The Higher the LDL, the Bigger the Mortality Benefit of Intensive Therapy: Meta-analysis

Intensive LDL cholesterol-lowering therapy reduces the risk of all-cause and cardiovascular mortality when compared with less intensive therapy, but the mortality benefit varies by baseline LDL cholesterol levels, according to the results of a new meta-analysis.

In fact, the mortality benefit with intensive therapy was only observed amongst patients with baseline LDL cholesterol levels 100 mg/dL or greater, suggesting the biggest benefit of adding ezetimibe or one of the two commercially available PCSK9 inhibitors may be in those with higher LDL cholesterol levels.

“The study really supports an LDL threshold approach,” one of the senior investigators, Jennifer Robinson, MD (University of Iowa, Iowa City), told TCTMD. “If somebody’s LDL cholesterol is over a certain level, say maybe 100 mg/dL, it might make sense to spend a little bit more energy, such as adding a PCSK9 inhibitor. But I also think our paper suggests that a ‘titration to goal’ approach is not the best way to do things. Everybody’s LDL cholesterol shouldn’t be less than 70, or less than 50, or less than 30, as some groups have advocated. We have to look at the incremental benefit from therapy.”

If you really want the bang for the buck, let’s focus on treating people whose LDL levels are higher. Jennifer Robinson

Seth Martin, MD (Johns Hopkins Medical Center, Baltimore, MD), who was not involved in the study, adopted a cautious take when asked about using 100 mg/dL as a potential “floor” for making treatment decisions, as did Ann Marie Navar, MD, PhD, and Eric Peterson, MD (both from Duke University Medical Center, Durham, NC), who wrote an editorial accompanying the study.

All three were particularly concerned about the use of trial-level rather than patient-level data, which may have confounded the meta-analysis’ results.

In modern cardiology practice, we do a pretty incredible job keeping people alive. Seth Martin

“There is a need for more rigorous, patient-level data to really get at this question,” Martin told TCTMD. “The interpretation has been centered on baseline LDL levels from the trials, but there’s also a lot of differences in the studies, such as who got in, when they were conducted, how long they lasted, and so on.”

Moreover, Martin said physicians don’t treat patients simply to reduce mortality, but to reduce the risk of other cardiovascular events as well. “In modern cardiology practice, we do a pretty incredible job keeping people alive,” he said. “When it comes to preventive cardiology, it’s not just about death, it’s about preventing events. While the study is provocative, and I think it’s hypothesis-generating and could be more formally tested in a patient-level analysis, I personally wouldn’t change my approach to patients based on the results.” 

Extensive Range of Clinical Trials

Published April 17, 2018, in the Journal of the American Medical Association, the meta-analysis included 34 randomized clinical trials of statins, ezetimibe, and the PCSK9 inhibitors alirocumab (Praluent, Regeneron/Sanofi) and evolocumab (Repatha, Amgen). Of these, eight studies were primary-prevention trials, 16 were performed in secondary prevention, and 10 included both primary- and secondary-prevention patients.  

The studies ranged from the 4S and WOSCOPS trials, published more than two decades ago, to FOURIER, a cardiovascular outcomes study testing evolocumab published in 2017. Other studies included IMPROVE-IT with ezetimibe, SPIRE-1/SPIRE-2 with the now discontinued bococizumab, and several older trials testing intensive statin therapy, such as PROVE-IT, TNT, IDEAL, and SEARCH.

To TCTMD, Robinson said consistent evidence has shown that statins reduce cardiovascular events, and that further lowering LDL cholesterol levels by intensifying statin therapy, adding ezetimibe, or adding a PCSK9 inhibitor provides an incremental reduction in cardiovascular risk. The effect on mortality is less clear, however.

For example, the FOURIER trial with evolocumab did not show evidence of a mortality benefit, although treating ACS patients with alirocumab in the ODYSSEY Outcomes trial reduced the risk of all-cause mortality by 15% (ODYSSEY Outcomes has not yet been published and was not included in the meta-analysis). Other smaller PCSK9 inhibitor studies, such as OSLER and ODYSSEY Long-Term, have both hinted at reductions in cardiovascular mortality, but these two trials included patients with much higher base LDL levels (and were not powered for hard endpoints).   

“I think there’s a lot of evidence to suggest something different might be happening in people with lower LDL cholesterol levels on treatment,” said Robinson.

In the meta-analysis, 136,299 patients received more intensive LDL cholesterol-lowering therapy and 133,989 received less intensive treatment. All-cause mortality was modestly lower among patients treated with more intensive LDL cholesterol-lowering treatment (7.08% vs 7.70%; RR 0.92; 95% CI 0.88-0.96). Similarly, cardiovascular mortality was also lower amongst those treated more intensively (3.48% vs 4.07%; RR 0.84; 95% CI 0.79-0.89). 

In a meta-regression analysis, more intensive LDL cholesterol-lowering was associated with greater reductions in all-cause and cardiovascular mortality with higher baseline LDL cholesterol levels. There was a 9% and 14% lower risk of all-cause and cardiovascular mortality, respectively, per 40-mg/dL increase in baseline LDL cholesterol levels, report investigators.

I think there’s a lot of evidence to suggest something different might be happening in people with lower LDL cholesterol levels on treatment. Jennifer Robinson

However, the all-cause and cardiovascular mortality benefit of more intensive LDL cholesterol-lowering was only evident when baseline LDL cholesterol levels were 100 mg/dL or greater (P < 0.001 for interaction).

“There is actually a greater risk reduction with higher baseline LDL cholesterol levels, which I think is really important because it tells us that cholesterol-lowering therapies are better when people have high cholesterol,” said Robinson. “LDL-lowering drugs reduce risk, even in the FOURIER trial, and that’s important in very high-risk people. It makes some sense to provide incremental risk reduction on top of high-intensity statin, but if you really want the bang for the buck, let’s focus on treating people whose LDL levels are higher.”

Limiting Additional Therapy Based on LDL Thresholds

Given the costs of the lipid-lowering agents—even ezetimibe, although generic, still isn’t cheap—using an LDL threshold, as well as an assessment of cardiovascular risk, for deciding when to give additional drugs atop maximally tolerated statins might be one way to guide treatment, said Robinson. All patients should receive a high-intensity statin, if they can tolerate it, then physicians can check LDL cholesterol levels to determine if more is warranted.

“We need to really think in a more sophisticated way about the risk of the patient and their LDL cholesterol level,” said Robinson. “[PCSK9 inhibitors] are expensive and they’re worth using, but payers have said they’re not going to pay for them for everybody. So how do we identify those who would gain high value from therapy?”

In the editorial, Navar and Peterson state that clinicians should consider not only a patient’s initial LDL cholesterol level but their overall risk profile. “Multiple factors beyond LDL cholesterol affect risk of downstream events including age, blood pressure, diabetes, and extent of vascular disease,” they write. “Thus, patients with high overall CVD risk may achieve large absolute risk reductions, even if their potential relative risk reduction with therapy is blunted by lower starting LDL cholesterol levels.”

Martin agreed, telling TCTMD that FOURIER analyses have started to emerge identifying higher-risk subgroups more likely to benefit from evolocumab, such as the peripheral arterial disease population. Additionally, patient willingness is also a major factor when deciding on additional therapy, with some patients more motivated than others to take more medications.