**15. Treating CV risk patients to new targets using apolipoproteins**

The apo-ratio, as shown in this paper, has commonly been shown to predict CV risk equally well or, in fact, more commonly even significantly better than conventional lipids in both prospective and treatment studies. So, which cut levels and targets of the apo-ratio should be recommended in the clinic to indicate CV risk before and after treatment? Since there is an almost linear increase (semi-log scale) in risk with increasing values of the apo-ratio from both AMORIS and the INTERHEART studies **(Figure 10)** it is clear that at values of the aporatio > 0.90 (values should be given in two decimals in order not to lose important information) there is a considerable increase in risk, whereas values from 0.70 to about 0.90 are indicative of a moderate risk. Values for men < 0.70 and for fertile females < 0.60 can be more normal especially if no other risk factors are present. The "ideal-biologically normal values" are rather < 0.50 as also documented in lipid-lowering trials in which CV events have been successfully reduced (176,177). So the target values during therapy must focus on these levels, the lower the apo-ratio the better is the therapy.

Lipids and apos are commonly correlated as also manifested in the AMORIS study (3 and others). In order to simplify for the physicians to learn what a value of LDL-C corresponds to regarding apoB **(Figure 11, left)**, a table has been compiled based on data from AMORIS also for the relationship between LDL-C and the apo-ratio **(Figure 11, right)**. A value of the apo-ratio of 0.80 roughly corresponds to a value for LDL-C of 3.0 mmol/L, and an apo-value of about 0.50 corresponds to LDL-C value 1.6 mmol/L for men and about 0.1 units lower for females**.** Notably, there is a large deviation from this correlation line. Those having a higher apoB or a higher apo-ratio at all levels of LDL-C (above the line) in general have a much higher CV risk than those below the line. Further details and relations between apolipoproteins, lipids and their relations to CV risk, and cut- and target levels of apoB and apoA-I have been reviewed (3). Since the target level for LDL-C according to many guidelines is set at LDL-C < 1.6 mmol/L, a target and normal value of the apo-ratio < 0.50 seems to be a realistic number.

**Figure 10.** This line of risk of myocardial infarction is based on the findings in the AMORIS (reference 3) and the INTERHEART (reference 58) studies. Tentative cut-values are indicated in green (low risk), yellow (medium risk), and red (high risk). Values for a particular patient can be indicated by the dots on the line. During lipid-lowering treatment it is easy to monitor how a patient moves upwards or downwards in the risk line for the apo-ratio.

126 Lipoproteins – Role in Health and Diseases

more than three to four years in the trial. LDL-C was reduced to 1.4 mmol/L and the apo-ratio was reduced from 0.95 to 0.49, p < 0.001. This indicates that "normal values" for the apo-ratio

In a recent publication from JUPITER the authors reported that LDL-C, non-HDL-C, apoB and lipid-ratios as well as the apo-ratio had about similar predictive value of remaining risk during treatment with rosuvastatin (177). However, in subgroup analyses they reported that apoA-I had a greater capacity to define remaining risk than HDL-C. Furthermore, they also found that any lipid-related ratios had a greater predictive value than single values of LDL-C, non-HDL-C or apoB. In addition, if LDL-C values reached < 100 mg/dL or < 70 mg/dL, or if non-HDL-C targets were reached < 130 mg/dL or < 100 mg/dL, the only lipid-related variable or ratio that still was associated with remaining significant risk was the apo-ratio. These data, although the number of events is small in the sub-cohorts, indicate that the apo-ratio is a realistic and a valid predictor of risk and may be better than conventional lipids. However, the authors indicated that differences were small and that LDL-C and non-HDL-C were still sufficiently good as

should be in the order of < 0.50 in order to obtain as low future risk as possible.

targets for treatment despite the fact that the results were in favor of the apo-ratio.

these levels, the lower the apo-ratio the better is the therapy.

seems to be a realistic number.

**15. Treating CV risk patients to new targets using apolipoproteins** 

The apo-ratio, as shown in this paper, has commonly been shown to predict CV risk equally well or, in fact, more commonly even significantly better than conventional lipids in both prospective and treatment studies. So, which cut levels and targets of the apo-ratio should be recommended in the clinic to indicate CV risk before and after treatment? Since there is an almost linear increase (semi-log scale) in risk with increasing values of the apo-ratio from both AMORIS and the INTERHEART studies **(Figure 10)** it is clear that at values of the aporatio > 0.90 (values should be given in two decimals in order not to lose important information) there is a considerable increase in risk, whereas values from 0.70 to about 0.90 are indicative of a moderate risk. Values for men < 0.70 and for fertile females < 0.60 can be more normal especially if no other risk factors are present. The "ideal-biologically normal values" are rather < 0.50 as also documented in lipid-lowering trials in which CV events have been successfully reduced (176,177). So the target values during therapy must focus on

Lipids and apos are commonly correlated as also manifested in the AMORIS study (3 and others). In order to simplify for the physicians to learn what a value of LDL-C corresponds to regarding apoB **(Figure 11, left)**, a table has been compiled based on data from AMORIS also for the relationship between LDL-C and the apo-ratio **(Figure 11, right)**. A value of the apo-ratio of 0.80 roughly corresponds to a value for LDL-C of 3.0 mmol/L, and an apo-value of about 0.50 corresponds to LDL-C value 1.6 mmol/L for men and about 0.1 units lower for females**.** Notably, there is a large deviation from this correlation line. Those having a higher apoB or a higher apo-ratio at all levels of LDL-C (above the line) in general have a much higher CV risk than those below the line. Further details and relations between apolipoproteins, lipids and their relations to CV risk, and cut- and target levels of apoB and apoA-I have been reviewed (3). Since the target level for LDL-C according to many guidelines is set at LDL-C < 1.6 mmol/L, a target and normal value of the apo-ratio < 0.50


.

**Figure 11.** Data from the AMORIS study. Relations between LDL-C and apoB (left), and LDL-C and the apoB/apoA-I levels (right). Various cut-levels of LDL-C correspond to apoB and apoB/apoA-I values (both figures from reference 3).

How much can effective lipid-lowering therapy reduce apoB and the apo-ratio and how much can apoA-I be increased? Physical exercise and diet, if effective and longstanding, can reduce

apoB by 5-10 % at the most and the apo-ratio by about 5% and increase apoA-I by about 5%. For more information see reference 3 and data on effects of statins in section 13 above.
