**6. General comments on the validity of using a ratio as a primary marker of risk**

Lipid and lipoprotein ratios like TC/HDL-C and LDL-C/HDL-C have been used in various international guidelines for decades to define CV risk. However, LDL-C has in the vast number of guidelines dominated as the primary risk marker why ratios rarely are used today in clinical practice. One major reason why the lipid ratios are questioned as relevant risk markers is due to the fact that HDL-C is included in the value for TC, so HDL-C occurs both in the nominator and denominator of the ratio. Similarly, since LDL-C most commonly is derived by the Friedewald formula, HDL-C is involved as a factor for calculating LDL-C and therefore also indirectly in the nominator and denominator of that ratio. Therefore physicians are hesitant to the mathematical way of dividing various lipid numbers to obtain a mathematical, but, in their mind, not a biologically relevant ratio. When so called direct methods are used for measuring LDL-C this problem is less. In recent years non-HDL-C has been recommended as the next primary risk variable and the new non-HDL-C/HDL-C ratio has been defined. Interestingly, this ratio gives the same final number of risk as that of the TC/HDL-C ratio.

Most researchers and guidelines recommend the use the TC/HDL-C ratio since calculation of this ratio is not dependent on that blood sampling has been performed in the fasted state. This is the same argument as for using non-HDL-C rather than calculated LDL-C. The challenge now is can the apo-ratio, which summarizes the CV risk related to all atherogenic and all anti-atherogenic variables into one number, be the next rational choice as a primary risk variable? Does the apo-ratio add to information already obtained by lipids and lipid ratios? And are the values for apoB, apoA-I and especially the apo-ratio much influenced by other confounding risk factors? These and many other questions are addressed in the sections below based on a vast number of publications.
