This systematic review and meta-analysis of randomized clinical trials stratified by follow-up time and degree of LDL-C lowering showed that:
- Benefits of LDL-C lowering are not fixed, but increase steadily with longer durations of treatment
- Causal effect of LDL-C on the risk of ASCVD is determined by both the absolute magnitude and the cumulative duration of exposure to LDL-C
- Results from short-term randomized trials were compatible with the very strong associations between LDL-C and cardiovascular events seen in Mendelian randomization (MR) studies
Study findings indicate that current guidelines underestimate the benefits of LDL-C lowering interventions that are continued for longer than 5 years, which has particular relevance to intervention in younger people.
Why This Matters
- Evidence from randomized clinical trials has shown that each mmol/L lower LDL-C* is associated with ≈24% lower risk of major vascular events.
- However, MR studies report that each mmol/L lower LDL-C is associated with >50% lower coronary risk, with the LDL cholesterol difference hypothesized to be attributed to the exposure duration.
This study evaluated the relationship between lipid-lowering drug exposure time and relative risk reduction of major cardiovascular events in randomized clinical trials, by stratifying the analysis to each year of follow-up, by effect size and LDL-C difference.
This was a systematic review and meta-analysis of randomized clinical trials of statins, ezetimibe, or PCSK9i that reported LDL-C levels and effect sizes for each year of follow-up
- Studies with a minimum of 1000 patient-years of follow-up
- Trials that reported the effect size/ summary estimate on clinical events per year of follow-up
- Follow-up LDL-C levels per year of follow-up
- Reporting ≥3 years of data
- Trials including dietary therapies
- Patients followed up for <6 months or treatment compared with medications other than cholesterol lowering drugs or placebo
- Major vascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary revascularization).
- Meta-regression comparing duration of treatment to log(HR) was used to examine the relationship between treatment duration and risk of major vascular events.
- Effect estimates from meta-analyses of randomized clinical trials were compared with the expected clinical benefit per unit reduction in LDL-C estimated by Ference et al.
Overall, 21 trials of LDL-C lowering were included in the analysis; 4 using ezetimibe and statins; 15 using statin therapy only; and 2 for PCSK9i vs placebo. (N = 184,012 patients; average mean follow-up = 4.4 years)
DURATION OF FOLLOW-UP AND LDL-C REDUCTION
- Each subsequent year of follow-up diminished the mean difference in LDL-C between the treatment and control arms.
- Average difference:
- After one year = 1.05 mmol/L
- By 3 years = 0.98 mmol/L
- By 7 years = 0.54 mmol/L
|LDL-C REDUCTION AND RELATIVE RISK REDUCTION IN MAJOR CV EVENTS|
| After standardizing for the degree of LDL-C reduction,
each mmol/L LDL-C reduction was associated with a relative risk reduction in major vascular events after treatment years
|AFTER 1 YEAR OF TREATMENT||AFTER 3 YEAR OF TREATMENT||AFTER 5 YEAR OF TREATMENT||AFTER 7 YEAR OF TREATMENT|
(95% CI: 8%–16%)
(95% CI: 16%–24%)
(95% CI: 18%–27%)
(95% CI: 14%–42%)
META REGRESSION AND SUMMARY ESTIMATES
|SUMMARY ESTIMATES FROM RANDOMIZED CLINICAL TRIALS AND MR†|
- Analysis was based on trial-level data; more reliable estimates would have arisen from analyses of individual patient data.
- A significant uncertainty existed about the extrapolation from 7 years of treatment in the included meta-analyses to a lifetime of treatment estimated from the MR studies.
- Some differences existed in the definition of major vascular event between the included randomized trials and the outcome used in the MR study by Ference et al.
- Present study was not registered in PROSPERO.
* Lowered through statins, ezetimibe, and PCSK9i
† From Ference et al. for increasing durations of treatment, stratified to per 1 mmol/L LDL-C lowered
ABBREVIATIONS: ASCVD, Atherosclerotic cardiovascular disease; CI, confidence interval; HR, hazard ratio; LDL-C, low-density lipoproteincholesterol; MR, Mendelian randomization; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors.
- Wang N, Woodward M, Huffman MD, Rodgers A. Compounding benefits of cholesterol-lowering therapy for the reduction of major cardiovascular events: Systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2022:101161CIRCOUTCOMES121008552. doi: 10.1161/CIRCOUTCOMES.121.008552. Epub ahead of print. PMID: 35430872.