Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials

Several statin trials with large type 2 diabetes subpopulations, including GREACE, TNT, and PROVE IT, have shown significant reductions in mortality and cardiovascular events.

“However, several statin trials with large T2D subpopulations, including the GREACE (GREek Atorvastatin and Coronary-Heart-Disease Evaluation) study, TNT (Treating to New Targets) study, and PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial, have shown significant reductions in mortality and CVD events.”

Statin therapy reduced the risk of all-cause mortality by 9% per 1.0 mmol/L LDL-C reduction.

“Statin therapy reduced the risk of all-cause mortality by 9% per 1.0 mmol/L LDL-C reduction.”

LDL-C is a valid surrogate parameter for the clinical endpoints MACE and cardiovascular death.

“thereby confirming LDL-C as a valid surrogate parameter for the clinical endpoints MACE and cardiovascular death.”

Circulating LDL particles are highly atherogenic and there is a direct, graded relationship between LDLC concentration and the incidence of ASCVD observed in randomized controlled trials, prospective epidemiological cohort studies, and Mendelian randomization studies.

“Circulating LDL particles are highly atherogenic and there is a direct, graded relationship between LDLC concentration and the incidence of ASCVD observed in randomized controlled trials, prospective epidemiological cohort studies, and Mendelian randomization studies [7,8].”

The clinical effectiveness of LDLC-guided management of cardiovascular risk is most strongly evidence-based.

“The clinical effectiveness of LDLC-guided management of cardio- vascular risk is most strongly evidence-based [7,8].”

The rate of major vascular events as defined by the CTT collaborators was significantly lower in the simvastatin-ezetimibe group (difference, 2.2 percentage points; hazard ratio, 0.928; P=0.007).

“The rate of major vascular events as defined by the CTT collaborators 3,4 (a composite of death from coronary heart disease, myocardial infarction, stroke, or coronary revascularization 30 days or more after randomization) was also significantly lower in the simvastatin-ezetimibe group (difference, 2.2 percentage points; hazard ratio, 0.928; P = 0.007).”

In IMPROVE-IT, using the CTT approach and end point, there was a proportional 7.2% lower rate of major vascular events.

“and a proportional 7.2% lower rate of major vascular events”

Statins can only reduce the risk of cardiovascular events by up to 50% depending on disease status and amount of statin used, leaving a large burden of residual disease risk.

“Although the lowering of LDL cholesterol (LDL-C) with the use of statins has revolutionized the treatment of atherosclerotic cardiovascular disease, statins can only reduce the risk of cardiovascular events by up to 50% depending on the disease status and the amount of statin used, which still leaves a large burden of residual disease risk.1–3”

Statin-adjusted LDL values were corrected for the overall random effect on LDL cholesterol for individuals in statin therapy (-33%).

“A third potential limitation is that the statin-adjusted LDL values were corrected for the overall random effect on LDL cholesterol for individuals in statin therapy (-33% [38][39][40]).”

Further intensifying statin therapy provides an additional MACE risk reduction of -15% (95% CI -11 to -18, p<0.0001).

“Further intensifying statin therapy provides an additional MACE risk reduction of − 15% (95% CI − 11 to − 18, p < 0.0001) [38].”

Overall, low-/moderate-intensive statin therapy reduces the risk of MACE by -22% (95% CI -19 to -24, p<0.0001).

“Overall, low-/moderate-intensive statin therapy reduces the risk of MACE by − 22% (95% CI − 19 to − 24, p < 0.0001) [38].”

According to an analysis of 170,000 patients, a 38.67 mg/dl (1 mmol/l) reduction in LDL-C was associated with a -22% (95% CI -20 to -24, p<0.0001) decreased risk in major adverse cardiovascular events.

“According to an analysis of 170,000 patients, a 38.67 mg/dl (1 mmol/l) reduction in LDL-C was associated with a − 22% (95% CI − 20 to − 24, p < 0.0001) decreased risk in major adverse cardiovascular events (MACE) [38]”

Evidence for an increased risk of haemorrhagic stroke with statins remains inconclusive.

“Evidence for an increased risk of haemorrhagic stroke remains inconclusive [38, 54, 55].”

In IMPROVE-IT, using the CTT approach and end point, there was a between-group difference in LDL cholesterol levels (with imputation for missing values) of 12.8 mg per deciliter.

“we observed a between-group difference in LDL cholesterol levels (with imputation for missing values) of 12.8 mg per deciliter”

Current data indicate that the same relationship between reduction in LDL cholesterol levels and clinical benefit is seen across different statins and statin doses.

“Although we studied only this regimen, current data indicate that the same relationship between reduction in LDL cholesterol levels and clinical benefit is seen across different statins and statin doses.4”

The higher rate of hemorrhagic stroke with simvastatin-ezetimibe is similar to that seen with statin therapy as compared with placebo.

“a finding similar to that seen with statin therapy as compared with placebo.3,4”

The consistency with expectations from the CTT analysis, in which a different class of drug was used, provides further evidence for a relationship between lipid lowering and improved outcomes.

“However, the consistency with expectations from the CTT analysis, in which a different class of drug was used, provides further evidence for a relationship between lipid lowering and improved outcomes.”

In the CTT meta-analysis, the hazard ratio for clinical benefit per millimole of LDL cholesterol reduction with statins was 0.78.

“as compared with 0.78 observed with statins in the CTT meta-analysis.3,4”

In FOURIER, additional lowering of LDL cholesterol levels had no effect on cardiovascular mortality.

“In an observation consistent with previous trials of more intensive LDL cholesterol-lowering therapy as compared with moderate-intensity statin therapy, 15,25 we found no effect of additional lowering of LDL cholesterol levels on cardiovascular mortality.”

If all ApoB-containing particles have approximately the same atherogenic effect, then to reduce cardiovascular event risk by 20% (as achieved by lowering LDL-C by 40 mg/dL), triglyceride levels must be reduced by approximately 200 mg/dL to achieve the same reduction in ApoB-containing lipoproteins.

“Therefore, if all ApoB-containing particles have approximately the same atherogenic effect as suggested by this study, then to reduce the risk of cardiovascular events by 20% as can be achieved by lowering LDL-C levels by 40 mg/dL, 3,4 triglyceride levels must be reduced by 5-fold this quantity, or approximately 200 mg/dL, to achieve the same corresponding reduction in ApoB-containing lipoproteins”

Each 40 mg per deciliter reduction in LDL-C is associated with approximately a 22% decrease in cardiovascular risk.

“Each 40 mg per deciliter reduction in LDL-C is associated with approximately a 22 % decrease in cardiovascular risk [3].”

Lowering LDL-C by 38.7 mg/dL results in a 22% reduction of cardiovascular events, as demonstrated by the Cholesterol Treatment Trialists' (CTT) Collaboration.

“Research conducted by the Cholesterol Treatment Trialists’ (CTT) Collaboration demonstrated that lowering LDL-C by 38.7 mg/dL results in a 22% reduction of cardiovascular events [51].”

A reduction of 2 to 3 mmol/L LDL-C by statins could reduce the risk of CVD by 40% to 50%.

“A previous meta-analysis indicated that a reduction of 2 to 3 mmol/L LDL-C by statins could reduce the risk of CVD by 40% to 50% because there was no evidence of any threshold within the cholesterol range studied.3”

Statins significantly reduced the total mortality rate by approximately 10% in CTT meta-analyses.

“The meta-analyses of statins by the Cholesterol Treatment Trialists’ (CTT) Collaboration [17–19] showed that the administration of statins significantly reduced the total mortality rate by ~ 10%.”

Lowering atherogenic lipoproteins, reflected in part by reduction of low-density lipoprotein cholesterol, favorably modifies the risks of MACEs and death.

“Lowering of atherogenic lipoproteins, reflected in part by reduction of low-density lipoprotein cholesterol (LDL-C), favorably modifies the risks of MACEs and death (7)”

The proposed linear link between LDL cholesterol lowering and cardiovascular risk reduction, plus limited long-term safety data at very low LDL cholesterol, supports aiming for low LDL cholesterol in highest-risk patients without raising adverse event risk.

“supports the notion of aiming for low LDL-C levels, especially in those patients with the highest absolute risk of a recurrent event (eg, T2DM, peripheral artery disease, recent incident of acute coronary syndrome, and multiple prior cardiovascular events), but not at the expense of elevating the risk of adverse events.127”

In a CTT meta-analysis of 26 randomized trials with 170,000 participants, each 39-mg/dL LDL cholesterol reduction was associated with a 10% decrease in all-cause mortality (RR 0.90 [95% CI 0.87-0.93]; P<0.0001), mainly from fewer cardiac deaths.

“This CTT meta-analysis of 26 randomized trials with 170 000 participants had determined that every 39-mg/dL (1.0 mmol/L) reduction in LDL-C culminated in a 10% decrease in all-cause mortality (RR, 0.90 [95% CI, 0.87–0.93]; P<0.0001) that was driven primarily by diminished cardiac-related deaths.127”

The graded intervention approach in Table 5 is based on evidence from multiple meta-analyses and randomized controlled trials showing consistent and graded reduction in atherosclerotic cardiovascular disease risk with reductions in total cholesterol and LDL-C.

“This graded approach is based on evidence from multiple meta-analyses and individual randomized controlled trials (RCTs), which show a consistent and graded reduction in ASCVD risk in response to reductions in TC and LDL-C levels (see Recommendations for cardiovascular disease risk estimation below) [31-41].”

The benefits of LDL-C reduction are not specific to statin therapy.

“The benefits related to LDL-C reduction are not specific for statin therapy [33].”

In IMPROVE-IT, there was no evidence of harm from ezetimibe or from further LDL-C reduction.

“There was no evidence of harm caused by ezetimibe or the further LDL-C reduction.”

In IMPROVE-IT, ischaemic stroke was reduced by 21% (P=0.008).

“Also, ischaemic stroke was reduced by 21% in this trial ( P =0.008).”

In IMPROVE-IT, 18,144 patients were randomized to statin or statin plus ezetimibe; over 7 years, 5314 had a cardiovascular event, with 170 fewer events in the simvastatin plus ezetimibe group (32.7% vs 34.7%, P=0.016).

“A total of 18 144 patients were randomized to statin or statin plus ezetimibe, and 5314 patients over 7 years experienced a CV event; 170 fewer events (32.7 vs. 34.7%) were recorded in the group taking simvastatin plus ezetimibe ( P =0.016).”

In IMPROVE-IT, average LDL-C during the study was 1.8 mmol/L in the simvastatin group and 1.4 mmol/L in the ezetimibe plus simvastatin group.

“The average LDL-C during the study was 1.8 mmoL/L (70 mg/dL) in the simvastatin group and 1.4 mmoL/L (55 mg/dL) in patients taking ezetimibe plus simvastatin.”

In IMPROVE-IT, the relative benefit of adding ezetimibe to simvastatin was similar in women and men.

“In the IMPROVE-IT study [33], the relative benefit of adding ezetimibe to simvastatin was similar in women and men [33].”

When added to statin therapy, ezetimibe lowers the risk of major vascular events.

“Ezetimibe lowers LDL-C by ∼24% and, when added to statin therapy, decreases the risk of major vascular events [33].”

Ezetimibe reduces LDL-C by approximately 24%.

“Ezetimibe lowers LDL-C by ∼24% and, when added to statin therapy, decreases the risk of major vascular events [33].”

In IMPROVE-IT, adding ezetimibe to simvastatin provided an additional benefit of a 6.4% relative risk reduction in the composite clinical endpoint in post-ACS patients.

“In the IMPROVE-IT trial, the addition of ezetimibe to simvastatin therapy provided an additional benefit (6.4% relative risk reduction in the composite clinical endpoint) to post-ACS patients [33].”

The most recent CTT meta-analysis of trials involving more than 170,000 patients confirmed a dose-dependent reduction in cardiovascular disease with LDL-cholesterol lowering.

“The most recent Cholesterol Treatment Trialists' Collaboration (CTT) meta-analysis of several trials involving .170000 patients confirmed the dose-dependent reduction in CVD with LDL-C lowering.15”

Target LDL-cholesterol levels for high-risk subjects are extrapolated from several clinical trials.

“Target levels for subjects at high risk are extrapolated from several clinical trials.15”

Each 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol is associated with a 22% reduction in cardiovascular mortality and morbidity.

“Every 1.0 mmol/L ( 40 mg/dL) reduction in LDL-C is associated with a corresponding 22% reduction in CVD mortality and morbidity.15”

Extrapolating from available data, reaching an LDL-cholesterol level below 1.8 mmol/L or achieving at least a 50% relative reduction provides the best cardiovascular benefit.

“Extrapolating from the available data, an absolute reduction to an LDL-C level ,1.8 mmol/L (less than 70 mg/dL) or at least a 50% relative reduction in LDL-C provides the best benefit in terms of CVD reduction.15”

The risk of major coronary events was reduced by 23% and the risk of stroke by 17% per mmol/L (40 mg/dL) LDL-cholesterol reduction.

“The risk for major coronary events was reduced by 23% and the risk for stroke was reduced by 17% per mmol/L (40 mg/dL) LDL-C reduction.”

In controlled trials, statins are generally well tolerated, and serious adverse events are uncommon.

“Statins are generally well tolerated, and serious adverse events are rare.”

Current evidence suggests that the clinical benefit of statins is largely independent of the type of statin and depends on the extent of LDL-cholesterol lowering.

“Current available evidence suggests that the clinical benefit is largely independent of the type of statin but depends on the extent of LDL-C lowering”

Large-scale clinical trials have shown that statins substantially reduce cardiovascular morbidity and mortality in both primary and secondary prevention.

“A number of large-scale clinical trials have demonstrated that statins substantially reduce CV morbidity and mortality in both primary and secondary prevention.15 -17”

Information on episodes of increased liver enzymes was not examined in this meta-analysis.

“Information on episodes of increased liver enzymes was not examined in this meta-analysis.”

There was no increased risk for any specific non-cardiovascular cause of death, including cancer, among those receiving statins.

“There was no increased risk for any specific non-CV cause of death, including cancer, in those receiving statins.”

The excess risk of rhabdomyolysis with statins was small and not significant.

“The excess risk of rhabdomyolysis with statins was small and not significant.”

The benefits of statins were significant within the first year but were greater in subsequent years.

“The benefits were significant within the first year, but were greater in subsequent years.”

Proportional reductions in major cardiovascular event rates per LDL-cholesterol reduction were very similar across all subgroups examined.

“The proportional reductions in major CV event rates per mmol/L (mg/dL) LDL-C reduction were very similar in all of the subgroups examined.”

In the CTT meta-analysis of more than 170,000 participants in 26 randomized trials, a 10% proportional reduction in all-cause mortality and a 20% reduction in coronary artery disease death were reported per 1.0 mmol/L (40 mg/dL) LDL-cholesterol reduction.

“In the CTT meta-analyses of individual participant data from .170000 participants in 26 randomized trials of statins, 15 a 10% proportional reduction in all-cause mortality and 20% proportional reduction in CAD death per 1.0 mmol/L ( 40 mg/dL) LDL-C reduction is reported.”

Two meta-analyses found no major effects on total mortality and CAD events in women compared with men for primary prevention with different lipid-lowering treatments.

“Two meta-analyses have addressed the effects of different lipid-lowering treatments on primary prevention of CV events in women with a broad range of TC from normal to elevated, and concordantly found no major effects on total mortality and CAD events in women as opposed to men.15,163”

The CTT meta-analysis and a recent meta-analysis of primary prevention trials showed no significant differences in relative risk reduction between younger and older people.

“The CTT meta-analysis showed no significant differences in RRR between younger and older people, 15 and neither did a recent meta-analysis of primary prevention trials.16”

Older adults are a high-risk group likely to benefit substantially from lipid-lowering therapy to reduce CV morbidity and mortality.

“According to published data, elderly individuals are a high risk group who could benefit significantly from lipid-lowering therapy to reduce CV morbidity and mortality.15”

Multiple prospective clinical trials have shown good outcomes of lipid-lowering therapy in elderly patients with CAD, despite including few elderly participants.

“Despite including few elderly participants, multiple prospective clinical trials have shown good outcomes of lipid-lowering therapy in elderly patients with CAD. 15”

The most recent CTT meta-analysis indicates that the overall benefit of lipid-lowering therapy is similar in men and women.

“The most recent CTT meta-analysis, 15 however, indicates that the benefit overall is similar in men and women.”

Statin therapy lowers the 5-year incidence of major cardiovascular disease events by about 20% for each mmol/L reduction in LDL-C, regardless of starting LDL-C or other baseline characteristics.

“Statin therapy reduces the 5 year incidence of major CVD events by 20% per mmol/L reduction in LDL-C regardless of initial LDL-C or other baseline characteristics based on meta-analysis.15”

In type 2 diabetes, cholesterol-lowering therapy produces relative risk reduction similar to that in non-diabetic patients.

“The CTT meta-analysis further indicates that subjects with type 2 diabetes will benefit from cholesterol-lowering therapy in RRR to a similar degree as non-diabetic patients”

In people with type 2 diabetes, statin therapy significantly reduces cardiovascular disease events.

“Trials specifically performed in subjects with type 2 diabetes as well as subsets of individuals with diabetes in major statin trials have consistently demonstrated significant benefits of statin therapy on CVD events in people with type 2 diabetes.15”

Lowering LDL cholesterol to 1.8 mmol/L or less is associated with the lowest risk of recurrent CVD events in secondary prevention populations.

“More recently trials have confirmed that lowering LDL cholesterol to ≤1.8 mmol/L ( 70 mg/dL) is associated with the lowest risk of recurrent CVD events in secondary prevention populations.459”

These trials are consistent in showing that the higher the initial LDL-C level, the greater the absolute reduction in risk, while the relative risk reduction remains constant at any given baseline LDL-C level.

“These trials are consistent in showing that the higher the initial LDL-C level, the greater the absolute reduction in risk, while the relative risk reduction remains constant at any given baseline LDL-C level.”

This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels.

“This graded approach is based on evidence from multiple meta-analyses and individual RCTs, which show a consistent and graded reduction in CVD risk in response to reductions in TC and LDL-C levels. 61-71”

The benefits of statins were similar in all subgroups examined.

“The benefits were similar in all subgroups examined.”

A 10% proportional reduction in all-cause mortality and a 20% proportional reduction in coronary artery disease death per 1.0 mmol/L (40 mg/dL) LDL cholesterol reduction was reported.

“A 10% proportional reduction in allcause mortality and 20% proportional reduction in CAD death per 1.0 mmol/L (40 mg/dL) LDL-C reduction was reported.”

In the Cholesterol Treatment Trialists analysis, more than 170,000 participants and 26 randomized controlled trials with statins were included.

“In the large Cholesterol Treatment Trialists (CTT) analysis data, . 170 000 participants and 26 RCTs with statins were included. 64”

There was no increased risk for any non-cardiovascular cause of death, including cancer, in those receiving statins.

“There was no increased risk for any non-CV cause of death, including cancer, in those receiving statins.”

The benefits of statins were significant within the first year but were greater in subsequent years.

“The benefits were significant within the first year, but were greater in subsequent years.”

Statin therapy reduces the 5-year incidence of major CVD events by 23% per 1 mmol/L reduction in LDL-C, regardless of initial LDL-C or other baseline characteristics, based on meta-analysis.

“Statin therapy reduces the 5-year incidence of major CVD events by 23% per 1 mmol/L reduction in LDL-C, regardless of the initial LDL-C or other baseline characteristics based on meta-analysis. 64”

Trials specifically in T2DM and diabetes subsets of major statin trials consistently show significant benefits of statin therapy on CVD events.

“Trials specifically performed in subjects with T2DM as well as subsets of individuals with diabetes in major statin trials have consistently demonstrated significant benefits of statin therapy on CVD events in people with T2DM. 64”

In a CTT meta-analysis, statin rate ratios for major vascular events were 0.78 in age younger than 65, 0.78 in 65-75, and 0.84 in older than 75.

“rate ratios for the effects of statins on major vascular events were 0.78, 0.78 and 0.84 in age groups , 65, 6575 and . 75 years, respectively. 64”

The CTT meta-analysis indicates that people with T2DM have a relative risk reduction comparable to non-diabetic patients, but because they are at higher absolute risk, their absolute benefit is greater and NNT is lower.

“The CTT meta-analysis further indicates that subjects with T2DM will have a relative risk reduction that is comparable to that seen in non-diabetic patients, but being at higher absolute risk, the absolute benefit will be greater, resulting in a lower number needed to treat (NNT).”

For every 1 mmol/L reduction of LDL-C, cardiovascular events are reduced by approximately 20%.

“for every 1 mmol/L reduction of LDL-C (~ 40 mg/dL), cardiovascular (CV) events are reduced by approximately 20% [5].”

The benefits of statins were similar in all subgroups examined.

“The benefits were similar in all subgroups examined.”

Per 1 mmol/L (40 mg/dL) LDL cholesterol reduction, the risk of major coronary events is reduced by 23% and the risk of stroke by 17%.

“The risk of major coronary events was reduced by 23% and the risk of stroke was reduced by 17% per 1 mmol/L (40 mg/dL) LDL-C reduction.”

Per 1.0 mmol/L (40 mg/dL) LDL cholesterol reduction, all-cause mortality is reduced by 10% and coronary artery disease death by 20%.

“A 10% proportional reduction in all-cause mortality and 20% proportional reduction in CAD death per 1.0 mmol/L (40 mg/dL) LDL-C reduction was reported.”

The Cholesterol Treatment Trialists analysis included more than 170,000 participants and 26 randomized controlled trials with statins.

“In the large Cholesterol Treatment Trialists (CTT) analysis data, >170 000 participants and 26 RCTs with statins were included.64”

The benefits of statins were significant within the first year but were greater in subsequent years.

“The benefits were significant within the first year, but were greater in subsequent years.”

There was no increased risk for any non-cardiovascular cause of death, including cancer, in those receiving statins.

“There was no increased risk for any non-CV cause of death, including cancer, in those receiving statins.”

In a CTT meta-analysis, rate ratios for the effects of statins on major vascular events were 0.78, 0.78, and 0.84 in age groups younger than 65, 65-75, and older than 75 years, respectively.

“In a CTT meta-analysis, rate ratios for the effects of statins on major vascular events were 0.78, 0.78 and 0.84 in age groups <65, 65e75 and >75 years, respectively.64”

Statin therapy reduces the 5-year incidence of major cardiovascular disease events by 23% per 1 mmol/L reduction in LDL-C, regardless of initial LDL-C or other baseline characteristics.

“Statin therapy reduces the 5-year incidence of major CVD events by 23% per 1 mmol/L reduction in LDL-C, regardless of the initial LDL-C or other baseline characteristics based on meta-analysis.64”

Statin therapy in adults at high cardiovascular risk due to LDL-C or other risk factors, including arterial hypertension, as well as in established cardiovascular disease, reduces the risk of ischaemic stroke or transient ischaemic attack.

“The use of statin therapy in adults at high risk of CVD due to LDL-C or other CV risk factors, including arterial hypertension, as well as in the setting of established CVD, reduces the risk of ischaemic stroke or TIA.64,69,128,330,422e426”

Risk reduction for a first ischaemic stroke is 21% per 1.0 mmol/L LDL-C reduction.

“Risk reduction for a first ischaemic stroke is 21% per 1.0 mmol/L LDL-C reduction, 64”

More intensive lipid lowering with statins is associated with a lower risk of stroke compared with less intensive regimens.

“More intensive lipid lowering with statins is associated with a lower risk of stroke compared with less intensive regimens.64,65,128,422”

Lowering serum cholesterol can reduce the risk of coronary heart disease.

“Lowering serum cholesterol can help reduce the risk of coronary heart disease (CHD).”

Statin therapy is the primary treatment for LDL-C reduction in current US and European guidelines because of strong evidence of reduced safety, efficacy and events.

“Statin therapy has been appropriately emphasized in the current US and European guidelines as the primary treatment for LDL-C reduction because of strong evidence of reduced safety, efficacy and events [8, 9].”

Patients treated with statin versus placebo, or with higher- versus lower-intensity statin therapy, experienced significantly greater ASCVD risk reduction with minimal serious adverse event rates, typically similar to the adverse event rates in placebo comparator groups.

“Patients treated with statin versus placebo, or with higher-versus lower-intensity statin therapy, experienced significantly greater ASCVD risk reduction with minimal serious adverse event rates, typically similar to the adverse event rates in placebo comparator groups (6).”