From Cholesterol to Total Risk: Nature’s Answer to What Medicine Has Missed
From Cholesterol to Total Risk: Nature’s Answer to What Medicine Has Missed
Why Cardiologists Must Remove the Blinders
Abstract
For decades, cardiovascular prevention has centered on LDL cholesterol reduction. Statins have saved countless lives, yet most patients who suffer heart attacks and strokes today already have “normal” cholesterol levels [1]. The gap between cholesterol control and true risk reduction represents a dangerous blind spot in modern medicine. Icosapent ethyl (IPE), a highly purified form of the natural omega-3 fatty acid eicosapentaenoic acid (EPA), has redefined cardiovascular prevention. In the landmark REDUCE-IT trial, IPE reduced major cardiovascular events by 25% with a Number Needed to Treat (NNT) as low as 9 in chronic kidney disease (CKD) patients — outperforming statins, aspirin, and most modern diabetes therapies [2,3]. Its benefit was unrelated to triglyceride lowering, underscoring that EPA’s unique anti-inflammatory, anti-oxidative, and plaque-stabilizing effects drive its efficacy [2,4]. Despite adoption into guidelines by the American Diabetes Association (ADA, 2019) [5] and repeated spotlight at the European Society of Cardiology (ESC) and American Heart Association (AHA) — most recently in August 2025 [6,7] — clinical inertia and cholesterol tunnel vision persist. Physicians remain siloed by subspecialty, focused on numbers rather than total risk, leaving insulin resistance and CKD underrecognized [8]. This article argues for a paradigm shift: from cholesterol reduction to total risk reduction. Nature has provided a solution in EPA, purified and proven through rigorous science. To honor the evidence, clinicians must remove the blinders, look beyond LDL, and treat the whole disease.
The Cholesterol Paradigm
For decades, cardiovascular medicine has been dominated by one number: cholesterol. Lower the LDL, check the box, and move on. This LDL-focused lens has been reinforced by guidelines, pharmaceutical marketing, and health system metrics [9] that prize “cholesterol control” over true patient outcomes. Lowering LDL with statins has saved millions of lives and remains one of the most important advances in modern medicine. But even as we celebrate that success, patients keep coming back with heart attacks, strokes, and hospitalizations — even when their cholesterol is at goal and looks “good.”[1]
The truth is unavoidable: statins alone are not enough. Atherosclerosis is not just about cholesterol. It is a cardiometabolic disease driven by multiple forces — triglyceride-rich lipoproteins, inflammation, lipoprotein(a), kidney dysfunction, oxidative stress, obesity, and diabetes.[10] Yet too many cardiologists and internists still practice with blinders on, equating cholesterol lowering with cardiovascular risk reduction. It is time to lift those blinders. The real goal is not cholesterol reduction.
The real goal is total risk reduction.
Residual Risk and Why Cholesterol Alone Misses the Mark:
The Part We Ignore
Residual risk is what remains after LDL cholesterol is “controlled.” And it is large.
Patients with diabetes and metabolic syndrome remain at high risk because their vascular biology is inflamed and insulin resistant.
Patients with chronic kidney disease (CKD) are at increased risk of arrhythmia, vascular calcification, and plaque rupture — even with normal cholesterol
Patients with elevated triglycerides and triglyceride-rich lipoproteins continue to have endothelial dysfunction and microvascular injury
Patients with elevated lipoprotein(a) [Lp(a)] are at increased risk because this particle carries oxidized phospholipids that trigger inflammation
Why Cholesterol Alone Misses the Mark
The cholesterol-only lens blinds us to all of these risks. LDL is necessary to measure, but insufficient to protect our patients.
One of the most striking realities: up to 70% of patients who present with an acute cardiac event have normal or near-normal cholesterol levels [1].
In a study of over 136,000 U.S. patients admitted for acute myocardial infarction, nearly 75% had LDL cholesterol at guideline-recommended targets, and nearly half had “optimal” LDL (<100 mg/ dL) [1].
Three out of four heart attack patients would not have been flagged as “high risk” if cholesterol alone had been considered. Their LDL looked fine. Their arteries told a very different story.
This disconnect is clear: cholesterol control is not the same as risk control. This should have dismantled the cholesterol only paradigm years ago. Yet in practice, many physicians still equate “LDL at goal” with “mission accomplished
“Cholesterol control is not the same as risk control.”
Relative Risk Reduction: What It Really Means
When the landmark REDUCE-IT trial in 2019 [2] reported a 25% relative risk reduction with icosapent ethyl (IPE), some shrugged, “Another number, Another percentage”. But let’s translate it.
Relative risk reduction means that compared to placebo, the IPE group had 25% fewer cardiovascular events. Over five years, the Number Needed to Treat (NNT) was 21. That means for every 21 patients treated, one life changing event — a heart attack, a stroke, a bypass, or a cardiovascular death — was prevented. And in patients with Chronic Kidney Disease or CKD (eGFR <60), so common yet so under recognized as will be discussed later, the results were even stronger. The NNT was only 9. Imagine that: for every nine patients with CKD treated with IPE, one event was avoided.
This is extraordinary when placed next to the therapies we use every day.
REDUCE-IT: Relative Risk Reduction in Perspective
The REDUCE-IT trial demonstrated a 25% relative risk reduction with IPE compared to placebo[2]. Over five years, the NNT was 21 — meaning one major cardiovascular event was prevented for every 21 patients treated. In CKD patients (eGFR <60), the benefit was even more dramatic: nearly 50% risk reduction, with an NNT of just 9 [3].
This makes IPE one of the most effective preventive therapies in cardiology today, outperforming many mainstays:
Statins (secondary prevention): NNT ~30 [11]
Antihypertensives: NNT 30–120 [12]
Aspirin (secondary prevention): NNT 40–60 [13]
SGLT2 inhibitors / GLP-1 agonists: NNT 30–60 [14]
Better than statins! Better than aspirin exclamation point better than most modern diabetes, drugs! It is one of the most effective preventive therapies we have in Cardiology today. Yet it remains under used because physicians still wear “ cholesterol blinders”.
Triglycerides: The Ticket In, Not the Mechanism
A persistent myth is that IPE “works by lowering triglycerides.” REDUCE-IT itself disproved this. Patients qualified for the trial if their triglycerides were ≥135 mg/dL. But when outcomes were analyzed, investigators found:
Benefits were unrelated to baseline triglycerides.
Benefits were unrelated to triglycerides at the end of treatment.
Benefits were unrelated to the change in triglycerides
Triglycerides were the entry ticket into the trial. But triglyceride lowering did not explain the benefit. This point cannot be repeated enough: IPE is not a triglyceride drug. It is a cardiovascular risk-reduction therapy that works through deeper mechanisms.
Icosapent ethyl (IPE) is not a synthetic invention. It is a highly purified form of eicosapentaenoic acid (EPA), a natural omega-3 fatty acid found in cold-water fish. EPA is one of nature’s ways of fighting inflammation inside blood vessels. Unlike cholesterol or blood pressure, its benefit cannot be tracked with a single number on a lab report.
Think of it like this: IPE is an airbag for your arteries. You don’t measure it like checking your oil level or tire pressure. You don’t see its effect day to day on a chart. Blood tests are not necessary to follow it’s benefits. But when danger strikes — when plaque is about to rupture or inflammation is peaking — it deploys silently in the background, reducing the severity of the event and protecting your life.
Although patients entered REDUCE-IT with triglycerides ≥135 mg/dL, the benefits of IPE were independent of triglyceride levels [2]. The same was confirmed in EVAPORATE, which showed plaque regression despite minimal triglyceride differences between groups [4].
EVAPORATE: Imaging the Proof
The EVAPORATE trial in 2020 used coronary CT angiography to track plaque changes [4]. The CT scan measured the amount and degree of plaque in patients with coronary artery disease and treated ALL patients with HIGH INTENSITY STATIN therapy. Half the group received icosapent ethyl and the other half placebo, meaning that half only had high intensity statins. In 18 months: Placebo group had triglycerides ↓93 mg/dL. This surprisingly was numerically a greater reduction than what was achieved with the “triglyceride lowering drug “, the group assigned to take the icosapent ethyl : triglycerides ↓89 mg/dL. Numerically higher but statistically and virtually the same.
Yet the differences were night and day on repeat CT scanning. In medical studies looking for effect size, 18 months is relatively short.
REGRESSION vs PROGRESSION
IPE patients: fibrofatty plaque REGRESSED by 34%.
Placebo patients (on statins): fibrofatty plaque PROGRESSED by 32%.
The biology could not be clearer: Plaque went BACKWARDS with IPE and FORWARDS without it, despite similar triglyceride changes. All were treated with high intensity statins. This proves once again, the benefit is not in the triglycerides. It is in the anti-inflammatory, antioxidant, and plaque stabilizing actions of EPA. Although it has been shown statins do improve cardiovascular risk , statins even when given as high intensity, demonstrated very little effect on the underlying disease process of inflammation and fibrofatty plaque formation.
The biology could not be clearer: the benefit is not triglycerides, but anti-inflammatory and plaque-stabilizing effects.
CKD: The Silent Accelerator of Risk
Kidney function, measured by GFR, naturally declines with age. By 60–70, many adults are living with the equivalent of one kidney (~60 mL/min/1.73 m²). [22] CKD is defined by eGFR <60. Importantly, this is not kidney failure. Dialysis-level failure (GFR <8) is rare because most patients die of cardiovascular disease before ever reaching it [15]. Over 20 years ago, Go et al. (NEJM 2004) showed that mortality and cardiovascular risk rise exponentially as GFR falls [15].
GFR 45–59: risk doubles.
GFR 30–44: risk triples.
GFR <15: risk ↑17-fold for CV events, ↑20-fold for death.
Kidney function is traditionally measured as the glomerular filtration rate (GFR). In a healthy young adult, normal GFR is about 120 mL/min/1.73 m². But with age, kidney function naturally declines. By the time most people reach 60–70 years old, their average GFR has dropped to around 60 — essentially meaning that they are functioning with the equivalent of just one kidney.
Chronic kidney disease (CKD) is defined as eGFR <60. Importantly, CKD is not kidney failure. Rather, it is kidney dysfunction that predisposes to progressive decline. True kidney failure, requiring dialysis, occurs when GFR falls below ~8. But this is relatively rare. Why? Because most people with progressive CKD die of cardiovascular disease before they ever reach dialysis.[15]
And this has not been a recent discovery. It was demonstrated over 20 years ago that cardiovascular risk accelerates long before kidney failure develops.
As:
GFR falls below 60, the risk of all-cause mortality and cardiovascular events rises exponentially.
GFR 45–59: risk doubles compared with normal
GFR 30–44: risk triples.
GFR <15: exponentially higher. By the time GFR falls below 15, the cardiovascular event rate is more than 17 times higher than those with normal kidney function — and the death rate increases almost 20-fold.
This risk is not related to the kidney actually failing. It is the progressive loss of kidney function itself — long before dialysis is ever considered — that drives cardiovascular mortality. And yet, many patients are falsely reassured because their serum creatinine looks “normal.” Creatinine is influenced by age, sex, and muscle mass. A frail 75-year-old woman may have a creatinine of 0.9, which appears normal on paper, yet her eGFR may only be 52 — already stage 3 CKD.
And yet, CKD remains underdiagnosed. Everyone knows their cholesterol number. Almost no one knows their GFR. Despite being as important — if not more predictive — than LDL regarding health outcomes , eGFR is rarely discussed with patients. Unfortunately this significance is frequently overlooked by physicians as the there is a disconnect between the heart and the kidney. If the GFR is acceptable and you don’t need dialysis then “you’re fine” without regard for its dire implications.
This disconnect means millions of at-risk patients are overlooked, even as their risk of heart attack, stroke, arrhythmia, and death is climbing dramatically.
As Dr. George Bakris, a widely respected international expert in both nephrology and cardiometabolic medicine, has often said: “The heart and the kidney are like Siamese twins — what’s good for one is good for the other.” The biology of CKD and heart failure overlap so closely that their treatments are nearly identical. Therapies that protect the kidney often protect the heart, and vice versa.
In REDUCE-IT, CKD patients had the largest relative benefit. Nearly 50% risk reduction. An NNT of 9. For every nine CKD patients treated, one major cardiovascular event was prevented. This outperforms nearly every preventive therapy in modern cardiology — a vivid demonstration of the heart–kidney connection Dr. Bakris has championed throughout his career.
The Subspecialization Trap
Modern medicine has fractured into silos. Cardiologists often ignore the kidney. Nephrologists ignore the heart. Endocrinologists manage diabetes without watching the heart or kidney. Primary care, overwhelmed, often just chooses which specialist to send the patient to next. And no one is tracking the common thread linking them all: insulin resistance.
This leaves patients lost in the system — treated by numbers, not risk.
Individuals are treated by statistics and gone are the days of individualized, personalized care. There is no one to put the whole picture together yet one of the hottest topics in medicine is the Cardiorenal syndrome. This is a rapidly evolving topic in medicine, referring to disorders of the heart and kidneys where acute or chronic dysfunction in one organ can cause acute or chronic failure in the other. This complex interplay significantly increases the risk of cardiovascular events, kidney disease progression, and mortality, making it crucial for interdisciplinary management and treatment . Yet no one is paying attention or willing to take charge.
Mechanisms Beyond Cholesterol
Why does IPE deliver such extraordinary results? Because it works where statins do not. Statins primarily lower LDL cholesterol, but IPE addresses the inflammation and instability inside blood vessels that truly drive heart attacks and strokes.
Inflammasome suppression – calming the body’s fire alarm: Inside immune cells sits the NLRP3 inflammasome, a fire alarm for infection or injury. When it’s overactive, it keeps blood vessels inflamed. IPE quiets this alarm, reduces caspase-1 activity, and restores autophagy, the cell’s “self-cleaning process.”[16]
Oxidized lipoproteins – stopping cholesterol from going rancid: LDL and lipoprotein(a) are most dangerous when oxidized. IPE reduced Lp(a) oxidation by 61% in lab studies, cutting off a toxic trigger of plaque growth.[17]
Endothelial healing – keeping vessels smooth and protective: The endothelium is like Teflon, but when injured it becomes sticky. IPE boosts protective proteins (HO-1, PPARγ) and lowers sticky adhesion molecules (ICAM-1), restoring resilience.[17]
Plaque stabilization – shrinking the most dangerous lesions: The plaques that rupture aren’t always the biggest, but the softest. In EVAPORATE, IPE regressed fibrofatty plaque by 34%, while statins alone led to progression of 32%.[4]:
IPE vs OTC Fish Oil
IPE is fish oil — but a purified, pharmaceutical-grade form of EPA. Unlike OTC fish oil, it excludes DHA (which raises LDL) and contaminants (mercury, arsenic, PCBs). To match IPE’s EPA dose, patients would need 20+ OTC capsules daily — along with unwanted fats and oxidized oils [18]. Omega-3s spoil quickly when exposed to oxygen. Like raw fish left too long on a counter, they become rancid. That’s why IPE comes in airtight capsules — never in liquid jars. Most importantly: IPE is proven. REDUCE-IT and EVAPORATE demonstrated outcomes. STRENGTH, testing OTC omega-3s, showed no benefit [19].
Icosapent ethyl (IPE) is fish oil — but it is a highly specific and purified form of fish oil. It contains only one active ingredient: eicosapentaenoic acid (EPA), concentrated and purified to pharmaceutical standards. The daily therapeutic dose is 4 g/day (2 g twice daily). By contrast, most OTC fish oils are mixtures of EPA, DHA, and other fats. A typical 1,000 mg capsule has ~180 mg EPA and ~120 mg DHA. To match IPE, a patient would need to swallow 20+ capsules daily — along with unnecessary fats, DHA that raises LDL, and contaminants. And contaminants matter. Many OTC fish oils have been found to contain oxidized oils or even mercury, arsenic, PCBs, and dioxins.[18] IPE is molecularly distilled and manufactured to pharmaceutical-grade standards, eliminating these risks.
Some patients worry that “4 grams a day in 4 large capsules” seems like a lot. In truth, those capsules contain less than a teaspoon of oil. And there’s a reason they must be in sealed capsules: omega-3 fatty acids are unsaturated oils. That’s why they’re liquid at room temperature — but also why they oxidize quickly.
Think of it this way: if you leave a piece of raw fish sitting out on the counter too long before cooking, it starts to smell bad and turn rancid. The same thing happens to omega-3 oils when they’re exposed to air. They spoil. They degrade. They lose their benefit. That’s why IPE will never come in a bottle of liquid like many OTC products. Instead, it’s protected in airtight, oxygen-free capsules that preserve potency and purity.
Most importantly: IPE is backed by outcomes. REDUCE-IT proved fewer heart attacks, strokes, and deaths. EVAPORATE proved plaque regression. The STRENGTH trial as well as in the New England journal of Medicine Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer proved OTC fish oil mixtures offer no cardiovascular benefit. [20] IPE is fish oil — but purified, protected, contaminant-free, and proven in outcomes.
The Persistence of Cholesterol-Only Dogma
Despite overwhelming data and international endorsements, the medical community continues to wrestle with cholesterol tunnel vision. For decades, LDL cholesterol has been the centerpiece of both education and reimbursement metrics. Lower the LDL, check the box, and declare success.
This narrow focus has been in part fueled by big pharma — specifically the statin industry, a multibillion-dollar enterprise. Statins absolutely earned their place as one of the great lifesaving therapies of modern medicine. But their commercial success also cemented an outsized narrative: that cholesterol control alone is synonymous with cardiovascular prevention.
The unintended consequence has been a generation of cardiologists and internists who equate cholesterol lowering with cardiovascular risk reduction. And nowhere is this mindset more clearly illustrated than in New York City, where a cardiologist at a prestigious university still proudly refers to himself as the “Cholesterol Nazi.” His claim to fame is his relentless pursuit of LDL control. But when asked recently about icosapent ethyl — a therapy proven to reduce heart attacks, strokes, hospitalizations, and cardiovascular death — his response was dismissive: “I see no role for omega-3s in cardiovascular disease.”
This wasn’t before the data. It was years after the New England Journal of Medicine published REDUCE-IT (Jan 3, 2019)[2], years after the American Diabetes Association adopted IPE into the Standards of Care (March 27, 2019)[21] and while the European Society of Cardiology (ESC) and the American Heart Association (AHA) [6,7]— as recently as August of this year — continue to spotlight IPE in late-breaking sessions as one of the most important preventive therapies in modern cardiology.
Clinical Inertia vs Clinical Intelligence
And this is the real problem: clinical inertia.
The science is in. The guidelines are written. The international conferences echo the same message. Yet adoption lags.
Why? Because habits and corporate metrics often outpace clinical intelligence. It is easier to keep checking cholesterol boxes than to think holistically about cardiometabolic risk. Easier to keep prescribing statins alone than to adopt therapies that don’t move a number on a lab report. Easier to defend the old framework than to embrace new evidence.
But inertia costs lives. Every year of delay means more heart attacks, more strokes, more preventable deaths.
IPE is not fringe science. It has been validated by the highest levels of medicine — NEJM, ADA, ESC, AHA.[2,6,7,21]. It is not a supplement. It is a prescription therapy with an NNT better than statins, aspirin, or most diabetes drugs.[2,3,11,12,13,14]
“Clinical intelligence demands we act on today’s data.”
And yet, because it doesn’t shift LDL or triglycerides in a way that satisfies old metrics, it is dismissed.
This is not science — this is Clinical inertia keeps patients trapped in yesterday’s paradigm.
Conclusion: From Cholesterol Numbers to True Risk Reduction
The science is in. Nature’s healing has prevailed.
Who would have thought that a purified omega-3 — EPA as IPE — could rival, and in some cases surpass, our most trusted therapies? IPE reduces cardiovascular events, stabilizes plaque, and lowers mortality. With an NNT of 9 in CKD [3] — a disease silently affecting baby boomers by their 60s and 70s [22] — it outperforms many standard therapies. Yet most patients don’t even know their GFR, though nearly everyone knows their cholesterol. This must change.
We are constantly searching for answers to illness and disease — especially when the stakes include life and death. The truth is, one solution already exists, but ignorance and clinical inertia too often stand in the way. Icosapent ethyl (IPE) is not a laboratory trick or marketing illusion. It is nature’s own solution — purified, protected, and clinically proven. Unlike synthetic approaches that chase numbers, IPE works in concert with human biology to restore balance where it’s been lost.
The message is urgent.
LDL control is necessary, but not sufficient.
Statins save lives, but statins alone are not enough.
Cardiovascular risk reduction means true event reduction — not simply lowering a lab value.
IPE has changed the landscape. Now medicine must change with it.
The future of chronic disease prevention does not lie in checking boxes or chasing lab targets. It lies in treating the root causes — insulin resistance, inflammation, endothelial dysfunction, and metabolic imbalance — the very drivers of disease that Western medicine too often ignores.
Unfortunately, even with all the specialists, what we truly need is intelligence, knowledge, and the courage to demand more. We cannot accept doctors who remain trapped in inertia, following outdated, pharma-driven, or corporate protocols. Each of us deserves individualized, evidencebased care — rooted in the latest science, guided by functional insight, and focused on the whole person, not just their numbers.
Author: Dr John Sciales
Director, CardioCore Metabolic Wellness Center
“Getting to the Core…the Path to Wellness -where being Healthy is Not an Accident"
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Dedicated to my Dear Friend John C. , a man with CardioMetabolic risk who has embraced Intelligence, Dedication and Determination in the pursuit of health and wellbeing. A role model for all of us to follow.
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Aging and the Glomerular filtration rate : pmc.ncbi.nlm.nih.gov/articles/PMC2744545/
