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- Materials and Methods
Adiponectin is a collagen-like peptide, abundantly secreted by adipose tissue, and has several biological activities, such as enhancement of insulin sensitivity and stimulation of fatty-acid oxidation[1, 2]. Hypoadiponectinemia is associated with an increased risk of type 2 diabetes, hypertension and dyslipidemia, which are risk factors for atherosclerosis. In addition, adiponectin has anti-arteriosclerotic properties by various mechanisms. For example, adiponectin has anti-inflammatory properties by inhibiting the nuclear factor kappa beta pathway, it downregulates adhesion molecule expression, stimulates production of nitric oxide and suppresses apoptosis in endothelial cells. In apolipoprotein E-deficient mice, breeding with adiponectin transgenic mice inhibits the progression of atherosclerosis despite unaltered glucose and lipid metabolism. These data suggest that high serum adiponectin levels might be related to a lower risk of coronary heart disease (CHD).
Several case–control and cohort studies have shown that high serum adiponectin levels are associated with a lower risk of CHD[11-16]. However, most previous studies were carried out in healthy Caucasians or patients with type 2 diabetes in Western countries. East Asian populations, including the Japanese, are less obese, less resistant to insulin and have a lower incidence of CHD than Caucasians[17, 18], and CHD is not necessarily a leading cause of mortality. In addition, compared with patients with type 2 diabetes in Western countries, those in East Asian countries have different features regarding cardiovascular complications, such as the relationship between predictors for macro- and microvascular complications, the effect of metabolic syndrome or lipid profiles. In Japanese patients with type 2 diabetes, serum triglyceride levels are a leading predictor of CHD, comparable with low-density lipoprotein (LDL), which is the best predictor of CHD in patients with type 2 diabetes in Western countries.
Based on the aforementioned findings, it is uncertain whether previous results in Caucasians can be extrapolated to the East Asian population, and ethnic specificity might need to be taken into account when the association between adiponectin and the risk of CHD is investigated.
Therefore, the present study aimed to investigate whether serum adiponectin levels can predict CHD in Japanese patients with type 2 diabetes, as observed in Caucasians, after adjustment for well-known CHD risk factors and various parameters, which affect serum adiponectin levels.
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- Materials and Methods
Baseline characteristics by quartile of serum adiponectin levels are shown in Table 1. Serum adiponectin levels were positively associated with age, percentage of women, the proportion of insulin use, duration of diabetes and HDL, and negatively associated with the proportion of fibrate use, BMI, waist circumference, DBP, TG and eGFR. There were no significant differences in smoking status, previous CHD, family history, the proportion of aspirin use, ACEI/ARB use, statin use, SBP, HbA1c (NGSP) and LDL.
Table 1. Baseline characteristics by quartiles of adiponectin in 504 patients with type 2 diabetes
|1 (n = 118)||2 (n = 133)||3 (n = 126)||4 (n = 127)|
|Adiponectin (μg/dL)||3.3 (1.9–4.1)||4.9 (4.2–5.8)||6.8 (5.9–8.6)||12.0 (8.7–35.6)|| |
|Age (years)||56.6 ± 9.9||61.8 ± 8.5*||62.6 ± 8.7*||67.4 ± 9.3*,**,***||<0.001|
|Smoking status (%)||0.103|
|Current smoker||36.8||23.3||19.0||16.3|| |
|Past smoker||26.5||32.3||30.2||27.6|| |
|Never smoker||36.8||44.4||50.8||56.1|| |
|Aspirin use (%)||16.9||18.0||10.3||23.6||0.048|
|Insulin use (%)||18.6||14.3||12.7||33.1||<0.001|
|ACEI/ARB use (%)||33.1||38.3||31.0||40.2||0.376|
|Statin use (%)||16.1||27.8||23.0||27.6||0.108|
|Fibrate use (%)||7.6||4.5||1.6||0.8||0.016|
|Previous CHD (%)||5.9||6.8||2.4||7.1||0.335|
|Family history (%)||1.7||3.9||2.4||8.5||0.057|
|BMI (kg/m2)||25.6 ± 3.4||25.5 ± 4.3||25.3 ± 6.2||23.4 ± 4.2*,**,***||<0.001|
|Waist (cm)||90.8 ± 9.5||92.0 ± 10.4||90.5 ± 13.3||86.6 ± 12.3*,**,***||0.001|
|SBP (mmHg)||141.6 ± 19.5||143.6 ± 17.8||143.2 ± 18.4||146.4 ± 19.1||0.234|
|DBP (mmHg)||84.5 ± 12.4||81.9 ± 11.4||83.9 ± 10.9||80.4 ± 10.3*||0.014|
|FPG (mg/dL)||160.0 ± 50.6||160.5 ± 52.5||148.8 ± 38.2||152.4 ± 49.7||0.144|
|HbA1c (NGSP; %)||9.2 ± 1.6||9.1 ± 1.6||8.8 ± 1.6||9.1 ± 1.8||0.374|
|Duration (years)||6.5 (2.0, 16.0)||8.0 (3.0, 18.0)||8.0 (3.0, 16.0)||17.0 (6.0, 25.0)*,**,***||<0.001|
|Tchol (mg/dL)||208.6 ± 35.9||208.0 ± 33.9||212.4 ± 36.4||206.1 ± 39.5||0.577|
|HDL (mg/dL)||49.7 ± 13.0||52.3 ± 13.7||55.7 ± 12.8*||61.0 ± 17.0*,**,***||<0.001|
|TG (mg/dL)||164 (117, 240)||149 (104, 213)||120 (82, 171)*,**||91 (61, 128)*,**,***||<0.001|
|LDL (mg/dL)||123.2 ± 31.5||120.9 ± 30.2||128.7 ± 31.4||123.0 ± 31.6||0.237|
|eGFR (mL/min/m2)||89.3 ± 21.0||86.1 ± 21.3||86.7 ± 23.4||77.9 ± 21.7*,**,***||<0.001|
During a median follow up of 5.7 years (2177 person-years), 40 participants had new CHD, 10 had recurrent CHD and 12 died of any diseases other than CHD. A total of 167 (33.1%) participants were lost to follow up. Baseline characteristics of participants lost to follow up and those who completed follow up are shown in Table 2. Participants lost to follow up were younger, less likely to be taking aspirin and insulin, less likely to have a history of CHD, and had a shorter duration of diabetes. The HR for the risk of CHD across quartiles of serum adiponectin levels is shown in Table 3. After adjustment for age, sex, waist circumference, HbA1c (NGSP) and duration of diabetes, participants in the highest compared with the lowest quartile of serum adiponectin levels had a significantly reduced risk of CHD (HR 0.40; 95% CI 0.16–0.96; P = 0.013). Further adjustment for HDL, LDL, log (TG), eGFR, SBP, DBP, aspirin use, insulin use, ACEI/ARB use, statin use, fibrate use, smoking status and family history of CHD at baseline did not significantly affect this relationship (HR 0.35; 95% CI 0.13–0.94; P = 0.017).
Table 2. Baseline characteristics of participants lost to follow up and those who completed follow up
|Variables||Lost to follow up (n = 167)||Completed follow up (n = 337)|| P |
|Adiponectin (μg/dL)||5.5 (4.1, 8.3)||5.9 (4.3, 8.7)||0.741|
|Age (years)||60.6 ± 11.4||63.0 ± 8.9||0.022|
|Smoking status (%)||0.479|
|Current smoker||24.2||19.8|| |
|Past smoker||31.5||31.7|| |
|Never smoker||44.2||48.5|| |
|Aspirin use (%)||11.4||20.2||0.014|
|Insulin use (%)||14.4||22.3||0.036|
|ACEI/ARB use (%)||30.5||38.9||0.067|
|Statin use (%)||21.0||27.9||0.231|
|Fibrate use (%)||5.4||2.7||0.122|
|Previous CHD (%)||0.6||8.0||0.001|
|Family history (%)||5.4||3.4||0.250|
|BMI (kg/m2)||25.2 ± 4.9||24.8 ± 4.6||0.367|
|Waist (cm)||90.8 ± 12.2||89.6 ± 11.3||0.261|
|SBP (mmHg)||143.9 ± 19.8||143.7 ± 18.2||0.925|
|DBP (mmHg)||82.6 ± 11.6||82.6 ± 11.2||0.982|
|FPG (mg/dL)||157.6 ± 50.2||154.3 ± 47.2||0.464|
|HbA1c (NGSP) (%)||9.0 ± 1.7||9.1 ± 1.6||0.650|
|Duration (years)||6.0 (1.0, 12.0)||11.0 (4.0, 20.0)||<0.001|
|Tchol (mg/dL)||209.1 ± 38.5||208.6 ± 35.4||0.876|
|HDL (mg/dL)||55.9 ± 16.1||54.1 ± 14.1||0.216|
|TG (mg/dL)||121 (82, 192)||134 (88, 192)||0.557|
|LDL (mg/dL)||123.7 ± 31.3||124.1 ± 31.2||0.898|
|eGFR (mL/min/m2)||86.2 ± 23.4||84.3 ± 21.6||0.380|
Table 3. Hazard ratios for new-onset or recurrent coronary heart disease by quartiles of adiponectin
| ||Quartile of adiponectin||P-trend|
|1 (n = 118)||2 (n = 133)||3 (n = 126)||4 (n = 127)|
|No. of cases||13||19||7||11|| |
|Model 1||1.00||1.19 (0.57–2.48)||0.41 (0.15–1.07)||0.59 (0.24–1.44)||0.069|
|Model 2a||1.00||1.18 (0.56–2.48)||0.41 (0.16–1.10)||0.40 (0.16–0.96)||0.013|
|Model 3a||1.00||1.05 (0.48–2.31)||0.34 (0.12–0.95)||0.34 (0.13–0.86)||0.011|
|Model 4a||1.00||1.18 (0.53–2.63)||0.37 (0.13–1.06)||0.35 (0.13–0.94)||0.017|
|Model 2b||1.00||1.26 (0.60–2.64)||0.43 (0.16–1.14)||0.42 (0.17–1.01)||0.013|
|Model 3b||1.00||1.12 (0.51–2.42)||0.36 (0.13–0.99)||0.36 (0.14–0.91)||0.013|
|Model 4b||1.00||1.25 (0.57–2.76)||0.39 (0.14–1.12)||0.38 (0.14–1.00)||0.019|
The HR for the risk of CHD according to a doubling of adiponectin at baseline is shown in Table 4. After adjustment for age, sex, waist circumference, HbA1c (NGSP) and duration of diabetes, adiponectin was associated with a reduced risk of CHD (HR 0.64; 95% CI 0.43–0.96 P = 0.032). After further adjustment, adiponectin remained significantly associated with a reduced risk of CHD (HR 0.61; 95% CI 0.39–0.97; P = 0.037). Similar results were obtained when adjusting for BMI instead of waist circumference (Tables 3 and 4).
Table 4. Hazard ratios for new-onset or recurrent coronary heart disease with a doubling of adiponectin
| ||Hazard ratio||95% Confidence interval|| P |
We repeated our analysis excluding participants who had a history of CHD before admission to hospital. After multivariate adjustment, participants in the highest compared with the lowest quartile of serum adiponectin levels had a reduced risk of CHD (HR 0.32; 95% CI 0.11–0.96; P = 0.036). The multivariate adjusted HR for CHD according to a doubling of adiponectin levels at baseline was 0.60 (95% CI 0.35–1.02), with borderline significance (P = 0.057).
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- Materials and Methods
The present prospective study showed that high serum adiponectin levels were significantly associated with a lower risk of CHD over a follow-up period of 5.7 years in Japanese patients with type 2 diabetes. This association was independent of well-known CHD risk factors.
The present study comprised several important features. First, this is the first prospective study in Japanese patients with type 2 diabetes. Several studies from other countries have shown that high serum adiponectin levels are associated with a lower risk of CHD. Zoccali et al. first reported that serum adiponectin level was an inverse predictor of CHD among patients with end-stage renal disease in a prospective cohort study. In the Health Professionals Follow-up Study, high baseline serum adiponectin levels were associated with a significant reduction in the risk of myocardial infarction among healthy men after adjustment for several CHD risk factors in multivariate analyses. This association was confirmed by an 8-year follow-up study reported by Frystyk et al. and by the Framingham Offspring Study. Pischon et al. reported that high serum adiponectin levels were associated with a lower risk of CHD among healthy women in the Nurses' Health Study. Schulze et al. reported a significant association between adiponectin and the risk of CHD among diabetic men in the Health Professionals Follow-up Study. All of these large-scale studies were carried out in Caucasians. In Japan, it was reported that serum adiponectin levels in patients with diabetes and CHD were lower than those in patients with diabetes without CHD. Kumada et al. reported that lower serum adiponectin levels were associated with an approximately doubled risk for CHD among 225 consecutive male patients who underwent coronary angiography and 225 voluntary blood donors. Another study found that serum adiponectin levels in 123 patients with CHD were significantly lower than those among 17 control subjects. However, all of these studies regarding an association between adiponectin and the risk of CHD in Japan were cross-sectional or case–control studies. The present study is the first prospective study to show that serum adiponectin levels can predict CHD in Japanese patients with type 2 diabetes, similar to the relationship in Caucasians. Second, in our prospective study, serum adiponectin levels were measured at the start of the study, unlike previous prospective studies, in which they were measured several years after sampling, using frozen serum at baseline. Therefore, serum adiponectin levels in the present study are more reliable data in this regard. Third, unlike the previous study of Schulze et al., which was designed for patients with type 2 diabetes, the present results were adjusted for diabetic and blood pressure control status, and the use of several drugs, which affect serum adiponectin levels.
Several other studies, including the British Regional Health Services follow-up study, the Strong Heart Study, as well as the British Women's Heart Health Study, have not supported an inverse association between serum adiponectin levels and a risk of CHD. Differences in the results between studies might reflect underlying differences in the sample size or incidence and risk of CHD. In addition, it is worth noting that, in these negative studies, renal dysfunction was not taken into consideration. Serum adiponectin levels are increased in patients with chronic kidney disease, although these patients show progression of arteriosclerosis. Similarly, adiponectin is inversely associated with creatinine clearance, and is increased in the presence of macroalbuminuria. High serum adiponectin levels with chronic kidney disease might not have numerous beneficial effects, because atherosclerosis is advanced with renal dysfunction. A recent study showed that adiponectin is inactivated by binding to cystatin C, which in turn contributes to elevated adiponectin levels in advanced kidney disease. Therefore, these negative results might be influenced by an increase in inactive adiponectin in renal dysfunction.
Several other studies, including the Pravastatin or Atorvastatin Evaluation and Infection Therapy-thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study, have reported that high serum adiponectin levels in patients with acute coronary syndrome or congestive heart failure are associated with a higher risk of recurrent cardiovascular events. The reason for this result, which conflicts with the present result, is unclear. Serum adiponectin levels are positively associated with plasma brain natriuretic peptide levels, and natriuretic peptide enhances adiponectin production in vitro and in patients with congestive heart failure. These data suggest that adiponectin might be elevated in a counter-regulatory fashion among patients with heart failure or excessive atherosclerosis. In the present study, the analysis could not be stratified by cardiac function or the degree of atherosclerosis, and therefore, we could not investigate this possibility.
Adiponectin, which is decreased by obesity, especially visceral fat accumulation, plays an important role in the development of obesity-related disorders, such as diabetes mellitus, hypertension and dyslipidemia, or so-called metabolic syndrome. Therefore, adiponectin is associated with a risk of CHD through these metabolic abnormalities. The present study showed that the inverse association between serum adiponectin levels and the risk of CHD was independent of components of metabolic syndrome and other cardiovascular risk factors, such as age, renal function and smoking status. Some medications, for example, ACEI/ARB, statin and fibrate, are reported to be associated with high adiponectin levels, but we adjusted for these variables. This result suggests that adiponectin has a direct role in the development of CHD, and is not just a mediator. Therefore, a strategy for intervention to increase serum adiponectin levels might be beneficial to prevent CHD.
We measured waist circumference at the level of the umbilicus. This method is different from the protocol used in the World Health Organization or the United States National Health and Nutrition Examination Survey. However, previous studies in Japan have shown that waist circumference measured at the level of the umbilicus is strongly associated with visceral fat area measured by computed tomography, and this is inversely associated with serum adiponectin levels, and plays an important role in the clustering of cardiovascular risk factors[47, 48]. In the present study, serum adiponectin levels were associated with a reduced risk of CHD, even when adjusting for BMI instead of waist circumference.
We measured total adiponectin levels, which included both low molecular weight isoforms (~30–60 kDa) and high molecular weight (HMW) isoforms (12–18 mers). HMW isoforms are reported to have more biological activity and are more strongly related to insulin sensitivity than other circulating isoforms, but most changes in the components of serum adiponectin consist of HMW isoforms. Therefore, the change in HMW adiponectin levels might have been in parallel with total adiponectin levels, and measurement of total and HMW adiponectin levels might be equally useful. Previous studies have reported that total and HMW adiponectin are significantly inversely associated with the risk of CHD, the incidence of diabetes and the development of metabolic syndrome to a similar extent.
A limitation of the present study was the relatively small sample size, which might have led to unstable estimates. The attenuation of an association in stratified analysis by previous CHD might be attributed to a lack of power. In addition, the total follow-up rate was relatively low (66.9%; 337/504), which might have led to bias. However, most of the parameters, including adiponectin, were not significantly different between participants lost to follow up and those who completed follow up. We recruited admitted patients with diabetes who had poor glycemic control (average HbA1c [NGSP], 9.1%) and a high risk of CHD. Therefore, the present results might not be able to generalize to all Japanese patients, but we adjusted for multivariate risk factors. Finally, we could not consider residual confounding, such as dietary habits, physical activities, cardiac function and several inflammatory cytokines. A larger investigation is expected to establish the association between adiponectin and the risk of CHD in the East Asian population.
In conclusion, a high serum adiponectin level is significantly associated with a lower risk of CHD over a follow-up period of 5.7 years in Japanese patients with type 2 diabetes, as similarly observed in Caucasians. This association is independent of various parameters, including well-known CHD risk factors. The regulation of serum adiponectin levels might be a good therapeutic strategy to prevent CHD.