Major cardiovascular event incidence

What acts on it

1. D3 versus placebo estimate: HR0.97; 95% CI0.85–1.12; P=0.69.

   Cholecalciferol → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   cross_nutrient

   false

   experimental_model

   VITAL primary prevention RCT; 25, 871 adults; median 5.3 years

   exposure

   D3 2000 IU/day versus placebo; randomized factorial omega 3 allocation; median 5.3 years.

   limitations

   Primary prevention population; secondary mortality finding is not the primary cancer-incidence endpoint. This record does not summarize later pooled analyses.

   nutrient_topic

   Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin D2 and D3

   organism

   Homo sapiens

   plain_language

   The supplement did not significantly lower the main cardiovascular outcome.

   primary_references

   [manson2019] Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. (2019). https://pubmed.ncbi.nlm.nih.gov/30415629/ DOI: 10.1056/nejmoa1809944

   tissue_or_cell_type

   Human clinical events

   Vitamin D2 and D3: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1548–1559

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · VITAL primary prevention RCT; 25, 871 adults; median 5.3 years · source_derived_draft · unverified_draft

   ### vd-vital-cvd D3 versus placebo estimate: HR0.97; 95% CI0.85–1.12; P=0.69. Condition category: normal nutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The supplement did not significantly lower the main cardiovascular outcome. organism: Homo sapiens tissue_or_cell_type: Human clinical events experimental_model: VITAL primary prevention RCT; 25, 871 adults; median 5.3 years limitations: Primary prevention population; secondary mortality finding is not the primary cancer-incidence endpoint. This record does not summarize later pooled analyses. exposure: D3 2000 IU/day versus placebo; randomized factorial omega 3 allocation; median 5.3 years. cross_nutrient: false [manson2019] Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. (2019). https://pubmed.ncbi.nlm.nih.gov/30415629/ DOI: 10.1056/nejmoa1809944

   Complete structured claim and evidence

2. Higher serum 2PY was associated with three-year major adverse cardiovascular events in both validation cohorts.

   N1-methyl-2-pyridone-5-carboxamide (2PY) → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   biomarker_context Imported condition classification; unverified.

   cross_nutrient

   Niacin precursor form and the measured endpoint are separate graph entities.

   evidence_span

   {"source_cache": "artifacts/niacin-clinical-sources/ferrell2024.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19", "start_char": 0, "end_char": 2066, "text_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19"}

   experimental_model

   Prospective stable cardiac patient cohorts with three-year event follow-up

   exposure

   Discovery cohort 1,162; US validation 2,331 and European validation 832; three-year cardiovascular follow-up; physiological-level mouse metabolite exposure

   limitations

   Human metabolite associations are not randomized effects of niacin intake. Renal handling and other determinants of levels matter. Mouse exposure results do not prove dietary niacin or supplements caused human events.

   nutrient_topic

   Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

   organism

   Homo sapiens

   plain_language

   A breakdown-product measurement tracked risk; that does not identify dietary niacin as the cause.

   primary_references

   [nia-clin-ferrell2024] A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. (2024). https://pubmed.ncbi.nlm.nih.gov/38374343/ DOI: 10.1038/s41591-023-02793-8

   tissue_or_cell_type

   Serum metabolites and clinical cardiovascular outcomes

   trigger_kind

   biomarker_context Imported condition classification; unverified.

   Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1557–1569

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective stable cardiac patient cohorts with three-year event follow-up · source_derived_draft · unverified_draft

   ### nia-clin-2py-risk Higher serum 2PY was associated with three-year major adverse cardiovascular events in both validation cohorts. Condition category: biomarker_context nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A breakdown-product measurement tracked risk; that does not identify dietary niacin as the cause. organism: Homo sapiens tissue_or_cell_type: Serum metabolites and clinical cardiovascular outcomes experimental_model: Prospective stable cardiac patient cohorts with three-year event follow-up limitations: Human metabolite associations are not randomized effects of niacin intake. Renal handling and other determinants of levels matter. Mouse exposure results do not prove dietary niacin or supplements caused human events. exposure: Discovery cohort 1,162; US validation 2,331 and European validation 832; three-year cardiovascular follow-up; physiological-level mouse metabolite exposure cross_nutrient: Niacin precursor form and the measured endpoint are separate graph entities. evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/ferrell2024.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19", "start_char": 0, "end_char": 2066, "text_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19"} [nia-clin-ferrell2024] A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. (2024). https://pubmed.ncbi.nlm.nih.gov/38374343/ DOI: 10.1038/s41591-023-02793-8

   Complete structured claim and evidence

3. Higher serum 4PY was associated with three-year major adverse cardiovascular events in both validation cohorts.

   N1-methyl-4-pyridone-3-carboxamide (4PY) → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   biomarker_context Imported condition classification; unverified.

   cross_nutrient

   Niacin precursor form and the measured endpoint are separate graph entities.

   evidence_span

   {"source_cache": "artifacts/niacin-clinical-sources/ferrell2024.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19", "start_char": 0, "end_char": 2066, "text_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19"}

   experimental_model

   Prospective stable cardiac patient cohorts with three-year event follow-up

   exposure

   Discovery cohort 1,162; US validation 2,331 and European validation 832; three-year cardiovascular follow-up; physiological-level mouse metabolite exposure

   limitations

   Human metabolite associations are not randomized effects of niacin intake. Renal handling and other determinants of levels matter. Mouse exposure results do not prove dietary niacin or supplements caused human events.

   nutrient_topic

   Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

   organism

   Homo sapiens

   plain_language

   A second terminal metabolite also tracked risk in the studied cardiac patients.

   primary_references

   [nia-clin-ferrell2024] A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. (2024). https://pubmed.ncbi.nlm.nih.gov/38374343/ DOI: 10.1038/s41591-023-02793-8

   tissue_or_cell_type

   Serum metabolites and clinical cardiovascular outcomes

   trigger_kind

   biomarker_context Imported condition classification; unverified.

   Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1571–1583

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Prospective stable cardiac patient cohorts with three-year event follow-up · source_derived_draft · unverified_draft

   ### nia-clin-4py-risk Higher serum 4PY was associated with three-year major adverse cardiovascular events in both validation cohorts. Condition category: biomarker_context nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: A second terminal metabolite also tracked risk in the studied cardiac patients. organism: Homo sapiens tissue_or_cell_type: Serum metabolites and clinical cardiovascular outcomes experimental_model: Prospective stable cardiac patient cohorts with three-year event follow-up limitations: Human metabolite associations are not randomized effects of niacin intake. Renal handling and other determinants of levels matter. Mouse exposure results do not prove dietary niacin or supplements caused human events. exposure: Discovery cohort 1,162; US validation 2,331 and European validation 832; three-year cardiovascular follow-up; physiological-level mouse metabolite exposure cross_nutrient: Niacin precursor form and the measured endpoint are separate graph entities. evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/ferrell2024.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19", "start_char": 0, "end_char": 2066, "text_sha256": "09530c87779c7a8db8507c847dcb29ae3b7e439967c9271dec5f7cbda6c33d19"} [nia-clin-ferrell2024] A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. (2024). https://pubmed.ncbi.nlm.nih.gov/38374343/ DOI: 10.1038/s41591-023-02793-8

   Complete structured claim and evidence

4. The AIM-HIGH composite endpoint occurred in 16.4% versus 16.2% of niacin and placebo participants: hazard ratio 1.02, 95% CI 0.87–1.21.

   Nicotinic acid → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   cross_nutrient

   Niacin precursor form and the measured endpoint are separate graph entities.

   evidence_span

   {"source_cache": "artifacts/niacin-clinical-sources/aimhigh2011.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "eefcc0d7eed5694eb9d1861a06fc5a256986753607c2095996304fd0de25f3aa", "start_char": 0, "end_char": 2340, "text_sha256": "eefcc0d7eed5694eb9d1861a06fc5a256986753607c2095996304fd0de25f3aa"}

   experimental_model

   AIM-HIGH randomized trial; 3,414 patients with established cardiovascular disease on intensive statin therapy

   exposure

   Extended-release nicotinic acid 1,500–2,000 mg/day versus placebo; mean 3-year follow-up

   limitations

   Pharmacological dosing added to statin therapy. Lipid changes are not equivalent to clinical benefit. Trial stopped for lack of efficacy; no inference about treating dietary niacin deficiency.

   nutrient_topic

   Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

   organism

   Homo sapiens

   plain_language

   Improved lipid numbers did not translate into fewer trial cardiovascular events in these statin-treated patients.

   primary_references

   [nia-clin-aimhigh2011] Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. (2011). https://pubmed.ncbi.nlm.nih.gov/22085343/ DOI: 10.1056/nejmoa1107579

   tissue_or_cell_type

   Circulating lipids and cardiovascular outcomes

   Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1389–1401

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · AIM-HIGH randomized trial; 3,414 patients with established cardiovascular disease on intensive statin therapy · source_derived_draft · unverified_draft

   ### nia-clin-aimhigh-events The AIM-HIGH composite endpoint occurred in 16.4% versus 16.2% of niacin and placebo participants: hazard ratio 1.02, 95% CI 0.87–1.21. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improved lipid numbers did not translate into fewer trial cardiovascular events in these statin-treated patients. organism: Homo sapiens tissue_or_cell_type: Circulating lipids and cardiovascular outcomes experimental_model: AIM-HIGH randomized trial; 3,414 patients with established cardiovascular disease on intensive statin therapy limitations: Pharmacological dosing added to statin therapy. Lipid changes are not equivalent to clinical benefit. Trial stopped for lack of efficacy; no inference about treating dietary niacin deficiency. exposure: Extended-release nicotinic acid 1,500–2,000 mg/day versus placebo; mean 3-year follow-up cross_nutrient: Niacin precursor form and the measured endpoint are separate graph entities. evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/aimhigh2011.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "eefcc0d7eed5694eb9d1861a06fc5a256986753607c2095996304fd0de25f3aa", "start_char": 0, "end_char": 2340, "text_sha256": "eefcc0d7eed5694eb9d1861a06fc5a256986753607c2095996304fd0de25f3aa"} [nia-clin-aimhigh2011] Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. (2011). https://pubmed.ncbi.nlm.nih.gov/22085343/ DOI: 10.1056/nejmoa1107579

   Complete structured claim and evidence

5. Niacin–laropiprant produced major vascular-event rates of 13.2% versus 13.7% with placebo: rate ratio 0.96, 95% CI 0.90–1.03, without a significant benefit.

   Nicotinic acid → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   cross_nutrient

   Laropiprant / MK-0524 (coadministered_drug)

   evidence_span

   {"source_cache": "artifacts/niacin-clinical-sources/hps2014.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "9f12db5e258418187e65c3b921cffd01bf3cc0f400d3caa19cb4005c5e6f4f05", "start_char": 0, "end_char": 2717, "text_sha256": "9f12db5e258418187e65c3b921cffd01bf3cc0f400d3caa19cb4005c5e6f4f05"}

   experimental_model

   HPS2-THRIVE randomized trial; 25,673 adults with vascular disease on statin-based therapy

   exposure

   Extended-release nicotinic acid 2 g plus laropiprant 40 mg daily; median 3.9 years

   limitations

   Combination regimen; observed harm cannot all be assigned to nicotinic acid alone. Run-in selected participants able to tolerate initial therapy. Outcomes do not address deficiency replacement.

   nutrient_topic

   Niacin research collection; topical membership is not evidence of a direct dietary effect. · Niacin (vitamin B3)

   organism

   Homo sapiens

   plain_language

   This large trial also found no clear event benefit when the combination was added to statin treatment.

   primary_references

   [nia-clin-hps2014] Effects of extended-release niacin with laropiprant in high-risk patients. (2014). https://pubmed.ncbi.nlm.nih.gov/25014686/ DOI: 10.1056/nejmoa1300955

   tissue_or_cell_type

   Major vascular events and adverse events

   Niacin: NAD metabolism, deficiency and nutrient interactions (2026-09-17) · lines 1403–1415

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HPS2-THRIVE randomized trial; 25,673 adults with vascular disease on statin-based therapy · source_derived_draft · unverified_draft

   ### nia-clin-hps-events Niacin–laropiprant produced major vascular-event rates of 13.2% versus 13.7% with placebo: rate ratio 0.96, 95% CI 0.90–1.03, without a significant benefit. Condition category: normal nutrient_topic: Niacin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This large trial also found no clear event benefit when the combination was added to statin treatment. organism: Homo sapiens tissue_or_cell_type: Major vascular events and adverse events experimental_model: HPS2-THRIVE randomized trial; 25,673 adults with vascular disease on statin-based therapy limitations: Combination regimen; observed harm cannot all be assigned to nicotinic acid alone. Run-in selected participants able to tolerate initial therapy. Outcomes do not address deficiency replacement. exposure: Extended-release nicotinic acid 2 g plus laropiprant 40 mg daily; median 3.9 years cross_nutrient: Laropiprant / MK-0524 (coadministered_drug) evidence_span: {"source_cache": "artifacts/niacin-clinical-sources/hps2014.abstract.txt", "locator": "Indexed primary abstract", "file_sha256": "9f12db5e258418187e65c3b921cffd01bf3cc0f400d3caa19cb4005c5e6f4f05", "start_char": 0, "end_char": 2717, "text_sha256": "9f12db5e258418187e65c3b921cffd01bf3cc0f400d3caa19cb4005c5e6f4f05"} [nia-clin-hps2014] Effects of extended-release niacin with laropiprant in high-risk patients. (2014). https://pubmed.ncbi.nlm.nih.gov/25014686/ DOI: 10.1056/nejmoa1300955

   Complete structured claim and evidence

6. Vitamin C assignment did not reduce major cardiovascular events (HR 0.99; 95% CI 0.89–1.11; P=0.91) over mean eight-year follow-up.

   L-Ascorbic acid → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   cross_nutrient

   Clinical outcome boundary for extrapolation from vitamin C/vitamin E redox recycling.

   experimental_model

   Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up.

   exposure

   Vitamin C 500 mg/day and separately randomized vitamin E 400 IU every other day; clinical CVD endpoints.

   limitations

   Older male physicians, not a selected scurvy cohort; separate vitamin E randomization is not proof of molecular synergy or antagonism.

   nutrient_topic

   Vitamin C research collection; topical membership is not evidence of a direct dietary effect. · Vitamin C

   organism

   Homo sapiens

   plain_language

   A long-term supplement trial did not turn the antioxidant rationale into fewer major cardiovascular events.

   primary_references

   [c-sesso2008] Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18997197/ DOI: 10.1001/jama.2008.600

   tissue_or_cell_type

   Human blood or whole-person endpoints

   Vitamin C: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1830–1841

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up. · source_derived_draft · unverified_draft

   ### c-cvd-prevention-null Vitamin C assignment did not reduce major cardiovascular events (HR 0.99; 95% CI 0.89–1.11; P=0.91) over mean eight-year follow-up. Condition category: normal nutrient_topic: Vitamin C research collection; topical membership is not evidence of a direct dietary effect. plain_language: A long-term supplement trial did not turn the antioxidant rationale into fewer major cardiovascular events. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Physicians Health Study II: placebo-controlled double-blind factorial trial, 14641 male physicians aged at least 50, mean eight-year follow-up. limitations: Older male physicians, not a selected scurvy cohort; separate vitamin E randomization is not proof of molecular synergy or antagonism. exposure: Vitamin C 500 mg/day and separately randomized vitamin E 400 IU every other day; clinical CVD endpoints. cross_nutrient: Clinical outcome boundary for extrapolation from vitamin C/vitamin E redox recycling. [c-sesso2008] Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial (2008). https://pubmed.ncbi.nlm.nih.gov/18997197/ DOI: 10.1001/jama.2008.600

   Complete structured claim and evidence

7. The primary cardiovascular death/MI/stroke composite occurred in 18.8% versus 19.8% (RR 0.95; 95% CI 0.84–1.07), without a significant treatment effect.

   Folic acid → Major cardiovascular event incidence source_derived_draftungraded
   Experimental context and source evidence

   experimental_model

   Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years.

   exposure

   Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate.

   limitations

   Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction.

   nutrient_topic

   Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

   organism

   Homo sapiens

   plain_language

   Improving homocysteine did not establish benefit for the primary clinical endpoint.

   primary_references

   [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

   tissue_or_cell_type

   Human blood or whole-person clinical endpoints

   Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1630–1640

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. · source_derived_draft · unverified_draft

   ### fol-hope2-primary-outcome-null The primary cardiovascular death/MI/stroke composite occurred in 18.8% versus 19.8% (RR 0.95; 95% CI 0.84–1.07), without a significant treatment effect. Condition category: normal nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Improving homocysteine did not establish benefit for the primary clinical endpoint. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Randomized HOPE-2: 5522 adults at least 55 years old with vascular disease or diabetes, mean five years. limitations: Distinct population, regimen and endpoint from CSPPT; this is an outcome boundary, not a contradiction to a biochemical reaction. exposure: Folic acid 2.5 mg, B6 50 mg and B12 1 mg/day together versus placebo; combined intervention, not isolated folate. [fol-hope2006] Homocysteine lowering with folic acid and B vitamins in vascular disease (2006). https://pubmed.ncbi.nlm.nih.gov/16531613/ DOI: 10.1056/nejmoa060900

   Complete structured claim and evidence