The aim of using surrogate markers is to predict the future, and we all know how difficult that can be.
Generally one considers testing these "biomarkers" because there is a known plausible mechanism whereby the thing we are measuring might lead to the outcome of interest.
A very common example is measuring blood pressure. Originally people who had "malignant hypertension" were found to have 50% mortality in 1 year. Many trials later we know that a rise in blood pressure of even 20/10 systolic/diastolic is associated with increased cardiovascular mortality.
"Associated with" does not mean caused, as the two things might both be results of yet another factor operating on them both.
Cholesterol is another common surrogate for this same clinical outcome of cardiovascular disease and mortality. The evidence that elevated cholesterol causes cvs disease is from a weak association. Nearly all the trial evidence is from use of statin drugs, and these have multiple relevant "pleiotropic" effects, quite apart from any possible benefit of cholesterol lowering.
Lowering cholesterol probably has very little to do with their benefits. It is a surrogate marker still, but only because of it leading to statin medication. The non statin drug ezetimibe lowers cholesterol with only a very "modest" proven benefit on clinical outcomes (2% over 7 years.)
That doesn't mean they have to be causally related to one "disease." Diseases as medically defined are artificial abstractions, just a small part of overall ill health in an individual.
Many factors over many years, are usually needed to produce one "disease." These same factors may contribute along the way to development of various other apparently unrelated "diseases."Maximizing QALYs is the clinical outcome it is all about - compressing morbidity into a shorter time at the end of life.
To quote briefly from Dr. John Harrison's book "Love Your Disease. It's Keeping You Healthy"...
"Disease is both self-created and self-cured. ...Having established the ways in which we contribute to the developement of our diseases, we will go on to investigate the ways in which we can minimise our discomfort and, if we so desire, eliminate our disease entirely. The decision is ours.
The delightful thing about such a concept is that you, the patient, can once again assume control over both your disease and your destiny...
...healing ourselves can be great fun - not only fun, but an opportunity to reorganise our whole lives, learn about ourselves and our environment, understand our children and , perhaps more importantly, prevent disease in both ourselves and our offspring."
These are proxy indicators of susceptibility to later disease.
Footsteps per day, as measured by a pedometer.
Natural walking speed.
Hours of sleep, especially before midnight.
Tiny amounts of albumin protein in one's urine in the morning (microalbuminuria.)
Blood pressure (ideally by 24 hour monitor)
Homocysteine in blood (ideally 4 hours after 4gm of methionine orally.)
Transferrin saturation and serum ferritin.
"What are the take homes lessons of the last decade when it comes to lipid management? First, the trials discussed above argue that lipid targets cannot be considered reliable surrogate endpoints. The medical literature is rich with examples of studies that used surrogate endpoints leading us to adopt ultimately harmful drugs (23). Future studies of statins should be powered to examine important clinical endpoints, and whether novel biomarkers will be able to overcome these deficits remains to be seen."
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