08/11/2026
Beyond LDL: Are We Looking at Cardiovascular Risk Too Late?
Reflections on the Global Burden of Disease 2023 LDL Cholesterol Study
A recent analysis from the Global Burden of Disease (GBD) 2023 LDL Cholesterol Collaborators, published in JAMA, provides some very interesting data about the global burden associated with elevated LDL cholesterol.
The study estimated that in 2023, elevated LDL-C accounted for approximately 3.6 million deaths worldwide and 90.7 million disability-adjusted life-years (DALYs). At the same time, despite an increase in the absolute global burden associated with LDL-C, the age-standardized mortality rate attributed to elevated LDL-C decreased by approximately 45.6% between 1990 and 2023.
The investigators attributed much of the increase in the absolute burden to population growth and aging.
Dr. Christian Razo, PhD, from the University of Washington, who has worked extensively with the Global Burden of Disease project, has emphasized an important message that deserves attention: cardiovascular prevention needs to move much earlier in life.
Instead of waiting until cardiovascular disease becomes clinically apparent, we should identify cardiometabolic risk decades earlier. Lipid screening beginning at younger ages is part of this strategy.
But perhaps even more important is the recognition that cardiovascular risk factors rarely occur in isolation. Obesity, elevated blood pressure, abnormal glucose metabolism, dyslipidemia, and other metabolic abnormalities frequently coexist in the same person. Therefore, our approach to prevention should increasingly evaluate these factors together rather than separately.
I strongly agree with this concept, and I would like to add a few observations of my own.
First: What Does “Elevated LDL” Really Mean?
An important detail in interpreting the GBD study is that the investigators estimated LDL-related cardiovascular burden relative to a theoretical minimum-risk LDL-C exposure range of 35–54 mg/dL.
This should not be interpreted as meaning that an LDL-C of 55 mg/dL is clinically “abnormal.”
In fact, an LDL-C below 55 mg/dL is currently used as a treatment target for some patients at very high cardiovascular risk, particularly those with established atherosclerotic cardiovascular disease.
For an otherwise healthy individual without established cardiovascular disease, an LDL-C around this level would generally be considered very low rather than pathologically elevated.
This distinction is important when interpreting population-level estimates from the GBD study. A theoretical minimum-risk exposure level used to calculate attributable disease burden is not necessarily the same thing as the clinical threshold we use to diagnose or treat an individual patient.
Second: LDL Matters—but It Is Not the Whole Story
The finding I find particularly interesting is that age-standardized cardiovascular mortality attributed to elevated LDL-C has declined substantially since 1990, even while the absolute global LDL-related burden has increased.
I do not interpret this finding as evidence that LDL cholesterol is unimportant.
There is extensive genetic, epidemiological, mechanistic, and clinical-trial evidence supporting LDL-containing atherogenic lipoproteins as an important causal factor in the development of atherosclerotic cardiovascular disease.
However, I believe these findings reinforce something equally important:
Cardiovascular disease cannot be understood by looking at LDL alone.
Atherosclerosis develops over decades and occurs within a much larger biological environment.
Blood pressure, glucose metabolism, insulin resistance, triglyceride-rich lipoproteins, visceral adiposity, smoking, physical inactivity, dietary patterns, genetics, and chronic low-grade inflammation may all contribute to an individual’s overall cardiometabolic risk.
Some of these abnormalities can be present for many years before diabetes, cardiovascular disease, chronic kidney disease, or other clinical complications become apparent.
This is the process I have described as “The Invisible Fire.”
The Invisible Fire
The concept is relatively simple.
Long before a heart attack, stroke, diabetes, fatty liver disease, or chronic kidney disease becomes clinically evident, metabolic abnormalities may already be developing silently.
Repeated postprandial glucose elevations, compensatory hyperinsulinemia, insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, and chronic low-grade inflammation may gradually interact over many years.
Not every patient will follow the same pathway, and LDL remains an important component of atherosclerotic risk. But focusing on a single biomarker may cause us to miss the larger cardiometabolic picture.
By the time the disease becomes obvious, the process may have been developing for decades.
That is why I believe the future of cardiovascular prevention should increasingly become the future of cardiometabolic prevention.
We Need to Look Earlier—and Look at the Whole Picture
Rather than asking only:
“Is the LDL elevated?”
perhaps we should also be asking:
What is happening metabolically in this person?
What is their blood pressure?
What is their fasting glucose?
What happens to glucose after meals?
What are their triglycerides and HDL?
Is there evidence of insulin resistance?
What is their waist circumference and visceral adiposity?
What are their physical activity, nutritional patterns, sleep, and other lifestyle factors?
And most importantly:
Are these factors beginning to move in the wrong direction even though the patient does not yet meet the conventional definition of disease?
This is where I believe the greatest opportunity for prevention exists.
From Disease Treatment to Early Cardiometabolic Detection
For decades, medicine has become extraordinarily effective at treating cardiovascular disease once risk becomes obvious—and especially after disease is established.
But perhaps the next major step is to move further upstream.
Identify risk earlier.
Assess multiple cardiometabolic factors together.
Determine the severity and trajectory of those abnormalities.
Then establish a long-term strategy in which lifestyle intervention, appropriate medical therapy when indicated, and ongoing monitoring work together.
The objective should not be to replace LDL cholesterol as an important cardiovascular risk factor.
The objective should be to put LDL into its proper context as one important component of a much larger cardiometabolic system.
In my opinion, this is where the findings from the Global Burden of Disease study become particularly relevant.
The most important cardiovascular event may be the one that never happens because we recognized the metabolic conditions that were developing 20 or 30 years earlier.
That is the opportunity behind early cardiometabolic prevention.
And that is also the central idea behind what I call The Invisible Fire.
Al W. Robaina, MD, ABIM, DABOM
This article represents the author’s interpretation and opinion and is intended for educational purposes. It should not be interpreted as individualized medical advice.
Reference
GBD 2023 LDL Cholesterol Collaborators. Global Burden of Elevated LDL-C: Findings From the Global Burden of Disease Study 2023. JAMA. Published online July 29, 2026. doi:10.1001/jama.2026.8628.
