Introduction

This protocol, grounded in the Council for Responsible Nutrition (CRN) Supplements to Savings report, highlights evidence-based ingredients that support cardiovascular health. It provides healthcare providers with a practical framework to integrate these ingredients into patient care, complementing standard therapies to promote heart health.

Ingredients

Omega-3 Fatty Acids

Dosing: 1,000–2,000 mg (combined eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) daily, minimum one year (Hu 2019)(Bernasconi 2021) 

Supporting evidence:

• This meta-analysis, including 13 randomized controlled trials (RCTs) with 127,477 participants, found that marine omega-3 supplementation was associated with statistically significant reductions in the risk of myocardial infarction (MI) (risk ratio (RR) 0.92), coronary heart disease (CHD) death (RR 0.92), total CHD (RR 0.95), cardiovascular disease (CVD) death (RR 0.93), and total CVD (RR 0.97), with a linear dose-response relationship observed. These risk reductions persisted even after excluding the REDUCE-IT trial, which used a high-dose purified EPA formulation. (Hu 2019)
• A larger meta-analysis of 40 studies involving 135,267 participants similarly found that supplementation with EPA and DHA was associated with a reduced risk of MI (RR 0.87), CHD events (RR 0.90), fatal MI (RR 0.65), and CHD mortality (RR 0.91), but not with a significant reduction in CVD events. The analysis demonstrated a dose-dependent effect, with higher doses of omega-3s conferring greater protective benefit for MI and CVD events. The number needed to treat (NNT) ranged from 128 for fatal MI to 431 for CHD mortality. (Bernasconi 2021)

Omega-3 Fatty Acids in the Fullscript catalog

Magnesium

Dosing: 400 mg daily for at least three months (Zhang 2016) 

• Note: While magnesium sulfate and magnesium oxide are frequently used in research and clinical studies, both forms have poor bioavailability and are more likely to cause gastrointestinal side effects, limiting their usefulness for long-term supplementation. (Ranade 2001)(Blancquaert 2019) For this reason, magnesium glycinate/bisglycinate is preferred in protocols for CAD, as it is better absorbed, less likely to cause diarrhea, and more suitable for sustained repletion of magnesium levels. (Uberti 2020) 

Supporting evidence:

• Low serum magnesium is an independent risk factor for CAD, particularly among women, with evidence showing that each 0.1 mmol/L genetically determined decrease in serum magnesium is associated with a 14% higher odds of developing CAD. (Rooney 2019)
• A 2013 meta-analysis of 16 studies and 313,041 individuals found that higher circulating magnesium levels are associated with a lower risk of CVD, with a 30% reduction in risk per 0.2 mmol/L increment in serum magnesium. Dietary magnesium intake was not significantly associated with overall CVD risk. However, higher dietary magnesium intake was linked to a 22% lower risk of CAD, and a nonlinear inverse association was observed for fatal CAD, meaning the protective effect was most evident up to a daily intake of about 250 mg, beyond which additional intake did not provide further risk reduction. (Del Gobbo 2013)
• A meta-analysis of 34 trials involving 2,028 participants suggests that dietary magnesium (median dose 368 mg per day) for three months significantly reduced systolic blood pressure (BP) by 2.00 mmHg and diastolic BP by 1.78 mmHg. (Zhang 2016) Integrating these results from the conclusions of the Framingham Heart Study, which stated that a 2.00 mm Hg diastolic BP reduction was associated with a 6% reduction in CAD risk, these results suggest that daily dietary magnesium may lead to a 5.3% risk reduction in CAD. (Cook 1995) 
• Multiple randomized double-blind placebo-controlled trials demonstrate improved cardiovascular biomarkers associated with supplemental magnesium in patients with CAD.
  • Patients with moderate CAD (n=64) were randomly assigned to receive either a placebo or 300 mg of magnesium sulfate daily for six months. Magnesium sulfate was associated with improvements in glycemic control, oxidative stress, and liver function, as measured by reductions in hemoglobin A1c (HbA1c), two-hour postprandial blood glucose, oxidized low-density lipoprotein (LDL) and its receptor (LOX1), serum glutamate pyruvate transaminase (SGPT), and serum glutamate oxaloacetate transaminase (SGOT). (Farshidi 2020)
  • Magnesium sulfate supplementation at 300 mg daily for three months was associated with anti-inflammatory benefits based on a measurable reduction in inflammatory cytokines (interleukin-18 and tumor necrosis factor-alpha). (Mohebi 2023)
  • Oral magnesium oxide supplementation demonstrated a significant reduction in median platelet-dependent thrombosis by 35% in patients with CAD on concurrent aspirin therapy compared to placebo. (Shechter 1999)

Magnesium in the Fullscript catalog

Dietary Fiber

Dosing: At least 25 g daily from dietary and supplemental sources, ongoing (McRae 2017)

Supporting evidence:

• A meta-analysis of 18 studies involving 672,408 individuals indicates that higher dietary fiber intake is linked to a 7% lower risk of developing CAD and a 17% lower risk of dying from a CAD-related event. (Wu 2015)
• This umbrella review of systematic reviews and meta-analyses found that higher dietary fiber intake is consistently associated with reduced risk of CVD, CVD mortality, CAD, pancreatic and gastric cancers, and all-cause mortality. (Veronese 2018)
• High dietary fiber intake (25–38 g per day) is associated with a significantly reduced risk of CVD incidence (RR 0.72–0.83), CVD mortality (RR 0.77–0.83), CAD (RR 0.76–0.93), and stroke (RR 0.83–0.93) compared to those with the lowest intake (17 g per day). Supplementation studies with β-glucan or psyllium fibers demonstrated statistically significant reductions in total and LDL cholesterol, with decreases ranging from 9.3–14.7 mg/dL and 10.8–13.5 mg/dL, respectively. These findings support the role of dietary fiber in CVD prevention, likely mediated by its hypolipidemic effects. (McRae 2017)

Dietary Fiber in the Fullscript catalog

Vitamin K2

Dosing: 180–360 mcg per day of menaquinone-7 (MK-7), minimum one year (Li 2023)

Supporting evidence:

• According to a prospective cohort study involving 53,372 Danish citizens with no prior atherosclerotic cardiovascular disease (ASCVD), the risk of an ASCVD-related hospitalization for participants with the highest intakes of vitamin K2 was 14% lower than for those with the lowest K2 intake (hazard ratio (HR) 0.86). (Bellinge 2021)
• In a prospective cohort study with 2,987 Norwegian men and women ages 46–49 years with a median follow-up time of 11 years, dietary intake of vitamin K2 was associated with a 48% lower risk of CAD when comparing the highest quartile of intake to the lowest after multivariable adjustment for confounders. (Haugsgjerd 2020)
• In a three-year study of 244 postmenopausal women, supplementation with MK-7 (a form of vitamin K2) showed significant improvement in arterial elasticity and reduced carotid-femoral pulse-wave velocity in those with higher baseline arterial stiffness. (Knapen 2015) A subsequent one-year trial involving 243 men and women found that MK-7 supplementation helped lower circulating levels of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), a biomarker of vitamin K status and vascular calcification, with more pronounced effects in women. (Vermeer 2020) Together, these findings suggest that vitamin K2 may help attenuate age-related vascular stiffening, an important risk factor in the development of CAD.
• According to a systematic review and meta-analysis of 14 RCTs, comprising a total of 1,533 patients, vitamin K supplementation (K2 100–360 mcg per day or K1 500 mcg–10 mg per day) helped significantly slow the progression of coronary artery calcification (CAC) in adults at risk for vascular calcification. Additionally, supplementation was associated with a significant reduction in dp-ucMGP. (Li 2023)
• This double-blinded, randomized, multicenter clinical trial assessed the impact of high-dose vitamin K2 supplementation (MK-7 720 µg per day) combined with vitamin D (25 µg per day) versus placebo over two years in 389 men (mean age 71 years). While both groups had an increase in CAC scores over the two years, participants with elevated baseline CAC (≥400 Agatston Units) experienced significantly less progression in the intervention group (288 AU vs. 380 AU). Supplementation also significantly reduced the risk of serious cardiovascular outcomes, such as acute MI, revascularization, and all-cause mortality (1.9% vs. 6.7%). (Hasific 2022)

Vitamin K2 in the Fullscript catalog