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Posted on Wednesday January 28, 2026 in Naked Heart
An article written by Dr Edward Leatham, Consultant Cardiologist © 2026 E.Leatham
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Statins have transformed cardiovascular prevention. Few drug classes have such a consistent and robust evidence base demonstrating reductions in myocardial infarction, stroke, and cardiovascular mortality. Lowering low-density lipoprotein cholesterol (LDL-C) clearly reduces atherosclerotic risk, and statins remain foundational therapy in both primary and secondary prevention.
However, when we move beyond headlines and examine absolute benefit, a more uncomfortable reality emerges. Even with optimal LDL-C lowering over the typical duration of modern cardiovascular trials — usually 2 to 3 years — the majority of cardiovascular events are not prevented. This ongoing burden is referred to as residual cardiovascular risk, and it represents one of the most important unmet needs in contemporary preventive cardiology.
Percent of subjects experiencing a cardiovascular event in eight large statin investigations Scandinavian Simvastatin Survival Study (SSSS), Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT 22), Heart Protection Study (HPS), Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID), Cholesterol and Recurrent Events (CARE), Treating to New Targets (TNT), Air Force/Texas Coronary Atherosclerosis Prevention Study (AFTEXCAPS), West of Scotland Coronary Prevention Study (WOSCOPS).
Average relative risk reduction was 25% and the absolute risk reduction was 3.4% illustrating the large number of subjects experiencing a cardiovascular (CV) event while on statin therapy with reduced LDL-C values. (Modified from reference (1)).
Figure reproduced unmodified from: Superko HR, Garrett B. Small dense LDL: scientific background, clinical relevance, and recent evidence still a risk even with “normal” LDL-C levels. Biomedicines. 2022;10(4):829. © 2022 The Authors. Distributed under the Creative Commons Attribution (CC BY 4.0) licence.
An important factor underpinning this observation is the design of modern clinical trials. Due to the substantial cost of running large cardiovascular outcome studies, most commercially funded trials enrol large numbers of patients to ensure statistical power, but observe them over relatively short periods. While this approach is sufficient to demonstrate biological efficacy, it inevitably underestimates the full lifetime benefit of therapy. The assumption is that a treatment effect observed at 2–3 years will continue — and likely widen — over longer horizons of 5, 10, or even 20 years. Such durations, however, are impractical for randomised trials, leaving long-term benefit inferred rather than proven. This limitation reinforces a core principle of preventive cardiology: earlier intervention in at-risk populations is likely to yield the greatest cumulative benefit, even if short-term absolute risk reductions appear modest.
The importance of residual risk lies not in diminishing the value of statins, but in recognising that other pathogenic factors, beyond LDL-C, are also at play. Atherosclerosis is biologically complex, and lowering LDL-C addresses only one component of risk. This recognition has, at times, led some critics to question whether the benefits of statins arise primarily from LDL-C reduction or from so-called pleiotropic effects, such as anti-inflammatory or endothelial actions.
However, this argument has been substantially weakened by consistent evidence showing that cardiovascular risk reduction closely tracks the degree of LDL-C lowering, regardless of how that lowering is achieved. Whether LDL-C is reduced by statins, ezetimibe, or PCSK9 inhibitors, the magnitude of clinical benefit is proportional to the absolute reduction in LDL-C. This concordance strongly reinforces the conclusion that the principal driver of statin benefit is LDL-C lowering itself, rather than off-target or ancillary effects.
Residual risk therefore does not negate the LDL hypothesis. Instead, it highlights that LDL-C lowering is necessary but not sufficient to fully address cardiovascular risk.
Relative Risk vs Absolute Risk: Why the Difference Matters
Statin trials are often presented in terms of relative risk reduction (RRR), typically around 20–30%. While impressive, relative risk can obscure how much risk is actually removed for an individual patient.
When outcomes are expressed as absolute risk reduction (ARR) and Number Needed to Treat (NNT), the scale of benefit — and the scale of what remains — becomes clearer.
In JUPITER, a primary prevention trial in patients with normal LDL-C but elevated hs-CRP, 83 patients needed to be treated for just under two years to prevent one major cardiovascular event(2). In FOURIER, despite background statin therapy and LDL-C driven down to ~30 mg/dL using a PCSK9 inhibitor, around 67 patients required treatment for ~2.5 years to prevent one event(3).
These are clinically meaningful benefits — but they also demonstrate that the majority of treated patients remain at risk.
The FOURIER trial was particularly revealing. LDL-C levels previously considered “ideal” — and then some — did not abolish cardiovascular events. Event curves continued to diverge slowly, but they never flattened. This observation forces an important conclusion:
LDL-C is necessary to treat, but insufficient to explain total cardiovascular risk.
Superko and Garrett highlight a key contributor to this residual risk: lipoprotein heterogeneity, particularly small, dense LDL (sdLDL) (1).
Not all LDL particles behave the same. sdLDL particles are:
Multiple studies show that sdLDL is associated with coronary heart disease independent of LDL-C levels, including in patients whose LDL-C is “normal” or well-controlled on statins(1,4,5).
Small dense LDL-C (sd-LDL-C) quartiles and large buoyant LDL-C (lb-LDL-C) quartiles and cardiovascular risk over 15 years of follow-up in ARIC. (Modified from reference(1,6)).
Figure reproduced unmodified from: Superko HR, Garrett B. Small dense LDL: scientific background, clinical relevance, and recent evidence still a risk even with “normal” LDL-C levels. Biomedicines. 2022;10(4):829. © 2022 The Authors. Distributed under the Creative Commons Attribution (CC BY 4.0) licence.
This is residual risk, quantified.
Statins reduce LDL-C concentration, but they do not reliably normalise LDL particle size or number, particularly in patients with underlying metabolic dysfunction. This raises the question: what drives sdLDL in the first place?
Insulin Resistance and Visceral Adipose Tissue: The Metabolic Engine of Residual Risk
A major, and often under-recognised, driver of residual cardiovascular risk is insulin resistance, closely linked to excess visceral adipose tissue (VAT).
Visceral fat is not passive energy storage. It is metabolically active and releases free fatty acids directly into the portal circulation, driving hepatic overproduction of VLDL. This results in the classic atherogenic dyslipidaemia pattern:
This phenotype is strongly associated with insulin resistance and metabolic syndrome(4,7,8).
Crucially, statins only partially address this lipid pattern. While LDL-C falls, triglyceride-rich lipoproteins, sdLDL, inflammation, and endothelial dysfunction often persist.
In practical terms, this means the biological drivers of atherosclerosis remain active, even when LDL-C looks excellent on a lipid panel.
Residual risk persists because:
This explains why:
Each slice of the chart shows the share of total heart disease in the population attributed to that factor — not the proportion of a single person’s risk.
For example:
These figures describe population impact, not how the risks divide within one person.
They help guide priorities in prevention — targeting LDL, visceral fat, blood pressure, and smoking yields the largest health gains for the community.
Statins remain essential. They reduce risk and save lives. But they should be viewed as foundation therapy, not the endpoint.
Meaningful reduction in residual risk requires:
Only by addressing both LDL-mediated risk and VAT-driven metabolic risk can we realistically hope to shrink the large residual burden of cardiovascular disease that persists despite modern lipid therapy.
8. Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008 Jul;28(7):1225–36.
Santa’s famous belly is festive, but it highlights an important metabolic lesson: WHERE fat is stored matters more than how it looks. Visceral fat, hidden deep around the organs, drives inflammation and cardiometabolic risk — unlike softer, subcutaneous fat. Understanding this difference is key to real metabolic health.
Ultimately, the approach to cardiac CT screening is highly individualized, reflecting the diverse presentations and risk factors among patients. By employing a sophisticated pre-consultation process, cardiologists can tailor their assessment and management plans to best suit each patient's unique needs, enhancing the precision and effectiveness of cardiac care.
GLP-1 drugs seem paradoxical: they enhance insulin action yet shrink dangerous belly fat. The explanation lies in restoring normal insulin timing, reducing chronic insulin exposure, and reversing fat “spillover” from liver to abdomen. Real patient cases show rapid visceral fat loss alongside smoother glucose profiles and lower cardiovascular risk.