A physician friend recently told me he had just taken a patient off a statin.
Not because the patient’s cholesterol had plummeted. Not because they were experiencing side effects. Not because the patient refused treatment. Quite the opposite.
The patient had become metabolically healthier.
Healthy enough, in fact, that their physician concluded the statin was no longer providing a meaningful net benefit.
If you’ve been told for years that elevated cholesterol automatically means lifelong statin therapy, that decision may sound strange, even reckless.
It certainly goes against cardiology dogma to take a patient off a statin.
But it follows directly from a reality that is often lost in public discussions of cardiovascular disease: The risk associated with LDL cholesterol (and ApoB) is context-dependent.
For people with obesity, insulin resistance, high blood pressure, elevated triglycerides, low HDL, and other markers of metabolic dysfunction, statins can provide net benefit. This is for reasons beyond LDL and ApoB lowering, including improvements in endothelial function and reductions in vascular inflammation.
That is… when a patient is metabolically unhealthy.
But as metabolic health improves, the risk-benefit equation changes.
Statins are not without costs.
They can cause insulin resistance, impair mitochondrial function, and carry other side effects that become increasingly relevant as their expected benefits diminish.
Even in the landmark trials that established statins as standard of care, when you examine participants with even modestly good metabolic health, the cardiovascular benefits become progressively smaller… and then become non-significant.
The risks, meanwhile, remain.
The implication is uncomfortable but evidence-based: some metabolically healthy people with elevated cholesterol may derive little benefit from statins, or could even experience net harm.
So, what changed for my friend’s patient?
The answer was a GLP-1 drug.
Over the course of roughly 18 months, the patient lost more than 60 pounds on the GLP-1-GIP dual agonist, tirzepatide. Their inflammatory markers improved. Triglycerides fell. HDL cholesterol rose. Insulin sensitivity improved dramatically.
They had effectively “graduated” from the category of metabolically unhealthy to metabolically healthy. (Someone toss a mortarboard into the air.)
As a result, their physician reasonably and, in my opinion, responsibly determined that the rationale for statin therapy had largely disappeared.
Why LDL Cholesterol Became the Main Character
The truth is that medicine is not always guided by the most important biological target, nor what is best for the patient per se.
Medicine it is guided by the targets we can reliably measure and the interventions we can readily deploy.
For decades, LDL cholesterol fit that role perfectly. We can measure it. We can lower it. And those are perceived as easy wins. As a result, LDL cholesterol became the centerpiece of cardiovascular prevention. The problem is that a biomarker is not a disease.
And while statins have their utility, especially in metabolically unhealthy people, focus on cholesterol has a poor track record. Deaths from acute cardiovascular events have fallen, that true. But that’s thanks in large part to advances in emergency medicine, surgical interventions, and critical care.
What about the overall burden of cardiometabolic disease? It remains staggering.
Obesity continues to rise. Diabetes continues to rise. Metabolic syndrome remains endemic. And cardiovascular disease remains a leading cause of death.
Despite billions of dollars invested in increasingly sophisticated cholesterol-lowering therapies, we have not fundamentally altered the trajectory of metabolic disease itself.
So, has barking up the LDL cholesterol tree worked?
No. It has not, at least not well.
The fact of the matter is that the roots of cardiovascular disease overlap extensively with the roots of many of our most devastating chronic diseases: obesity, type 2 diabetes, fatty liver disease, dementia, and so on.
Insulin resistance, chronic inflammation, impaired energy metabolism, and excess adiposity sit near the center of all of them. Ideally, this shift in focus would have been driven primarily by lifestyle interventions.
But history suggests that broad changes in medical practice often require more than compelling evidence. They require tools.
And that is why I believe GLP-1 receptor agonists may prove so transformative. Not simply because they help people lose weight. ut because they create an entirely new incentive structure within medicine.
They redirect attention toward metabolic health itself. They give physicians, health systems, researchers, and pharmaceutical companies a common target that extends far beyond cholesterol. For the first time in decades, we have a class of therapies that is forcing the medical community to ask a different question…
Not: “How low can we get LDL?”
But: “How metabolically healthy can we make people?”
And in my view, that is the far more important question.
But saying “metabolic health matters” is easy. The harder question is: how do you actually measure it?
If LDL and ApoB are only pieces of the cardiovascular puzzle, what should we be looking at instead?
This is where we’re going next!
There are measurable markers available today that capture dimensions of cardiovascular and metabolic health that LDL simply cannot.
One has been linked to exceptional longevity in humans.
Another was ~14X more predictive of cardiovascular risk than LDL in a large prospective dataset.
And one of my favorites isn’t even measured in your blood.
And GLP-1 drugs appear to influence all three. That convergence is the part of this story I think most people are missing.
In the rest of today’s letter for StayCurious Metabolism premium members, we’ll explore:
How GLP-1s improve cardiovascular health
Markers you can measure today
How GLP-1s influence these markers
If you’re someone who enjoys exploring the frontier of metabolic health, please consider joining our community.
If you’re willing to take the leap and invest in joining our premium community, the cost amounts to just 67 cents per letter for monthly subscribers, and I promise I do everything in my power to give you the best possible value. Even today, we’re beginning to roll out new perks, which I’ll tell you about in the postscript.
I really hope you become part of this exceptional StayCurious community, because I believe we’re planting the seeds of something that’s going to change the health landscape!
