Dr. Steven Rigatti, Consulting Medical Director to CRL, discusses why the cholesterol-to-HDL ratio is the most reliable predictor of all-cause mortality and the potential of apoB in refining cardiovascular risk assessment.
Introduction
At the American Academy of Insurance Medicine annual meeting in Montreal, Quebec, Canada, Dr. George Thanassoulis presented a talk entitled “Cardiovascular Risk - What are the New Players?”. In this talk he went into some detail about the way different lipid particles influence the risk of coronary disease and atherosclerosis. One of the key points he made was that essentially all of the non-HDL lipid particles in the blood are atherogenic. These atherogenic particles, whether chylomicrons, VLDL, LDL, or IDL, each contain a single molecule of apolipoprotein B (apoB). In clinical literature, this apoB measurement has proven to be a valuable predictor of cardiovascular risk even in patients treated with “statin” medications. However, because apoB is a separate test and not commonly seen in medical records, a quick substitute for it is the non-HDL cholesterol which is the simple difference between the total cholesterol and the HDL. In life insurance, however, it is the cholesterol to HDL ratio that has long been used as a determinant of possible Preferred underwriting classes.
Because CRL has abundant testing data which includes total cholesterol and HDL, it is opportune to compare which of these two measures, non-HDL cholesterol or the cholesterol to HDL ratio, is a better predictor of all-cause mortality. And, since it is only one simple step away, we can also compare the performance of these two measures to the calculated LDL cholesterol using the Friedewald formula (LDL = total cholesterol - HDL - triglycerides/5).
Methods
The CRL data was investigated to find cases where both total cholesterol and HDL were available. The non-HDL cholesterol was calculated as the difference between the total cholesterol and the HDL. The cholesterol to HDL ratio was calculated as the total cholesterol divided by the HDL. The LDL cholesterol was calculated using the Friedewald formula. Since we are mostly interested in categorizing Standard or better risks, cases were selected only if there was no admission of diabetes, heart disease, smoking, and there was no evidence of hepatitis B, C or HIV. Also, all cases with a positive urine cotinine (over 200mg/dl) were excluded, as were women who admitted to pregnancy or who were determined to likely be pregnant based on a previously developed model.
The, separately for men and women, Cox models were fit, controlled for age, and using the each of the 3 lipid measures as the independent variable. The dependent variable was all-cause mortality. Each variable was centered and scaled before inclusion, meaning that the hazard ratios are for a 1 standard deviation change in the lipid measure. Because the measures are on the same scale, we can use the magnitude of the hazard ratios to compare the relative importance of each measure.
Results
After selection the data contained approximately 3.6 million women and 4.3 million men. The mean follow up time was 9.5 years, and there were more than 170,000 deaths. The hazard ratios for the 3 lipid measures are shown in the table below. Although each of the measures was significantly associated with all-cause mortality (except LDL in women), the cholesterol-HDL ratio had the largest hazard ratio in both men and women. The non-HDL cholesterol had the next largest hazard ratio, and the LDL cholesterol had the smallest hazard ratio.
Discussion
The results of this analysis suggest that the cholesterol to HDL ratio is the best predictor of all-cause mortality in both men and women. This is consistent with the long-standing use of this ratio in life insurance underwriting. This is perhaps unsurprising given that both non-HDL and the ratio are simply different ways of expressing the same information, a difference vs. a ratio, and it simply may be that the ratio magnifies the mortality relationship.
While this is an interesting finding it does not negate Dr. Thanassoulis’ point that apoB, as an indirect measure of particle size, can be a way to refine the risk prediction when the usual lipid panel measures look OK. Unfortunately, the CRL data does not contain apoB measurements, so we cannot directly compare the performance of apoB to the other lipid measures. However, since apoB is rapidly gaining acceptance as a valuable predictor of cardiovascular risk, we may start seeing it more in clinical records submitted by applicants.
About the Author
Dr. Steven J. Rigatti is a consulting medical director with Clinical Reference Laboratory, with 12 years’ experience in the life insurance industry. He is the current chair of the Mortality Committee of the American Academy of Life Insurance Medicine.