**11. Relations between the apo-ratio and the metabolic syndrome, glucose - insulin metabolism and diabetes - Risk predictors for CV manifestations**

#### **11.1. Metabolic syndrome (MetS) and diabetes**

114 Lipoproteins – Role in Health and Diseases

introduced in current clinical practice.

smoking), hs-CRP and albuminuria.

lipid ratios in the risk assessment in patients with CAD.

traditional lipid risk factors in a low-risk Korean population.

apo-ratio and Lp(a) should be included in clinical practice.

**10. Meta-analysis of studies on CV risk** 

for any lipids.

discriminator of CAD risk in the atherosclerosis-prone Indian population, than any of the conventional lipid ratios. They suggested that the apo-ratio should be an alternative to other

In a comparative observational study by Agoston-Coldea et al. (121) on 289 subjects were divided into two groups: 144 subjects with old MI, and 145 subjects without CHD, but with CV risk factors. The multivariate analysis indicated that apoB over 1.7 g/L are closely correlated with MI (p = 0.001) independent of age, smoking, diabetes, hypertension, lipid TC/HDL-C and the LDL-C/HDL-C ratio. The protective effect of apoA-I was also significant (p = 0.004) in multivariate analysis. They concluded that the predictive value of the apo-ratio is superior to that of serum lipid fractions and that the apo-ratio therefore should be

In the prospective case-cohort study (PREVEND cohort) (122) 6,948 subjects without previous CHD they studied the risk factors predicting major coronary events. The age- and sex-adjusted HR was 1.37 (95% CI, 1.26-1.48) for the apo-ratio and 1.24 (1.18-1.29) for the TC/HDL-C ratio (both p < 0.001). The risks of the two ratios were only marginally attenuated by additional controlling for traditional risk factors TG, hypertension, diabetes, obesity and

In a Korean study by Kim et al (123) they studied the association between plasma lipids, and apolipoproteins and coronary artery disease: a cross-sectional study in a low-risk Korean population in 544 subjects. In the lowest quartile of TC, TG and LDL-C, and the highest quartile of HDL-C, only the apo-ratio was associated with CAD in both men and women. They concluded that the apo-ratio is the only variable that differentiates the patients with CAD from those without and, furthermore, gives additional information to that supplied by

Agoston-Coldea et al. (124) studied 208 patients (100 men and 108 women), with and without previous MI by coronary angiography. They showed that the apo-ratio had a stronger correlation with MI than the TC/HDL-C ratio. Multivariate analysis performed with adjustments for conventional risk factors, showed that the levels of apoB, the apo-ratio and Lp(a), are significant independent CV risk factors. Therefore they recommend that the

In 2006 Thomson and Danesh published a meta-analysis based on data from 23 relevant prospective studies in which apoB, apoA-I and the apo-ratio were associated with risk of MI (8). They compared risk in the top versus the bottom tertile of baseline values. The relative risks were; apoB 1.86 (95% CI 1.55-2.22, cases n = 6,320), apoA-I 1.62 (1.43-1.83, cases n = 6,333), and the apo-ratio 1.86 (1.55-2.22, cases n = 3,730). ApoB and the apo-ratio were directly related to risk, whereas apoA-I was protective. In that study no results were given

In 2009 the Emerging Risk Factor Collaboration (ERFC) published an extended metaanalysis in which they included 302,430 men and women without previous vascular disease In subjects with the MetS and in patients with diabetes several studies have been performed indicating advantages of using apos, especially apoB, over conventional lipids. In our previous review (3) we summarized these results from Stewart et al. (125), Korean studies (126-128) and studies from India (129) and Canada (130). In these papers the highest values

for the apo-ratio were found in those who had most manifestations of the MetS. The aporatio was also related to atherosclerosis verified by angiography even if LDL-C values were low. In the Swedish ULSAM study (131) at the 26.8 year follow-up 462 patients had developed MI. The apo-ratio was highest in those who developed a MetS, and their aporatio was inversely related to glucose disposal. These findings were independent of LDL-C and smoking. Both the apo-ratio and MetS independently predicted MI.

Sierra-Johnson et al. (132) studied 2,955 adults (mean age 47 years; 1,457 women) without diabetes from the US NHANS III population. The apo-ratio was an independent predictor of insulin resistance after adjustment for age and race, and remained significant after further adjustment for MetS components including TG, HDL-C, traditional and inflammatory risk factors. They recommended that the apo-ratio should be recognized and implemented in future clinical guidelines. In the follow-up paper (133) of a multi-ethnic representative subset of 7,594 US adults (mean age 45 years; 3,881 men, 3,713 women) there were 673 CV deaths of which 432 were from CHD. Both the apo-ratio (HR 2.14, 95% CI, 1.11 – 4.10) and the TC/HDL-C ratio (HR 1.10, 1.04 – 1.16) were related to CHD death. Only apoB (HR 2.01, 1.05 – 3.86) and the apo-ratio (HR 2.09, 1.04 – 4.19) remained significantly associated with CHD death after adjusting for CV risk factors **(Figure 8 left)**. This suggested that the measurement of apolipoproteins has superior clinical utility over traditional risk markers such as the TC/HDL-C ratio in identifying subjects at risk for fatal CV disease. In addition, the combined elevation of glucose and a high apo-ratio increases the risk of MI as documented in the AMORIS study (3) **(Figure 8, right)**.

Zhong et al. (134) found also in China that the apo-ratio increased significantly with number of MetS components. Belfki et al (135) have shown in a Tunisian population that the aporatio increased significantly with each of the components as well as with increasing numbers of components of the MetS after adjusting for age and gender. Similarly, the apo-ratio was associated with insulin resistance.

**Figure 8.** Cumulative survival (y-axis) in relation to quartiles of the apoB/apoA-I ratio in patients with the metabolic syndrome (left) (from NHANES cohort, reference 133). Risk of myocardial infarction in relation to glucose and the apoB/apoA-I ratio (right) (AMORIS study, reference 3).

Based on the findings in subjects with MetS Sniderman and Faraj (136) have argued for including both apoB and apoA-I as stronger risk markers especially compared to LDL-C (often low in MetS), TG and HDL-C. These apos also have strong relations to glucose and insulin homeostasis. Therefore the apo-ratio should be a valid component of the MetS especially since the apo-ratio has so strong predictive value of CV risk. The apo-ratio also summarizes the risk for individuals with MetS into one simple and predictive risk number. In another paper Sniderman et al. (137) have also analyzed pros and cons for using the aporatio.

116 Lipoproteins – Role in Health and Diseases

for the apo-ratio were found in those who had most manifestations of the MetS. The aporatio was also related to atherosclerosis verified by angiography even if LDL-C values were low. In the Swedish ULSAM study (131) at the 26.8 year follow-up 462 patients had developed MI. The apo-ratio was highest in those who developed a MetS, and their aporatio was inversely related to glucose disposal. These findings were independent of LDL-C

Sierra-Johnson et al. (132) studied 2,955 adults (mean age 47 years; 1,457 women) without diabetes from the US NHANS III population. The apo-ratio was an independent predictor of insulin resistance after adjustment for age and race, and remained significant after further adjustment for MetS components including TG, HDL-C, traditional and inflammatory risk factors. They recommended that the apo-ratio should be recognized and implemented in future clinical guidelines. In the follow-up paper (133) of a multi-ethnic representative subset of 7,594 US adults (mean age 45 years; 3,881 men, 3,713 women) there were 673 CV deaths of which 432 were from CHD. Both the apo-ratio (HR 2.14, 95% CI, 1.11 – 4.10) and the TC/HDL-C ratio (HR 1.10, 1.04 – 1.16) were related to CHD death. Only apoB (HR 2.01, 1.05 – 3.86) and the apo-ratio (HR 2.09, 1.04 – 4.19) remained significantly associated with CHD death after adjusting for CV risk factors **(Figure 8 left)**. This suggested that the measurement of apolipoproteins has superior clinical utility over traditional risk markers such as the TC/HDL-C ratio in identifying subjects at risk for fatal CV disease. In addition, the combined elevation of glucose and a high apo-ratio increases the risk of MI as

Zhong et al. (134) found also in China that the apo-ratio increased significantly with number of MetS components. Belfki et al (135) have shown in a Tunisian population that the aporatio increased significantly with each of the components as well as with increasing numbers of components of the MetS after adjusting for age and gender. Similarly, the apo-ratio was

**Figure 8.** Cumulative survival (y-axis) in relation to quartiles of the apoB/apoA-I ratio in patients with the metabolic syndrome (left) (from NHANES cohort, reference 133). Risk of myocardial infarction in

relation to glucose and the apoB/apoA-I ratio (right) (AMORIS study, reference 3).

and smoking. Both the apo-ratio and MetS independently predicted MI.

documented in the AMORIS study (3) **(Figure 8, right)**.

associated with insulin resistance.

Bruno et al. (138) studied diabetic subjects and they found that apoB and the apo-ratio were associated with CV mortality independently of non-HDL-C. They recommended that apoB and apoA-I should be measured routinely in all people with diabetes, particularly in the elderly.

Bayu et al. (139) studied 224 diabetic patients (85 type 1 and 139 type 2). After adjusting for age, sex, diabetes duration, systolic blood pressure and diabetes medications they found that the apo-ratio was the best predictor of diabetic retinopathy. Traditional lipids improved the ROC area by only 1.8 % whereas the apo-ratio improved the area by 8.2 %.

Enkhma et al. (140) have studied several ethnic groups of European and African Americans and developed a CV risk score which was found to be significantly increased across tertiles of the apo-ratio. They concluded that the apo-ratio differed across ethnicities and was associated with presence of the MetS in both groups. Among African Americans, an elevated apo-ratio independently predicted a greater risk of CAD.

Ounis et al. (141) studied thirty-two obese 13 years old children with 16 subjects who participated in a 8-week training period and 16 subjects serving as a control group. The aporatio was positively correlated with TG (r = 0.46, p < 0.01), blood glucose (r = 0.48, p < 0.01), waist circumference (r = 0.34, p < 0.01), systolic (r = 0.31, p < 0.01) or diastolic (r = 0.29, p < 0.05) blood pressure and was negatively correlated with HDL-C (r = 0.51, p < 0.01), Fat max (r = 0.45, p < 0.01) and VO2 peak (r = 0.39, p < 0.01). When adjusted for pubertal stage, the relationships between the apo-ratio and other variables were not significantly altered. The multiple regression analysis showed that the change in total HDL-C is the most significant predictor of the change of the apo-ratio explaining 82% of the variance of its change over the training program.

Gatz et al. (142) studied thirty same-sex twin pairs in which both members were assessed at baseline and one twin subsequently developed dementia, at least 3 years subsequent to the baseline measurement, while the partner remained cognitively intact for at least three additional years. Eighteen of the 30 cases were diagnosed with Alzheimer's disease. Baseline assessments were conducted when twins' average age was 70.6 (SD = 6.8) years. Which twin would develop dementia was predicted by less favorable lipid values defined by higher apoB and higher apo-ratio, poorer grip strength, and — to a lesser extent — higher emotionality on the EAS Temperament Scale. Given the long preclinical period that characterizes Alzheimer's disease, these findings may suggest late life risk factors for dementia. Alternatively, there may be early development of atherosclerosis in critical cerebral arteries based on an elevated apo-ratio over time.

Carnevale-Schianca et al. (143) enrolled 616 patients with normal glucose tolerance (NGT) (273 men and 343 women), and measured insulin resistance, lipid profile, the apo-ratio and the factors compounding the MetS. An unfavorable apo-ratio (> 0.90 for males and > 0.80 for females) was present in 13.9 % of 108 patients with LDL-C < 100 mg/dL. Compared to subjects with lower apo-ratio, they had more elements of MetS and their lipid profile strongly correlated with high CV risk. In NGT individuals with LDL-C < 100 mg/dL, a higher apo-ratio indicated an atherogenic lipid profile, suggesting that LDL-C alone is insufficient to define CV risk. This study demonstrates that the apo-ratio is at least complementary to LDL-C in identifying a more correct CV risk profile of asymptomatic NGT subjects.

Wen et al. (144) measured high sensitive hsCRP, apoB, apoA-I, and the profiles of coronary angiograms, echocardiography and oral glucose tolerance tests (OGTT)s as well as traditional risk factors in 1,757 cardiology patients. The hsCRP or the apo-ratio were significantly correlated with the presence and severity of angiographic profiles, the levels of left ventricular (LV) ejection fraction, LV mass and LV mass index, and the presence of abnormal OGTT. The combination of the apo-ratio and hsCRP had greater correlation with abnormal glucose metabolism than its individual components in patients with normal fasting glucose, and was an independent predictor for coronary artery disease.
