Metabolic Health
CARDIOVASCULAR & LIPID OPTIMIZATION
Total cholesterol and LDL-C are poor predictors of heart disease. The markers that actually matter — ApoB, LDL particle number, Lp(a), and insulin resistance — aren't on a standard lipid panel. Here's what real cardiovascular risk assessment looks like.
WHY STANDARD LIPID PANELS MISS THE REAL RISK
The standard lipid panel — total cholesterol, LDL-C, HDL-C, and triglycerides — has been the default cardiovascular screening tool for decades. It was designed in an era when we understood far less about the biology of atherosclerosis. Today, the science has moved well beyond it. The clinical guidelines have not caught up.
The core problem: total cholesterol and LDL-C measure the concentration of cholesterol inside lipoprotein particles. They do not tell you how many particles you have, how big or small they are, or whether your lipid profile is being driven by insulin resistance, genetics, thyroid dysfunction, or inflammation. Two patients with identical LDL-C values can have wildly different cardiovascular risk based on their particle number, particle size, Lp(a) status, and metabolic health.
The INTERHEART study (Yusuf et al., 2004) — one of the largest case-control studies of myocardial infarction ever conducted, spanning 52 countries — found that the ApoB/ApoA1 ratio was a stronger predictor of heart attack than LDL-C. Ference et al. (2017), in a landmark Mendelian randomization analysis published in JAMA Cardiology, demonstrated that cardiovascular risk is determined by the number of ApoB-containing particles, not by the cholesterol mass they carry. The particle is the causal agent. The cholesterol inside it is a passenger.
This means a "normal" LDL-C can coexist with dangerously high particle counts. And an "elevated" LDL-C can exist with low particle counts and low actual risk. Testing only LDL-C is like counting the number of passengers on a highway without counting the cars. The cars cause the accidents, not the passengers.
The takeaway: Atherosclerosis is driven by ApoB-containing particles penetrating the arterial wall. Not by cholesterol floating in your blood. A standard lipid panel measures cholesterol concentrations. An advanced panel measures the particles that actually cause disease. These are different questions with different answers.
THE MARKERS THAT ACTUALLY MATTER
If you want to understand your real cardiovascular risk, you need to go beyond LDL-C. These are the markers that drive clinical decisions at Moonshot — and the science behind each one.
ApoB (Apolipoprotein B)
Every atherogenic lipoprotein — LDL, VLDL, IDL, Lp(a), and chylomicron remnants — carries exactly one ApoB molecule on its surface. This makes ApoB a direct count of every particle in your blood that is capable of crossing the endothelium, embedding in the arterial wall, and initiating plaque formation. It is the single best predictor of cardiovascular risk available on a blood test. The European Atherosclerosis Society, the Canadian Cardiovascular Society, and the National Lipid Association have all endorsed ApoB as either equal or superior to LDL-C for risk assessment. When ApoB and LDL-C are discordant — meaning one is high and the other is normal — ApoB wins. Risk tracks with particle number, not cholesterol concentration.
LDL Particle Number (LDL-P) vs. LDL Cholesterol (LDL-C)
LDL-C tells you how much cholesterol is packed inside your LDL particles. LDL-P tells you how many LDL particles you actually have. These two numbers are concordant (both high or both low) in roughly 60-70% of patients. In the remaining 30-40%, they are discordant — and that discordance has massive clinical implications. A patient with low LDL-C but high LDL-P has far more risk than their standard panel suggests. This discordance is most common in patients with insulin resistance, metabolic syndrome, and type 2 diabetes — exactly the population at highest cardiovascular risk. The Framingham Offspring Study and the MESA trial both showed that LDL-P was a better predictor of cardiovascular events than LDL-C, especially when the two were discordant.
Small Dense LDL vs. Large Buoyant LDL
Not all LDL particles are created equal. Large buoyant LDL particles (Pattern A) are less atherogenic — they are less likely to penetrate the arterial wall, less susceptible to oxidation, and cleared from the bloodstream more efficiently. Small dense LDL particles (Pattern B) are the opposite: they penetrate the endothelium more easily, are more prone to oxidation, bind more readily to arterial proteoglycans, and have a longer circulating half-life. A patient dominated by small dense LDL has significantly more risk per particle. And here's the critical connection: insulin resistance is the primary driver of the shift from large buoyant to small dense LDL. High triglycerides and low HDL are the clinical clues that this shift has occurred. You can have a "normal" LDL-C and still be carrying a high concentration of the most dangerous particle subtype.
Lp(a) — Lipoprotein(a)
Lp(a) is an LDL-like particle with an additional apolipoprotein(a) protein attached. It is one of the strongest independent genetic risk factors for cardiovascular disease, affecting approximately 20% of the global population. Elevated Lp(a) increases the risk of myocardial infarction, stroke, and calcific aortic valve stenosis — and it does so independently of LDL-C, ApoB, and all other traditional risk factors. The critical fact: Lp(a) is almost entirely genetically determined. It is not meaningfully lowered by statins, diet, exercise, or lifestyle modification. Most physicians have never tested it. Most patients have never heard of it. If your Lp(a) is elevated, it fundamentally changes your risk profile and treatment strategy. Antisense oligonucleotide therapies targeting Lp(a) are in late-stage clinical trials, but today the primary approach is aggressive management of all other modifiable risk factors. You should test Lp(a) at least once in your lifetime.
Triglyceride/HDL Ratio
The triglyceride-to-HDL ratio is one of the simplest and most powerful metabolic markers available — and it is sitting on every standard lipid panel, hiding in plain sight. A TG/HDL ratio above 3.0 (in mg/dL) is a strong surrogate marker for insulin resistance, elevated small dense LDL, and increased cardiovascular risk. A ratio above 3.5 is highly predictive of metabolic syndrome. Conversely, a ratio below 2.0 generally indicates good insulin sensitivity and a favorable lipid particle profile. This single ratio often tells us more about a patient's metabolic health than LDL-C ever could. It costs nothing extra to calculate — the numbers are already on the standard panel — yet it is almost never discussed with patients.
hs-CRP (High-Sensitivity C-Reactive Protein)
Atherosclerosis is not just a lipid accumulation disease. It is an inflammatory disease. Lipid particles enter the arterial wall, but it is the immune response — macrophage infiltration, foam cell formation, cytokine release — that drives plaque growth, instability, and rupture. hs-CRP is a systemic marker of inflammation and is an independent predictor of cardiovascular events, even in patients with low LDL-C. The JUPITER trial (Ridker et al., 2008) demonstrated that patients with elevated hs-CRP but "normal" LDL-C still benefited from statin therapy — a finding that fundamentally challenged the cholesterol-centric model of heart disease. Optimal hs-CRP is below 1.0 mg/L. Values above 3.0 mg/L indicate elevated systemic inflammation and meaningfully increased cardiovascular risk.
Why this matters: A standard lipid panel gives you four numbers. An advanced assessment gives you the actual risk picture: how many atherogenic particles you have (ApoB, LDL-P), what kind they are (small dense vs. large buoyant), whether you carry a genetic wild card (Lp(a)), whether insulin resistance is driving a hidden dyslipidemia (TG/HDL ratio), and whether your arteries are inflamed (hs-CRP). These are different questions. They require different tests. And they lead to fundamentally different treatment decisions.
INSULIN RESISTANCE: THE HIDDEN ENGINE OF HEART DISEASE
If there is one root cause that ties together the majority of cardiovascular risk in the modern population, it is insulin resistance. Not cholesterol. Not genetics in most cases. Insulin resistance.
When cells become resistant to insulin, the pancreas compensates by producing more. Chronically elevated insulin (hyperinsulinemia) drives a cascade of downstream effects that create the most common atherogenic lipid pattern we see in clinical practice — a pattern called atherogenic dyslipidemia:
Elevated Triglycerides
Insulin resistance increases hepatic VLDL production. The liver produces more triglyceride-rich particles, flooding the bloodstream with atherogenic remnants. Triglycerides above 150 mg/dL are a red flag. Above 200 mg/dL is a metabolic alarm.
Low HDL-C
Excess triglyceride-rich particles exchange triglycerides for cholesterol esters with HDL via CETP. This makes HDL particles triglyceride-enriched, which accelerates their clearance by the liver. The result: HDL drops. In men, HDL below 40 mg/dL and in women below 50 mg/dL signals metabolic dysfunction.
Shift to Small Dense LDL
The same CETP-mediated lipid exchange makes LDL particles triglyceride-enriched. Hepatic lipase then removes those triglycerides, leaving behind smaller, denser, cholesterol-depleted LDL particles. Each particle carries less cholesterol (so LDL-C may look "normal") but there are far more particles, and each one is more atherogenic. This is the concordance/discordance trap.
Elevated ApoB
More VLDL production plus more small dense LDL particles equals a higher total ApoB count — even when LDL-C is in the "normal" range. This is exactly why ApoB catches risk that LDL-C misses, and why it is especially important in the metabolically unhealthy population.
This entire pattern — high triglycerides, low HDL, small dense LDL, elevated ApoB — is present in an estimated 40-50% of American adults. And a standard lipid panel will often miss it entirely because LDL-C may be within range. The patient is told their cholesterol is "fine." Meanwhile, their arteries are accumulating atherogenic particles at an accelerated rate.
The connection to visceral fat is direct. DEXA body composition scans quantify visceral adipose tissue (VAT) — the metabolically active fat stored around the organs. VAT is an independent predictor of cardiovascular events, type 2 diabetes, and all-cause mortality, even in patients with a "normal" BMI. Visceral fat drives insulin resistance. Insulin resistance drives atherogenic dyslipidemia. This is why body composition data, not just blood work, is part of a real cardiovascular risk assessment.
The pattern: Insulin resistance → increased hepatic VLDL output → elevated triglycerides → low HDL → small dense LDL → elevated ApoB → accelerated atherosclerosis. This is the most common pathway to cardiovascular disease in the modern world. And it has nothing to do with eating too many eggs.
THYROID, HORMONES, AND YOUR LIPID PROFILE
Before reaching for a statin, a competent clinician should ask: is anything else driving this lipid profile? Two of the most common — and most overlooked — drivers are thyroid dysfunction and hormone imbalance.
Hypothyroidism and Lipids
Thyroid hormone (T3) directly upregulates LDL receptors in the liver. When T3 is low, LDL receptor expression drops, and the liver clears fewer LDL particles from the bloodstream. The result: elevated LDL-C and ApoB. Hypothyroidism also increases Lp(a) levels, raises total cholesterol, and impairs reverse cholesterol transport. Even subclinical hypothyroidism (TSH 2.5–10 mIU/L with normal Free T4) has been shown to significantly elevate LDL and total cholesterol. A meta-analysis by Razvi et al. (2008) demonstrated that treating subclinical hypothyroidism improved lipid profiles meaningfully. The clinical implication is straightforward: if you are prescribing a statin without checking a full thyroid panel, you may be medicating a thyroid problem. Fix the thyroid, and the lipids often normalize on their own.
Testosterone and Cardiovascular Risk
Testosterone at physiologic replacement doses generally has favorable effects on cardiovascular risk markers. It reduces triglycerides, improves insulin sensitivity, decreases visceral fat, and supports lean mass — all of which contribute to a better lipid profile and reduced atherosclerotic risk. Testosterone may modestly reduce HDL-C, but this effect is dose-dependent and needs to be interpreted in context: HDL-C is a poor proxy for cardiovascular risk compared to ApoB and particle metrics. The TRAVERSE trial (2023), a large randomized controlled trial, found no increase in major adverse cardiovascular events with testosterone replacement in hypogonadal men. Low testosterone, on the other hand, is independently associated with increased cardiovascular mortality, insulin resistance, increased visceral fat, and atherogenic dyslipidemia. Optimizing testosterone to physiologic levels is protective, not harmful.
Estrogen, Progesterone, and Lipid Metabolism
Estrogen increases LDL receptor expression and raises HDL-C — which is part of why premenopausal women have lower cardiovascular risk than age-matched men. The menopausal transition, with its decline in estrogen, is associated with unfavorable lipid changes: rising LDL, falling HDL, increasing triglycerides, and a shift toward smaller, denser LDL particles. Hormone replacement therapy in the early menopausal window has been shown to attenuate these changes. The point: lipid profiles don't exist in isolation. They are shaped by the entire endocrine environment. Treating lipids without evaluating thyroid and sex hormones is incomplete medicine.
The clinical sequence matters: Evaluate thyroid function. Assess sex hormones. Quantify insulin resistance. Measure body composition and visceral fat. Address every root cause that is driving the lipid profile before defaulting to pharmacotherapy. This is not anti-medication. It is anti-treating-a-symptom-while-ignoring-the-cause.
TREATMENT PHILOSOPHY: ROOT CAUSE FIRST
Moonshot's approach to cardiovascular and lipid optimization follows a clear hierarchy: identify and fix what is driving the problem before adding medication to suppress the numbers. This is not an ideological stance against statins. It is a commitment to treating causes rather than markers.
Step 1: Advanced Diagnostics
Full advanced lipid panel (ApoB, LDL-P, Lp(a), particle size distribution), metabolic markers (fasting insulin, HOMA-IR, HbA1c, fasting glucose), inflammatory markers (hs-CRP, homocysteine), full thyroid panel, sex hormones, and DEXA body composition scan with visceral fat quantification. You cannot treat what you have not measured. And you cannot identify root causes from a standard lipid panel.
Step 2: Address Metabolic Root Causes
If insulin resistance is driving the lipid profile — and it is in a large percentage of patients — the intervention is metabolic: body composition improvement (reducing visceral fat via caloric management and resistance training), dietary modification (reducing refined carbohydrates and processed foods, adequate protein), structured exercise (both resistance training and cardiovascular conditioning), sleep optimization, and stress management. If thyroid dysfunction is contributing, optimize thyroid. If hypogonadism is a factor, optimize testosterone or estrogen as appropriate. These are not "lifestyle recommendations" offered as lip service. They are primary interventions that address the mechanism driving disease.
Step 3: Pharmacotherapy When Indicated
Medication is appropriate — and sometimes essential — in the right clinical context. Statins, ezetimibe, PCSK9 inhibitors, icosapent ethyl (Vascepa), and bempedoic acid all have evidence-based roles. Statins are clearly indicated for secondary prevention (patients with established cardiovascular disease), familial hypercholesterolemia, persistently elevated ApoB after root-cause optimization, and elevated Lp(a) where aggressive LDL lowering provides marginal risk reduction. Where statins are overused: low-risk primary prevention patients with elevated LDL-C driven entirely by correctable metabolic dysfunction. The decision to start a statin should be based on particle-level data, inflammatory markers, metabolic status, and a full risk assessment — not on a single LDL-C number.
Step 4: Ongoing Monitoring
Cardiovascular risk management is not a one-time event. We recheck advanced lipid panels, metabolic markers, and inflammatory markers every 3–6 months during active optimization, then every 6–12 months once stable. DEXA scans are repeated every 6–12 months to track visceral fat trends. The goal is measurable, sustained improvement in the markers that actually predict outcomes — ApoB, hs-CRP, fasting insulin, and visceral fat — not just LDL-C on a standard panel.
The principle: Medication is a tool, not a default. The first question is always "what is causing this?" The second question is "can we fix the cause?" The third question — and only when the first two are answered — is "does this patient also need pharmacotherapy?" That sequence matters.
WHAT WE TEST AND HOW OFTEN
A real cardiovascular risk assessment requires more than four numbers on a standard panel. Here is what Moonshot's advanced cardiovascular and metabolic workup includes:
| Marker | What It Tells Us | Frequency |
|---|---|---|
| ApoB | Total atherogenic particle count — the single best blood marker of cardiovascular risk | Every 3–6 months |
| LDL-P (Particle Number) | Direct LDL particle count, catches discordance with LDL-C | Every 3–6 months |
| Lp(a) | Genetic cardiovascular risk factor, independent of all other lipid markers | Once (genetically fixed) |
| hs-CRP | Systemic inflammation — the process that drives plaque growth and rupture | Every 3–6 months |
| Fasting Insulin & HOMA-IR | Insulin resistance — the root driver of atherogenic dyslipidemia | Every 3–6 months |
| Triglycerides & HDL-C | TG/HDL ratio as a proxy for insulin resistance and particle quality | Every 3–6 months |
| Full Thyroid Panel | Hypothyroidism directly raises LDL and ApoB — must rule out before treating lipids | Every 3–6 months |
| HbA1c & Fasting Glucose | Glycemic control and long-term blood sugar trends | Every 3–6 months |
| Homocysteine | Independent cardiovascular risk factor, linked to B-vitamin metabolism | Every 6–12 months |
| DEXA (Visceral Fat / VAT) | Visceral adipose tissue — the metabolically active fat that drives insulin resistance and CV risk | Every 6–12 months |
Lp(a) only needs to be tested once. Because it is genetically determined, your Lp(a) level is essentially fixed for life. It does not respond to statins, diet, or exercise. One test gives you the answer. Every other marker is monitored longitudinally to track your response to treatment and quantify your trajectory over time.
COMMON QUESTIONS
Why is ApoB a better predictor of cardiovascular risk than LDL cholesterol?
LDL-C measures the amount of cholesterol carried inside LDL particles, but it doesn't tell you how many particles you have. Each atherogenic lipoprotein — LDL, VLDL, IDL, and Lp(a) — carries exactly one ApoB molecule on its surface. So ApoB gives you a direct count of every particle capable of penetrating the arterial wall and driving atherosclerosis. Two patients can have the same LDL-C but very different particle counts. The one with more particles (higher ApoB) has significantly more risk. The INTERHEART study, Ference et al. 2017, and multiple Mendelian randomization analyses have all confirmed that ApoB is a stronger predictor of cardiovascular events than LDL-C. This is why Moonshot tests ApoB on every advanced lipid panel.
What is Lp(a) and why should I get tested?
Lipoprotein(a), or Lp(a), is a genetically determined lipoprotein particle that is structurally similar to LDL but carries an additional protein called apolipoprotein(a). Elevated Lp(a) — which affects roughly 20% of the population — is an independent risk factor for heart attack, stroke, and aortic valve stenosis. The critical point: Lp(a) levels are largely determined by genetics and are not meaningfully lowered by statins, diet, or exercise. Most people have never had Lp(a) tested because it's not included on standard lipid panels. If your Lp(a) is elevated, it changes your entire risk calculus and treatment strategy. You only need to test it once because it doesn't change much over a lifetime. Everyone should know their number.
Can insulin resistance cause high cholesterol?
Yes. Insulin resistance is one of the most common drivers of atherogenic dyslipidemia — a pattern characterized by high triglycerides, low HDL, increased small dense LDL particles, and elevated ApoB. This happens because insulin resistance increases hepatic VLDL production, impairs lipoprotein lipase activity, and shifts LDL particles toward the smaller, denser, more atherogenic subtype. This pattern is often present even when LDL-C looks "normal" on a standard panel, which is why a standard lipid panel misses it entirely. Fixing the underlying insulin resistance — through body composition improvement, exercise, dietary modification, and metabolic optimization — often corrects the lipid pattern without medication.
Does testosterone therapy affect cholesterol levels?
At physiologic replacement doses, testosterone generally has a favorable or neutral effect on cardiovascular risk markers. It tends to reduce triglycerides, may modestly lower total and LDL cholesterol, and improves insulin sensitivity and body composition — all of which contribute to a better lipid profile. Testosterone can lower HDL-C slightly, but this effect is dose-dependent and the clinical significance is debated, especially since HDL-C is a poor predictor of risk compared to ApoB and particle metrics. Supraphysiologic doses (abuse-level dosing) are a different story and can significantly worsen lipid profiles. At Moonshot, we optimize testosterone to physiologic levels and monitor lipids as part of ongoing care.
When do statins actually make sense?
Statins are effective tools when used for the right patients. They make the most sense for patients with established cardiovascular disease (secondary prevention), persistently elevated ApoB or LDL-P despite lifestyle optimization, familial hypercholesterolemia, elevated Lp(a) where aggressive LDL lowering provides additional risk reduction, and patients with high calculated residual risk after addressing metabolic root causes. Where statins are overused is in low-risk primary prevention patients whose elevated LDL-C is driven by insulin resistance, hypothyroidism, or metabolic dysfunction that would respond to root-cause treatment. The question should never be "is your LDL high?" It should be "what is driving your LDL, what does your ApoB look like, and have we addressed the underlying cause first?"
References
- 1. Yusuf S, et al. "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study." Lancet. 2004;364(9438):937-952.
- 2. Ference BA, et al. "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel." Eur Heart J. 2017;38(32):2459-2472.
- 3. Ference BA, et al. "Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease." JAMA. 2019;321(4):364-373.
- 4. Sniderman AD, et al. "Apolipoprotein B particles and cardiovascular disease: a narrative review." JAMA Cardiol. 2019;4(12):1287-1295.
- 5. Mora S, et al. "LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA)." Atherosclerosis. 2007;192(1):211-217.
- 6. Nordestgaard BG, et al. "Lipoprotein(a) as a cardiovascular risk factor: current status." Eur Heart J. 2010;31(23):2844-2853.
- 7. Tsimikas S, et al. "A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies." J Am Coll Cardiol. 2017;69(6):692-711.
- 8. Ridker PM, et al. "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein (JUPITER trial)." N Engl J Med. 2008;359(21):2195-2207.
- 9. Razvi S, et al. "The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism." J Clin Endocrinol Metab. 2007;92(5):1715-1723.
- 10. Lincoff AM, et al. "Cardiovascular Safety of Testosterone-Replacement Therapy (TRAVERSE trial)." N Engl J Med. 2023;389(2):107-117.
- 11. Reaven GM. "Banting lecture 1988. Role of insulin resistance in human disease." Diabetes. 1988;37(12):1595-1607.
- 12. Otvos JD, et al. "Clinical implications of discordance between LDL cholesterol and LDL particle number." J Clin Lipidol. 2011;5(2):105-113.
- 13. Cromwell WC, et al. "LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study." J Clin Lipidol. 2007;1(6):583-592.
- 14. McLaughlin T, et al. "Use of metabolic markers to identify overweight individuals who are insulin resistant." Ann Intern Med. 2003;139(10):802-809.
YOUR STANDARD LIPID PANEL ISN'T ENOUGH
If your doctor has only tested total cholesterol and LDL-C, you don't know your real cardiovascular risk. An advanced lipid panel with ApoB, Lp(a), and metabolic markers gives you the full picture — and the data to make informed decisions.
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