Question explored with the scientific record
Why do treatments that improve a health marker sometimes fail to help patients?
The short version: a health marker can improve while the patient gets no better, because the marker is not the disease.
A marker like LDL cholesterol, a natriuretic peptide, or a lab value is a stand-in, not the outcome that matters [7]. The meta-analysis of 100,610 patients is the cleanest example: adding ezetimibe or a PCSK9 inhibitor to a statin cut cardiovascular events by 18% and heart attacks by 16%, but did not significantly reduce all-cause death [7]. The LDL fell. People still died at the same rate. The same pattern shows in heart failure, where only very large drops in BNP and NT-proBNP tracked with better outcomes, and small drops meant nothing [6]. A marker can move for reasons that have nothing to do with the disease process that actually kills.
The second reason is that the marker may be measuring the wrong layer of the illness. In dialysis patients, the ratio of extracellular to intracellular fluid predicted death strongly, but that is a measure of fluid balance and cell health, not a single lab value [5]. In heart failure, a drop in the GRK2 protein after exercise predicted survival, while the usual echo numbers barely moved [2]. And in one striking case, a patient's symptoms improved after a device implant even though every echocardiographic parameter stayed the same [4]. The marker said nothing. The patient got better anyway.
The third reason is who paid for the evidence and what they chose to measure. Much of this research leans on surrogate endpoints because they are cheap and fast, and the trials that use them are often funded by the companies selling the drug [1][3]. A systematic review of bovine colostrum, for example, found mostly surrogate outcomes and no consistent clinical benefit [3]. A marker that improves is not proof the treatment works. It is proof the marker moved.
| Outcome | Ezetimibe/PCSK9 + statin vs statin alone |
|---|---|
| Cardiovascular events | 18% reduction |
| Heart attack | 16% reduction |
| Ischemic stroke | 23% reduction |
| All-cause death | No significant reduction |
My call: a treatment that only improves a lab value has not shown it helps you live longer or feel better. Confidence: high, on the mortality data; the rest of the marker literature is too thin and too conflicted to trust.
Sources used 7
-
Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review
A comprehensive systematic review evaluating exogenous ketosis in adults with established medical conditions finds potential therapeutic signals across neurological, metabolic, and cardiovascular diseases but notes overall evidence is limited, heterogeneous, and largely based on…
DOI: 10.3390/nu17193125 -
Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure
In patients with advanced heart failure undergoing a 3-month aerobic exercise program, lymphocyte GRK2 protein levels fall, and the magnitude of this change strongly predicts mid-term survival, with smaller or absent reductions associated with worse outcomes.
DOI: 10.1177/2047487313491656 -
Clinical applications of bovine colostrum therapy: a systematic review
This systematic review critically evaluates the clinical evidence for bovine colostrum as a dietary supplement across diverse human conditions, finding heterogeneous study quality with limited, largely surrogate outcomes and no consistent demonstration of clinical benefit, thoug…
DOI: 10.1111/nure.12089 -
A Case of Cardiomyopathy in Patients with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke (MELAS) Syndrome Showing Markedly-elevated Myocardial Oxidative Stress
In a 64-year-old man with ischemic cardiomyopathy and severe mitral regurgitation, symptoms improved after CRT-D implantation and Doppler-guided AV/VV optimization despite no improvement in echocardiographic parameters except slight QRS narrowing.
DOI: 10.1016/j.cardfail.2013.08.479 -
Annual change in the extracellular fluid/intracellular fluid ratio and mortality in patients undergoing maintenance hemodialysis
A retrospective cohort study in maintenance hemodialysis patients showing that both the baseline extracellular fluid/intracellular fluid (ECF/ICF) ratio and its annual change (ΔECF/ICF) independently predict all-cause and cardiovascular mortality and substantially improve mortal…
DOI: 10.1038/s41598-021-04366-6 -
Only Large Reductions in Concentrations of Natriuretic Peptides (BNP and NT-proBNP) Are Associated with Improved Outcome in Ambulatory Patients with Chronic Heart Failure
This study investigates the prognostic significance of changes in B-type natriuretic peptides (BNP and NT-proBNP) in chronic heart failure patients, finding that only substantial decreases in these peptides are associated with improved outcomes.
DOI: 10.1373/clinchem.2008.108928 -
P5015Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events: A meta-analysis
In a meta-analysis of 9 randomized controlled trials including 100,610 patients, intensified lipid-lowering therapy with ezetimibe or PCSK9 inhibitors added to statins reduced cardiovascular events by 18%, myocardial infarction by 16%, and ischemic stroke by 23%, but did not sig…
DOI: 10.1093/eurheartj/ehz746.0193