SO MANY THINGS

IMPROVE CARDIOVASCULAR RISK

Many patients come to my practice seeking alternatives to statin therapy for cardiovascular disease prevention—whether due to adverse reactions, personal preferences, or simply wanting a more comprehensive approach. This has driven me to focus on evidence-based, non-pharmaceutical strategies that can significantly reduce cardiovascular disease (CVD) risk.

My approach to CVD risk, informed by my family medicine training (rather than traditional cardiology), focuses on addressing multiple risk factors simultaneously. I understand the argument that the number of harmful lipid particles is the primary driver—that plaques can't form without LDL regardless of other factors—but I wonder if that is the best way to think about the problem for all patients. For example, research shows statins are significantly less effective in non-inflamed patients, suggesting there’s more than one way to address a problem.

What is not controversial is that even LDL optimization leaves significant “residual risk,” maybe 65-70% of the CVD risk (CTT Collaboration, 2010). That is definitely risk we can tackle.

Quick Takes

• 🏋️ Resistance Training Wins: AGAIN. New meta-analysis shows resistance exercise (30-60 min sessions) beats cardio for reducing CVD risk across multiple markers.

• 📊 HbA1c Sweet Spot: The safest HbA1c range is 5.3-5.6%. Below 5.3% may increase mortality risk in some patients, by as much as 57%.

• BP Target Reality Check: Getting below 130 systolic cuts CVD risk by 35%, but needing too many meds to get there might backfire.

• TMAO Alert: High levels of this gut metabolite (from red meat/eggs, but depending on the gut biome) predicts CVD.

• 😴 Sleep = Cardio Medicine: Perfect sleep pattern (7-8 hours, regular timing, minimal snoring) cuts major heart events by 24-42%.

• 🔥 CRP Still King: High inflammation (sustained hsCRP >3) doubles heart attack risk. Still unclear if it's causal, but it's a powerful predictor.

• 💊 CoQ10, B vitamins, vitamin D3 and K2, Omega 3 fatty acids: There are many more factors to evaluate and optimize — beyond lipids.

Favorite Finds

Risk Calculators

• Framingham Risk Score Calculator - Classic 10-year CVD risk assessment

• ASCVD Risk Calculator - ACC/AHA's updated risk prediction tool

• Reynolds Risk Score - Includes CRP for enhanced prediction in women

• Prevent Calculator - Newer than the others, adds kidney health, BMI and zip code; resulted in 50% fewer patients being recommended statins (!)

• USPSTF guidelines - What is the strength of the evidence for which situations warrant statin treatment?

🍽️ Dietary Interventions

• ProLon Fasting Mimicking Diet - 5-day protocol that improves insulin resistance (HOMA-IR reduction similar to caloric restriction); discounts available to patients of my practice.

• Time-Restricted Eating Apps (Zero, Life Fasting) - Tools for implementing early TRE protocols shown to reduce HOMA-IR by -1.09

🏃‍♀️ Exercise Resources

• Resistance Training Templates - Evidence-based 30-60 minute protocols for maximum CV benefit

• Tai Chi/Baduanjin Videos - Mind-body exercises proven optimal for HDL/LDL improvement

• Heart Rate Variability Apps (HeartMath, Elite HRV) - Biofeedback tools for autonomic nervous system training

 🔬 Testing & Monitoring

• Continuous Glucose Monitors - Track glucose patterns that correlate with HbA1c optimization: the Stelo is available without a prescription

• Sleep Tracking Devices - Monitor the 7-8 hour, regular pattern associated with 24-42% MACE reduction; Sleep Cycle is a free app on your phone (though it works best if you sleep alone)

• OmegaQuant and the index test kit through Nordic Naturals allow you to obtain this index at home.

DEEP DIVE:

MODIFYING CARDIOVASCULAR RISK FACTORS

Understanding and modifying cardiovascular disease (CVD) risk factors represents one of the most impactful approaches to preventing heart disease and improving long-term health outcomes. While traditional risk factors like cholesterol and blood pressure remain important, emerging research reveals a more nuanced picture of cardiovascular health that encompasses exercise protocols, metabolic markers, inflammatory processes, and lifestyle interventions.

Exercise: The Foundation of Cardiovascular Health

Exercise stands as perhaps the most powerful modifiable risk factor for cardiovascular disease. The evidence strongly suggests a causal relationship, with exercise modifying both traditional and non-traditional risk factors, including endothelial function (how blood vessels function) and hemostasis (clotting characteristics of blood) (Ross et al., 2022).

Recent research has provided specific guidance on optimal exercise protocols. Resistance exercise performed for 30-60 minutes per session emerges as the most effective intervention for reducing cardiovascular risk, showing the most impact across multiple cardiovascular risk markers including ICVD score, HOMA-IR (a measure of insulin resistance), fasting plasma glucose, BMI, total cholesterol, and both systolic and diastolic blood pressures (Hua et al., 2025).

Additionally, different exercise modalities offer unique benefits. Moderate aerobic exercise lasting more than 30 minutes per session provides substantial cardiovascular protection, while combined aerobic and resistance training proves optimal for reducing HbA1c and triglycerides (Hua et al., 2025). Interestingly, mind-body training approaches such as Tai Chi and Baduanjin demonstrate particular effectiveness in improving lipid profiles, especially HDL and LDL cholesterol levels (Hua et al., 2025).

Heart Rate Variability: Autonomic Nervous System Optimization

Heart Rate Variability (HRV) biofeedback interventions demonstrate efficacy in autonomic nervous system regulation. Studies show HRV-guided training reduces arrhythmia incidence in patients who have had a recent adverse coronary event, though specific CVD outcome data remain limited in the reviewed literature.

Blood Pressure: The Goldilocks Zone

Blood pressure management reveals a nuanced relationship with cardiovascular outcomes. Patients achieving systolic blood pressure below 130 mmHg demonstrate a 35% lower risk of major adverse cardiovascular events (MACE) compared to higher levels (Vrsalović et al., 2024). The STEP trial, which randomized patients to target ranges of 110-130 versus 130-150 mmHg, found lower MACE rates in the intensive treatment group (Zhang et al., 2024).

However, achieving very low blood pressure targets may require careful consideration of medication burden. Post-hoc analysis suggests that requiring multiple medication classes to achieve intensive blood pressure control may paradoxically increase mortality risk, though successful achievement of lower targets still provides net benefit (Zhang et al., 2024).

For primary prevention (targeting people who have never had a heat attack or stroke), clear benefits exist for treating systolic blood pressure above 140 mmHg, but evidence becomes less compelling for treatment of lower levels (Brunström & Carlberg, 2018).

HbA1c: The U-Shaped Curve of Risk

Hemoglobin A1c levels (a summary measure of the last 2 months of blood glucose) demonstrate a complex relationship with cardiovascular mortality, following a U-shaped curve rather than a linear relationship. Analysis of 4,700 high-risk patients followed for 2.8 years revealed that HbA1c levels below 5.3% carried a 57% increased mortality risk, while the safest range appeared to be 5.3-5.6% (Dykun et al., 2025).

The mortality risk progressively increases with higher HbA1c levels: 5.6-5.9% carries a 5% increased risk, 5.9-6.6% shows a 50% increased risk, and levels above 6.6% demonstrate even higher mortality rates (Dykun et al., 2025). Levels below 5.0% likely have an increased risk of all-cause mortality. Very low HbA1c levels may indicate malnutrition or functional decline rather than optimal metabolic health (Carson et al., 2010).

Insulin Resistance: A Central Mechanism

Insulin resistance represents a causal factor in cardiovascular disease development through multiple mechanisms including dyslipidemia, chronic inflammation, endothelial dysfunction, hypertension, and oxidative stress (Kosmas et al., 2023). The relationship between insulin resistance and cardiovascular risk varies according to glucose tolerance status, with the highest HOMA-IR (a measure of insulin resistance) quartile showing a 23% increased risk compared to the lowest quartile in the general population (Wang et al., 2022).

Ideal HOMA-IR (see calculation in Favorite Finds) is <0.9. In people without prediabetes, the highest quartile HOMA-IR is > 2.0. However, there is no increased MACE in that population, no matter the quartile. In patients with prediabetes, the highest quartile of HOMA-IR is above 2.6 and it confers a 13% increased risk of MACE. Diabetics can have a HOMA-IR above 4.

Various interventions can improve insulin resistance with corresponding HOMA-IR reductions. Early time-restricted feeding shows promise with a -1.09 impact on HOMA-IR (Jamshed et al., 2019), while specific probiotic strains, particularly Lactobacillus and Bifidobacterium, demonstrate a -1.36 impact in type 2 diabetes patients (Wang et al., 2024). Bariatric surgery provides the most dramatic improvement with a -3.7 reduction compared to dietary intervention alone (Brzozowska et al., 2023).

Dietary approaches also show measurable benefits: Mediterranean diet reduces HOMA-IR by -0.4 (Vitale et al., 2023), while plant-based diets (vegan and vegetarian) show a -0.97 improvement (Qian et al., 2024). Tackling insulin resistance also frequently reduces LDL-C and LDL-particle number. Another trick for lowering LDL is to avoid French press coffee and drink filter coffee instead (De Roos B, 2000).

GLP-1 agonist medications can improve HOMA-IR though specific number were not available.

Inflammatory Markers: CRP as a Predictor

C-reactive protein (CRP) serves as a powerful predictor of cardiovascular risk. Individuals with low-risk CRP levels (<1 mg/L) have significantly better outcomes than those with high-risk levels (>3 mg/L), who demonstrate a 38% increased risk of CVD and double the risk of myocardial infarction (Li et al., 2017) when the CRP elevation is sustained for years.

While a clear causal role remains uncertain (Ridker & Luscher, 2014), CRP can be reduced through various interventions—including statins, weight loss, diet modification, exercise, smoking cessation, and some supplements.

Novel Biomarkers: TMAO

Trimethylamine N-oxide (TMAO) represents an emerging cardiovascular risk marker. Healthy individuals average 3.5 μmol/L, while CVD patients average 5 μmol/L. The cutoff of 2.26 μmol/L associates with higher cardiovascular mortality risk, and individuals in the highest quartile (above 6.2 μmol/L) show a 27% increased relative risk of coronary artery disease (Tang et al., 2021).

TMAO is made by gut bacteria metablolizing choline and L-carnitine. Thus it depends on dietary intake of choline and L-carnitine, and gut microbiome composition. Choline is highly beneficial to the brain, being involved in synthesis of the neurotransmitter acetylcholine, which is related to memory function. Thus the solution would be to improve the gut biome rather than avoid all choline intake. TMAO inhibits cholesterol metabolism, induces platelet aggregation and thrombosis, and promotes atherosclerosis (Zhen et al., 2023).

Sleep: Always the Underappreciated Risk Factor

Sleep optimization provides measurable cardiovascular benefits. A healthy sleep pattern—defined as 7-8 hours of sleep, regular sleep timing, low insomnia symptoms, minimal snoring, and little daytime sleepiness—associates with a 24-42% lower risk of MACE (You et al., 2024).

Behavioral sleep interventions improve HbA1c by 0.84% and reduce body weight/BMI, though effects on blood pressure remain limited (McCarthy et al., 2024).

Endothelial Function and Hemostasis

Endothelial dysfunction represents a causal mechanism through which various risk factors impact cardiovascular disease. Multiple interventions can improve endothelial function, including mind-body therapy, statins, ACE inhibitors, other antihypertensive agents, folic acid, L-arginine, and enhanced external counterpulsation (Deanfield et al., 2007).

Hemostasis optimization through antiplatelet therapy, statins, exercise, and ACE inhibitors provides cardiovascular protection through improved clotting mechanisms (Anderson, 2002).

Omega-3 Fatty Acids: The Optimal Range

Omega-3 fatty acids demonstrate compelling cardiovascular benefits when assessed through blood levels. An omega-3 index of 8-11% has been associated with the lowest incidence of major adverse cardiovascular events (MACE). The Framingham Heart Study Offspring Cohort, following participants for a median of 7.3 years, found that individuals with the lowest Omega-3 Index (<4.2%) had a 34% higher risk of death from any cause and a 39% higher risk of incident cardiovascular disease compared to those with the highest Omega-3 Index (>6.8%) (Harris et al., 2018).

Analysis of 17 prospective cohort studies including 42,466 individuals with 16 years of follow-up demonstrated that those in the highest versus lowest quintile of circulating long-chain omega-3 fatty acids (EPA, DPA, DHA) had a 15-18% lower risk of all-cause and cardiovascular mortality (Harris et al., 2021). Notably, no association was found with plant-based omega-3 (alpha-linolenic acid), emphasizing the importance of EPA and DHA.

Clinical trials support supplementation benefits, particularly in high-risk populations. People with previous myocardial infarctions benefit from omega-3 supplements, and healthy individuals without previous MI also demonstrate cardiovascular benefits from supplementation (Lentjes et al., 2017).

Homocysteine: B-Vitamin Intervention for Stroke Prevention

Elevated homocysteine levels consistently associate with higher risk of cardiovascular disease, stroke, and dementia in observational studies, making it a valuable biomarker for vascular risk assessment. While early randomized trials showed mixed results for cardiovascular endpoints, newer evidence demonstrates clear benefits for stroke prevention.

B-vitamin supplementation with folic acid (B9), vitamin B6 (pyridoxine), and vitamin B12 reliably lowers blood homocysteine levels. Recent Cochrane systematic review analysis shows that homocysteine-lowering interventions reduced stroke risk by 10% (Martí-Carvajal et al., 2017). There may be further benefits for cognitive health.

The China Stroke Primary Prevention Trial (CSPPT) provides particularly compelling evidence: in hypertensive patients, folic acid supplementation reduced ischemic stroke by 24%, with even greater reductions in subgroups with high cholesterol or very high homocysteine levels (Brown et al., 2023). Note that cyanocobalamin (one form of vitamin B12) should be avoided in patients with renal failure due to potential toxicity concerns.

More Targeted Supplementation

Specific supplements show promise for cardiovascular risk reduction. Vitamin K2 supplementation combined with vitamin D may provide cardiovascular benefits (Hasific et al., 2023). Coenzyme Q10, a mitochondrial cofactor and antioxidant, improves cellular energy production, reduces oxidative stress, and supports endothelial function, with demonstrated benefits in chronic heart failure and post-myocardial infarction patients (Alehagen et al., 2021). CoQ10 effectiveness appears enhanced when baseline selenium levels are low (<85 mcg/L) (Rabanal-Ruiz et al., 2021).

Vitamin D combined with magnesium may reduce blood pressure (Cheung et al., 2022). Magnesium alone may prevent heart failure and MACE in diabetics (Cheng et al., 2025).

Conclusion

Optimizing cardiovascular disease risk factors requires a comprehensive approach that extends much beyond traditional cholesterol and smoking cessation advice.

The evidence supports targeted exercise protocols, optimal metabolic marker ranges, inflammatory control, sleep optimization, and selective supplementation as evidence-based strategies for cardiovascular risk reduction. The key lies in understanding that many relationships follow non-linear patterns, requiring individualized approaches rather than one-size-fits-all recommendations.

We have a workbook for that!! It will take you systematically through all the ways you can measure your cardiovascular risk, assess the contributing factors you can modify, and set some goals for success.

REFERENCES

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