Experts: LDL cholesterol causes artery disease

Overview

Ference BA et al.. Eur Heart J 2017 · PMID 28444290 · DOI 10.1093/eurheartj/ehx144

Genetic studies, cohorts and drug trials agree: more LDL over time means more atherosclerosis.

Does the study support the specific claim? No · Methodological quality: moderate

Original publication

Plain-language summary

Scientific in-depth review

1. Full reference

Authors

Ference BA et al.

Journal

Eur Heart J

Year

2017

Identifier

PMID 28444290 DOI 10.1093/eurheartj/ehx144

Verification

verified – PubMed efetch 2026-10-25

Retracted

no

Corrections

none

Extent checked

full text

Conflicts of interest and funding

Travel and meeting logistics supported by unrestricted educational grants from MSD and Amgen to the EAS (companies stated not present at meetings, no role in content). Open access charges paid by EAS. Most panel members declare research grants and/or honoraria from manufacturers of LDL-lowering drugs (e.g. Amgen, Sanofi-Regeneron, Merck/MSD, AstraZeneca, Pfizer); two members report no disclosures.

2. Research question

Does LDL cause atherosclerotic cardiovascular disease?

3. Study design and population

Study design

Guideline / position statement – Consensus statement of the European Atherosclerosis Society Consensus Panel appraising, against modified Bradford Hill causality criteria, published meta-analyses of monogenic-disorder studies, prospective cohorts (IPD meta-analyses), Mendelian randomisation studies and randomised LDL-lowering trials. Not a systematic review: meta-analyses were identified from MEDLINE/EMBASE, reference lists, GWAS consortia data and discussion among panel members; no protocol, no formal risk-of-bias or certainty grading of primary studies.

Population

Totality of evidence (>2 million participants)

Country

International

Period

n/a

Sample size

Evidence base described as >200 studies, >2 million participants, >20 million person-years, >150 000 cardiovascular events; incl. ERFC IPD meta-analysis (302 430 persons, 68 studies), Prospective Studies Collaboration (892 337 persons, 61 cohorts, 33 744 IHD deaths), MR meta-analyses (>300 000 participants, 80 000 CHD cases), CTT IPD meta-analysis of 26 statin trials (~170 000 individuals), and >30 RCTs (>200 000 participants, 30 000 ASCVD events).

Inclusion and exclusion criteria

Most updated meta-analyses preferred, giving preference to individual-participant-data meta-analyses; selection partly by panel discussion; no explicit exclusion criteria.

4. Methods and endpoints

Exposure / intervention

LDL cholesterol

Comparator

Lower LDL-C

Endpoints

ASCVD.

Statistical methods

Narrative synthesis of published meta-analyses; log-linear effect per mmol/L LDL-C compared across evidence types (Figure 2); modelled proportional and absolute risk reductions (Tables 2-4) using 22% relative reduction per mmol/L over 5 years (trials) and 54% per mmol/L over 40 years (MR).

5. Actual results

Results

Statins (CTT, 26 trials): 22% proportional reduction in major cardiovascular events per mmol/L LDL-C reduction over median 5 years (22-24% per year after year 1). IMPROVE-IT (n=18 144): ezetimibe+statin lowered LDL-C by 0.40 mmol/L, 6.5% proportional reduction in major CV events. SHARP (n=9270): LDL-C -0.85 mmol/L, -17% major CV events. FOURIER (n=27 564): evolocumab LDL-C -1.4 mmol/L to 0.78 mmol/L, -20% CV death/MI/stroke over median 2.2 years. Cholestyramine (LRC-CPPT): LDL-C -0.7 mmol/L, -19%; ileal bypass (POSCH): -1.85 mmol/L, -35%. Meta-analysis of 49 studies (312 175 participants, 39 645 major vascular events): 20-25% reduction per mmol/L across 9 lipid-lowering therapy types. MR: variants in >50 genes, similar per-unit effects incl. HMGCR, NPC1L1, PCSK9 (I2 = 0%); long-term lower LDL-C associated with up to three-fold greater proportional reduction per unit than later statin treatment. Exception: CETP inhibitor evacetrapib (ACCELERATE) lowered LDL-C by 0.75 mmol/L without reducing events. No 95% CIs are given in the consensus text itself.

Absolute risks

No observed absolute rates in the text; Tables 2-4 give MODELLED absolute risk reductions, e.g. 10-year CVD risk 20% with baseline LDL-C 5 mmol/L halved to 2.5 mmol/L: ARR 8.6%, NNT 11.7 over 5 years; 10-year risk 5% with LDL-C 2 to 1 mmol/L: ARR 1%, NNT 100. These are projections, not trial results.

Authors' conclusion

Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD; LDL is not merely a biomarker but a causal factor; effect depends on absolute magnitude and cumulative duration of exposure.

6. Strengths

• Triangulation across independent evidence types (monogenic disorders, IPD cohort meta-analyses, Mendelian randomisation, RCTs) with concordant per-unit effect sizes
• Randomised evidence from MR and trials largely free of confounding
• Explicit causality criteria (Table 1)
• Acknowledges discordant result (CETP inhibitors)

7. Weaknesses

• Not a systematic review: no protocol, selection of meta-analyses partly by panel discussion, no formal risk-of-bias or GRADE assessment
• Extensive financial ties of panel members to manufacturers of LDL-lowering drugs; meeting logistics funded by MSD and Amgen
• No confidence intervals reported in the text for most estimates
• Absolute risk tables are model projections (assumes constant 22%/mmol/L and MR-derived long-term effects)
• Addresses LDL-C (biomarker) as exposure, not specific dietary fats or foods; diet-to-LDL link is not covered

8. Risk of bias

Orienting tool

none applicable (expert consensus statement / non-systematic overview of meta-analyses)

Type of assessment

structured assessment based on the full text by a single reviewer (no formal double review)

Full formal assessment

no

Overall risk of bias

some concerns

Rationale

Single-reviewer structured judgement from the full text; a formal assessment would need two independent reviewers and a protocol. The causal conclusion LDL -> ASCVD is considered robust; concerns relate to process (non-systematic selection, COI) and to modelled absolute benefits, not to the direction of the main conclusion. Previous abstract-based rating 'low' changed to 'some_concerns' because of the non-systematic methods and panel COI documented in the full text.

Full-text review (25 October 2026): Design clarified as non-systematic consensus overview; n detailed per evidence stream; results now give per-mmol/L trial numbers (CTT 22%, IMPROVE-IT, SHARP, FOURIER, CETP exception); absolute risk now notes modelled ARR/NNT tables; COI completed (MSD/Amgen logistics grants, extensive panel industry ties); bias overall low -> some_concerns; methodological_quality high -> moderate.

9. Assessment of the statistical interpretation

Relative effects per mmol/L are concordant across MR (lifelong) and RCTs (5 years), supporting causality and a cumulative effect; the consensus reports no CIs in its own text. Absolute benefits depend on baseline risk and are modelled, not observed.

10. Relevance to the specific claim

Contradicts C-FAT-01, C-FAT-02 and C-FAT-05.

11. Independent contrary findings

None substantive.

12. Transferability to Germany and Europe

High.

13. Overall methodological judgement

Strong, triangulated evidence that LDL causes ASCVD; process is expert consensus with substantial industry COI rather than a systematic review, but the conclusion matches independent RCT and genetic evidence. It does not directly address whether specific foods (ghee, butter) raise LDL in a given person.

14. Open questions

Diet-specific effects on LDL-C and ASCVD are not addressed; validity of 30-40-year modelled absolute benefits; discordance of CETP inhibitors.

15. Linked fact checks

• Natural fats such as baladi ghee and butter are not a cause of clogged arteries (contrary to the previously dominant view); 'good fats do not stick'. – Studies contradicting or limiting the claim
• Blood contains no fat (everything in plasma is water-soluble), so it is impossible for arteries to be blocked by fat. – Studies contradicting or limiting the claim
• Cholesterol is not your enemy: when insulin falls, the liver produces cholesterol not because it is harmful but because it is the raw material for vitamin D, sex hormones, cortisol and bile salts. – Studies contradicting or limiting the claim