Lower Is Better for LDL Even at Very Low Levels: New Meta-Analysis

November 09, 2010

November 9, 2010 (Oxford, United Kingdom and Sydney, Australia) — Further reductions in low-density lipoprotein (LDL) cholesterol with more intensive statin regimens safely produce definite further reductions in vascular events, even down to very low LDL levels, lower than current targets, results of two new meta-analyses show [1]. There was no evidence of any lower threshold where the benefit is not seen.

The two meta-analyses, published online in the Lancet today, were conducted by the Cholesterol Treatment Trialists' (CTT) Collaboration, which includes researchers from both University of Oxford, UK, and the National Health and Medical Research Council Clinical Trials Centre (CTC) at the University of Sydney, Australia.

Beneficial Right Down to 1.3 mmol/L (50 mg/dL)

Lead author of the studies, Dr Colin Baigent (University of Oxford), told heartwire that these results "added substantially" to current knowledge in showing that reducing LDL well below current targets is beneficial. "By combining individual patient data from all the statin studies, we have a large group of people who started at the current LDL target level of 1.8 mmol/L (70 mg/dL) and got down to levels of around 1.3 mmol/L (around 50 mg/dL), and this group also showed a definite reduction in vascular events. This has not been shown before."

He noted, however, that these figures applied to patients at high risk of cardiovascular disease. "I would say anyone with a risk of cardiovascular disease greater than 2% per annum should be lowering their LDL as much as possible. This will give them massive benefits, without any hazard. The relative risk reductions will also probably be there in lower-risk patients, but the absolute risk will be much smaller, so we are not advocating that as a public-health strategy in low-risk groups."

The researchers conclude: "Each 1-mmol/L LDL cholesterol reduction reduces the risk of occlusive vascular events by about a fifth, irrespective of baseline cholesterol concentration, which implies that a 2- to 3-mmol/L reduction would reduce risk by about 40% to 50%. These findings suggest that the primary goal for patients at high risk of occlusive vascular events should be to achieve the largest LDL-cholesterol reduction possible without materially increasing myopathy risk."

They add that in contrast to current therapeutic guidelines, which tend to emphasize particular LDL-cholesterol targets, these new results suggest that lowering of LDL cholesterol further in high-risk patients who achieve such targets would produce additional benefits, without an increased risk of cancer or nonvascular mortality.

They also suggest that rather than using 80 mg of generic simvastatin to achieve these benefits, the more potent statins such as 80-mg atorvastatin or 20-mg rosuvastatin may be a better approach to avoid myopathy.

Commenting on the meta-analysis for heart wire , Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) said: "I agree in general that lower is better and that simvastatin 80 mg is not as good a choice as atorvastatin 80 mg or rosuvastatin 20 mg, which have better safety profiles and greater efficacy."

Data From a Total of 170 000 Patients

The first meta-analysis combined individual patient data from five trials of more vs less intensive statin therapy. Overall, among the 39 612 participants, mean baseline LDL was 2.53 mmol/L. During the 5.1-year mean follow-up, first major vascular events (coronary death, myocardial infarction [MI], coronary revascularization, or stroke) occurred at a rate of in 4.5% per annum in the more intensive treatment group vs 5.3% per annum in those allocated to less intensive therapy, a highly significant further proportional risk reduction of 15% per year with an LDL reduction of 0.51 mmol/L. This corresponds to a mean risk reduction of 28% per 1.0-mmol reduction in LDL.

For the second analysis, the researchers updated a previous meta-analysis with individual patient data from new trials, with a total of 21 trials of statin vs control involving 129 526 patients. In this analysis, mean baseline LDL cholesterol was 3.70 mmol/L. After a mean follow-up of 4.8 years, results showed a rate of first major vascular events of 2.8% per annum in the statin patients vs 3.6% per annum in the control patients, corresponding to a highly significant 22% risk reduction per year with a 1.07-mmol/L LDL reduction. This corresponds to a mean 21% risk reduction per 1.0-mmol/L reduction in LDL.

After differences in the absolute reductions in LDL cholesterol were accounted for, the proportional reduction in the incidence of major vascular events per mmol/L was slightly larger in the trials of more vs less intensive therapy than in those of statin vs control. Taking all 26 trials together, the risk reduction was 22%.

Question Over Hemorrhagic Stroke

There was no significant evidence in the meta-analysis of trials of more vs less intensive therapy that further lowering of LDL cholesterol produced any adverse effects, even in participants with baseline LDL cholesterol lower than 2.0 mmol/L, with no increase in nonvascular mortality or site-specific cancer incidence.

The one adverse effect that may be of concern with lower cholesterol level is hemorrhagic stroke. In the present meta-analyses, which included nearly 500 confirmed hemorrhagic strokes, lowering of LDL cholesterol with statin therapy was associated with a nonsignificant excess (257 vs 220; p=0.2). The authors point out that in two trials unavailable for this meta-analysis (SPARCL and CORONA), there were more hemorrhagic strokes in the statin group, and if these events were included in the meta-analysis then this would give a significant excess (hazard ratio 1.21; p=0.01) per 1.0-mmol/L LDL-cholesterol reduction. But they add that the size of the potential hazard would be about 50 times smaller (perhaps a few extra hemorrhagic strokes annually per 10 000 treated) than the definite absolute benefits (a few hundred occlusive events avoided annually per 10 000 treated) for patients who are at high risk of occlusive vascular events.

Numbers More Persuasive in Patients at High Cardiovascular Risk

In an accompanying editorial [2], Drs Bernard Cheung and Karen Lam (University of Hong Kong) note that as epidemiological data suggest that there is a log–linear association between cholesterol concentration and cardiovascular risk, with no flattening of the curve at low concentrations of cholesterol, and "therefore a tempting option is to decrease LDL-cholesterol concentration as much as possible."

But they point out that clinical benefit depends more on the absolute risk reduction or the number needed to treat than on relative risk reduction, and they conclude: "A low baseline LDL concentration is not a reason to withhold statin therapy if the patient is at a definite risk of cardiovascular events (eg, secondary prevention or diabetes). In this setting, the absolute risk reduction, number needed to treat, and risk/benefit and cost/benefit ratios are favorable. These numbers will be less persuasive for people at low cardiovascular risk, such as young people with no risk factors. At the population level, statins are underused, so the urgent priority is to identify people who would benefit most from statin therapy and to lower their LDL cholesterol aggressively, with the more potent statins if necessary."

SEARCH Lipid Arm Published

Also published along with the two meta-analyses is the lipid arm of the SEARCH trial, which was first presented at the 2008 American Heart Association meeting [3]. In this study, 2064 patients with a history of MI were randomized to either 80-mg or 20-mg simvastatin daily. Results showed that the more intensive lipid-lowering arm produced a further 0.35-mmol/L reduction in LDL cholesterol, which translated into a nonsignificant 6% proportional reduction in vascular events. These occurred in 24.5% of the 80-mg group vs 25.7% in the 20-mg group (risk ratio 0.94, 95% CI 0.88–1.01; p=0.10). Myopathy was increased with the 80-mg simvastatin dose. Compared with two (0.03%) cases of myopathy in patients taking 20-mg simvastatin daily, there were 53 (0.9%) cases in the 80-mg group. This is one of the five trials of more vs less intensive statin therapy included in the current meta-analysis.