Longevity & Prevention

Ranked levers to lower ASCVD risk, with longevity-oriented targets

Mohammad Ghalichi, M.D. on December 5, 2025

Cardiovascular disease, specifically what doctors call atherosclerotic cardiovascular disease (ASCVD), is the leading cause of death worldwide. This disease is the slow formation of plaque in the blood vessels over time. People do not feel plaque being laid down, and it usually takes many years or decades to develop. As plaques get bigger they can cause blockages, which is why someone might need a heart stent or bypass surgery. As plaques grow they can also become unstable and more likely to rupture. When a plaque breaks inside an artery it becomes a site of injury. When blood touches that injured area it forms a clot. If this happens in a coronary artery that feeds the heart, it causes a heart attack. If it happens in one of the carotid arteries in the neck, it causes a stroke.

The tragedy is that this remains the top killer while it is also the most preventable of all the major causes of death.

This document ranks the major interventions that reduce ASCVD risk, based on realistic effect sizes from large cohorts and randomized trials. The focus is on relative risk reduction for major cardiovascular events and on numeric targets that are appropriate for aggressive but sensible prevention in generally healthy adults.

1. High-volume physical activity and cardiorespiratory fitness

(One of the most powerful tools we have)

Longevity-oriented targets

• At least 150 to 300 minutes per week of moderate to vigorous aerobic activity
  or
  At least 75 to 150 minutes per week of vigorous activity
• Plus 2 or more days per week of resistance training for all major muscle groups
• For additional benefit, 300 to 450 minutes per week total activity, spread across the week
• Keep daily sedentary time as low as practical, with frequent movement breaks

Key evidence

• A 2023 dose-response meta analysis of large prospective cohorts found that, compared with inactivity, achieving about 8.75 mMET-hours per week of non-occupational physical activity (roughly 150 minutes per week of moderate to vigorous activity) was associated with:
  • 31 percent lower all-cause mortality (relative risk 0.69)
  • 29 percent lower cardiovascular disease mortality (relative risk 0.71) [1]
• Earlier work showed that around 150 minutes per week of moderate leisure-time activity was associated with about 14 percent lower risk of coronary heart disease, and 300 minutes per week with about 20 percent lower risk, compared with no activity [2].

Why it ranks first

These relative risk reductions are as large as, or larger than, what we see from single drug therapies. Physical activity improves many pathways at once: blood pressure, apolipoprotein B (ApoB) and non-HDL cholesterol, triglycerides, insulin sensitivity, visceral fat, inflammation, and autonomic balance [3]. High-volume regular activity is therefore one of the most powerful levers for lowering global cardiovascular risk and should be treated as a core therapy, not as a lifestyle afterthought.

2. Complete smoking cessation

Longevity-oriented target

• No cigarette smoking or vaping at all
• Minimize exposure to secondhand smoke

Key evidence

• A large meta analysis of 141 cohort studies showed that even about one cigarette per day carries around half the excess risk of coronary heart disease and stroke seen with smoking a pack per day. There is no safe level of smoking for cardiovascular disease [4].
• Compared with never-smokers, daily smokers often have about double the risk of coronary heart disease and stroke. Stopping smoking leads to large risk reductions over 5 to 15 years, and in many cohorts the risk approaches that of never-smokers over time [4,5].

Why it ranks near the top

Moving from daily smoking to complete abstinence can easily provide a 30 to 50 percent reduction in major cardiovascular events over time, especially when combined with other risk-factor control. Cutting down helps a little but is not enough. Full cessation is needed to capture most of the benefit.

3. Large, sustained reduction in ApoB and LDL cholesterol

ApoB is the best single blood marker of atherogenic lipoprotein burden. Low-density lipoprotein (LDL) cholesterol is useful but is a less direct measure.

Longevity-oriented targets

• ApoB
  • Goal for most adults who want aggressive prevention: ApoB ≤ 60 mg/dL
  • In very high-risk patients, long-term ApoB in the 30 to 40 mg/dL range is reasonable if well tolerated
• LDL cholesterol
  • Primary prevention: LDL cholesterol < 70 mg/dL
  • High-risk or secondary prevention: LDL cholesterol 40 to 55 mg/dL is reasonable if tolerated

Key evidence

• Genetic and epidemiologic work summarized by Ference and colleagues shows that ApoB-containing lipoproteins are a necessary and sufficient cause of ASCVD, and that risk depends on cumulative exposure over time [6,7]. Mendelian randomization data show that lifelong genetically lower LDL and ApoB produce much larger risk reductions than short-term drug therapy with the same on-treatment LDL level.
• Large randomized-trial meta analyses, including statins, ezetimibe, and PCSK9 inhibitors, show that each 1.0 mmol/L (about 39 mg/dL) reduction in LDL cholesterol yields roughly a 20 to 25 percent reduction in major vascular events, largely independent of which drug is used, and that benefit continues with LDL cholesterol lowered to about 20 to 40 mg/dL without clear safety signals [12,13].
• Cohort and trial analyses show that when ApoB and LDL cholesterol disagree, ApoB predicts risk better. When both ApoB and non-HDL cholesterol are included in the same model, ApoB usually remains significant while non-HDL cholesterol does not [9]. In large contemporary datasets, ApoB is the only lipid measure independently associated with myocardial infarction after adjustment for other lipid markers [10,11].

Taken together, Mendelian, trial, and cohort data support the idea that lower ApoB is better within the ranges achieved in modern lipid-lowering trials. Values in the 30 to 60 mg/dL range have been common in PCSK9 inhibitor trials with no clear safety signal, which supports using ≤ 60 mg/dL as a reasonable ceiling for prevention, with even lower levels for very high-risk patients when tolerated.

Why it ranks here

High-intensity lipid lowering that produces a 1 to 2 mmol/L LDL cholesterol reduction (and equivalent ApoB reduction) can reduce events by 35 to 45 percent if maintained over years. Because ApoB directly reflects the number of atherogenic particles, it is the most useful blood target in this category.

4. Blood pressure lowering

Longevity-oriented target

For most adults without clear contraindications:

• Resting systolic blood pressure around 110 to 120 mm Hg
• Resting diastolic blood pressure around 60 to 80 mm Hg

Use averages from home readings or repeated office measurements when possible. Avoid pushing systolic pressure chronically below about 105 to 110 mm Hg if this causes symptoms (lightheadedness, fatigue, falls) or kidney issues, especially in older or frail patients.

Key evidence

• A large meta analysis of 123 randomized trials found that each 10 mm Hg reduction in systolic blood pressure produced:
  • 20 percent lower major cardiovascular events
  • 17 percent lower coronary heart disease
  • 27 percent lower stroke
  • 28 percent lower heart failure
  • 13 percent lower all-cause mortality [14].
• Trials such as SPRINT suggest that targeting systolic blood pressure below 120 mm Hg in high-risk adults over 50 can reduce major events and mortality compared with a target around 135 to 140 mm Hg, although at the cost of higher rates of hypotension, syncope, electrolyte abnormalities, and acute kidney injury [14].

Why it ranks just below ApoB

A realistic 10 to 20 mm Hg drop in systolic blood pressure can produce 20 to 40 percent reductions in major cardiovascular events, especially stroke and heart failure. Combined with ApoB lowering, blood pressure control is one of the main pharmacologic levers for ASCVD prevention.

5. Multifactorial diabetes and glycemic control

Here we focus on people without diabetes who want to avoid it, and on the broad effects of glycemic control in established diabetes.

Longevity-oriented target for people without diabetes

• Hemoglobin A1c 5.0 to 5.4 percent is a good “sweet spot”
• 5.0 to 6.0 percent is acceptable, but try not to drift above 5.6 to 5.7 percent if other risk factors are present

Key evidence

• A large systematic review and meta analysis found that, in people without diabetes, all-cause and cardiovascular mortality were lowest when hemoglobin A1c was between 5.0 and 6.0 percent, with higher risk above 6.0 and a J-shaped increase in risk below 5.0 percent [15].
• The UKPDS 35 analysis in people with type 2 diabetes showed that each 1 percent lower hemoglobin A1c was associated with:
  • 21 percent lower risk of any diabetes-related endpoint
  • 14 percent lower myocardial infarction (heart attack) risk
  • 37 percent lower risk of microvascular complications [16].
• The Emerging Risk Factors Collaboration found that diabetes roughly doubles vascular risk, with about two-fold higher risk of coronary heart disease, ischemic stroke, and vascular death, independent of standard risk factors [15].

Newer agents such as sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists provide additional reductions in major cardiovascular events and heart-failure hospitalizations in high-risk patients, beyond their effect on hemoglobin A1c [17].

6. Sustained reduction in weight and visceral adiposity

Body mass index is a crude measure. For cardiovascular and metabolic risk, visceral fat mass is more informative.

Longevity-oriented targets

Visceral fat mass measured by DEXA scan (dual-energy X-ray absorptiometry):

• Ideal: less than 0.5 kg (1.1 lb), usually below the 25th percentile for age and sex
• Acceptable: 0.5 to 1.0 kg (1.1 to 2.2 lb)
• Higher risk: more than 1.0 kg (over 2.2 lb)

As a rule of thumb in a 70-kg adult, 0.5 to 1.0 kg of visceral fat corresponds to about 0.7 to 1.4 percent of body weight.

Key evidence

• In the Million Women Study, each 5 kg/m² higher body mass index was associated with about 23 percent higher incident coronary heart disease risk after adjustment [18].
• An umbrella review of observational and Mendelian randomization studies found that each 5 kg/m² increase in body mass index was associated with 10 to 49 percent higher cardiovascular risk, depending on the outcome, and with about 49 percent higher cardiovascular mortality [19].
• DEXA-derived visceral fat mass and CT-derived visceral area strongly predict metabolic syndrome, insulin resistance, and fatty liver, often more tightly than body mass index or total fat mass [18,19].

Why this matters

Visceral adiposity drives insulin resistance, abnormal glucose patterns, elevated triglycerides, lower HDL cholesterol, higher blood pressure, and fat accumulation in the liver. Keeping visceral fat in the sub-0.5 kg range when realistic, or at least below 1.0 kg, is a powerful way to keep cardiometabolic risk low, even if body mass index is not extremely low.

7. High-dose marine omega-3 (EPA and DHA)

Longevity-oriented target

• Omega-3 Index (red-blood-cell EPA + DHA) 8 to 12 percent

Achieved through:

• Regular intake of oily fish (for example, salmon, sardines, mackerel)
• Often 1 to 2 grams per day of combined EPA + DHA as a supplement, adjusted based on follow-up Omega-3 Index testing
• In selected high-risk patients with elevated triglycerides, 4 grams per day of purified EPA (icosapent ethyl) under physician supervision

Key evidence

• The Omega-3 Index concept comes from data showing that an index at or above 8 percent is associated with the lowest risk of fatal coronary heart disease and sudden cardiac death, while 4 percent or below is associated with the highest risk [17].
• The REDUCE-IT trial tested 4 grams per day of icosapent ethyl (purified EPA) in statin-treated patients with elevated triglycerides and either established cardiovascular disease or diabetes plus additional risk factors. It found a 25 percent reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, or unstable angina (hazard ratio 0.75) [21].
• The EVAPORATE trial showed that the same EPA dose slowed or reversed progression of low-attenuation coronary plaque on CT angiography [22].
• The STRENGTH trial, which used 4 grams per day of combined EPA and DHA in a similar high-risk population, was neutral and showed no reduction in cardiovascular events compared with a corn-oil placebo [23].
• A 2020 meta analysis of 40 randomized trials involving more than 135 000 participants found that EPA plus DHA supplementation was associated with reduced risk of myocardial infarction and coronary heart disease events. Each 1 gram per day of EPA plus DHA was associated with about a 5.8 percent reduction in cardiovascular events and about a 9 percent reduction in myocardial infarction, up to doses of about 5.5 grams per day [24].

How to interpret this

Dietary fish intake and a higher Omega-3 Index appear beneficial for primary prevention. High-dose purified EPA at 4 grams per day is a powerful add-on for secondary prevention or high-risk patients with elevated triglycerides already taking a statin. EPA plus DHA combinations likely provide a dose-dependent benefit, although results have been mixed in some large trials.

Pro-tip: omega-3 supplements are better absorbed with fat. Take them with food.

8. Targeted anti-inflammatory therapy

Inflammation is central in atherothrombosis. Several trials show that targeting specific inflammatory pathways can reduce events beyond standard lipid and blood-pressure management.

Longevity-oriented role

• These therapies are primarily for secondary prevention and very high-risk patients.
• There is no simple numeric target as there is for ApoB or blood pressure, but lowering high-sensitivity C-reactive protein (hsCRP) and other inflammatory markers is often used as a guide.

Key evidence

• CANTOS tested canakinumab, an interleukin-1 beta inhibitor, in patients with prior myocardial infarction and hsCRP at least 2 mg/L who were already on good standard therapy. The 150-mg dose every three months reduced the primary composite cardiovascular endpoint by about 15 percent (hazard ratio 0.85) compared with placebo, without changing LDL cholesterol [25].
• COLCOT tested colchicine 0.5 mg daily in patients with a recent myocardial infarction and found about a 23 percent reduction in the primary composite endpoint (hazard ratio 0.77) [26].
• LoDoCo2 tested colchicine 0.5 mg daily in patients with chronic coronary disease and found about a 31 percent reduction in the primary composite endpoint (hazard ratio 0.69) [27].
• CIRT, which tested low-dose methotrexate in stable coronary artery disease, showed no reduction in interleukin-1 beta, interleukin-6, or hsCRP and no reduction in cardiovascular events compared with placebo [28]. This negative trial underscores that not all anti-inflammatory drugs help, and that the specific pathway and biomarker response matter.

These agents can provide meaningful additional risk reduction, but only after the primary levers (exercise, smoking, ApoB, blood pressure, glycemia, and visceral fat) have been addressed.

Non-medication methods to lower inflammation

• Consistent exercise
• Fixing chronically disrupted sleep
• Losing visceral fat (fat around and within organs is strongly pro-inflammatory)
• Some people lower inflammation by reducing foods their body may be reacting to, such as gluten, wheat, or dairy.

Summary: Evidence-informed targets for prevention and longevity

These are aspirational targets for generally healthy adults who want aggressive prevention, not minimum thresholds for treatment. All targets must be individualized for age, comorbidities, medications, pregnancy, and tolerance.

Marker	Longevity-oriented target	Notes
Exercise and fitness	At least 150 to 300 minutes per week of moderate to vigorous aerobic activity (or 75 to 150 minutes vigorous), plus 2 or more resistance training sessions per week. Additional benefit out to about 300 to 450 minutes per week total, with reduced prolonged sitting.	A 2023 meta analysis shows about 31 percent lower all cause mortality and 29 percent lower CVD mortality at ~150 minutes per week of moderate to vigorous activity. Earlier work shows about 14 to 20 percent lower CHD risk between 150 and 300 minutes per week.
ApoB	≤ 60 mg/dL for nearly everyone focused on prevention. 30 to 40 mg/dL if very high risk and tolerated.	Mendelian and trial data suggest continued benefit with ApoB in the 30s with no clear harm.
LDL-C	< 70 mg/dL for primary prevention. 40 to 55 mg/dL reasonable in high risk or secondary prevention if tolerated.	CTT and PCSK9 trials show log linear benefit to very low LDL-C, with no safety signal at 20 to 40 mg/dL. ApoB is the preferred marker, but LDL-C is a useful surrogate.
Blood pressure (office or averaged home)	SBP around 110 to 120 mm Hg, DBP 60 to 80 mm Hg, if asymptomatic.	Observational and trial data show lowest CVD mortality around SBP 110 to 120. Below about 110 there is more hypotension and potential harm in some subgroups, so deeper lowering must be individualized.
HbA1c (no diabetes)	5.0 to 5.4 percent sweet spot. 5.0 to 6.0 percent acceptable.	Large meta analyses suggest lowest all cause and CVD mortality between 5.0 and 6.0 percent, with higher risk above 6.0 and a J curve below 5.0. Within diabetes, intensifying therapy to push HbA1c very low can also increase risk in some groups.
Omega-3 Index (RBC EPA + DHA)	8 to 12 percent.	Original Omega-3 Index work and later reviews show lowest CHD and sudden death risk at ≥8 percent and highest risk at ≤4 percent. Typically requires regular oily fish intake plus 1 to 2 g per day EPA + DHA, sometimes more.
Visceral fat by DXA	Mass ideally < 0.5 kg. Acceptable 0.5 to 1.0 kg. High risk > 1.0 kg. Roughly <25th percentile for age and sex is “ideal.”	Higher VAT mass and area strongly predict metabolic syndrome, insulin resistance, fatty liver, and CHD risk, independent of BMI. In a 70 kg adult, 0.5 to 1.0 kg of VAT is about 0.7 to 1.4 percent of body weight, yet carries large metabolic consequences.

These targets map onto the main modifiable drivers of ASCVD: movement and fitness, exposure to ApoB containing lipoproteins, blood pressure, glycemia, omega-3 status, and visceral adiposity. When combined, realistic changes in each of these domains can cut lifetime cardiovascular event risk by more than half for many people.

Key references

This page is for educational purposes only and is not a substitute for personalized medical advice. Decisions about testing and treatment should be made with your own clinician.