after adjustment for HDL-cholesterol or adjustment for Framingham risk. Lastly, nonfasting triglycerides add no predictive information of CVD risk beyond the Framingham CHD risk score.