Higher Initial LDL and CV Risk Seen to Magnify Expected LDL-Lowering Clinical Gains

April 20, 2018

The higher the levels of low-density-lipoprotein (LDL) cholesterol at the start of LDL-lowering therapy, the greater its survival benefit, a new meta-analysis demonstrates.

Conversely, it suggests, smaller clinical gains should be expected from initiating an LDL-lowering therapy when such levels are "normal" or slightly elevated by the usual standards, either naturally or after treatment.

In shared decision-making, the meta-analysis findings could inform expectations of patients and their physicians about likely gains from initiating LDL-lowering treatments, whether a new prescription or intensification of current treatment, Jennifer G Robinson, MD, MPH, University of Iowa, Iowa City, told theheart.org | Medscape Cardiology.

They also argue against a narrow focus on LDL "goals" as a main driver of LDL-lowering treatment because its potential benefit will vary from patient to patient depending on their risk profile.

For example, "If the LDL is really high and the risk is low, that person may have the same or more benefit as somebody whose risk is really high but their LDL is 72 mg/dL," Robinson said.

She is corresponding author for the meta-analysis of 34 trials that pit a "more intensive" against a "less intensive" LDL-lowering intervention, published April 17 in JAMA with lead author Eliano P Navarese, MD, PhD, from the Inova Heart and Vascular Institute, Falls Church, Virginia.

More intensive treatment in the trials was compared with a control intervention and could be, for example, a standard-dose statin (vs placebo), a high-dose (vs low-dose) statin, or a statin plus a nonstatin LDL-lowering agent (vs the statin alone). Nonstatin agents included ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Throughout the meta-analysis, more intensive (compared with less intensive) treatment led to greater reductions in both all-cause and cardiovascular (CV) mortality when LDL cholesterol (LDL-C) at baseline was 100 mg/dL or higher, but not when it was lower.

More intensive treatment led to greater reductions in myocardial infarction (MI), revascularization procedures, and major adverse cardiac events (MACE) regardless of the initial LDL-C concentration.

The report's main argument, Robinson said, is against the use of LDL targets as the sole guide to therapy. It also questions the concept of routinely using multiple LDL-lowering agents, for example statins plus PCSK9 inhibitors, to achieve extremely low LDL levels.

"Titration to goals seems to be an idea whose time has passed. The focus needs to be, What's the potential for net benefit from therapy? That's based on the absolute risk of the patient, but also the LDL level and the relative-risk reduction from therapy."

"Always Start by Assessing Risk"

The current findings "are in some ways not surprising or new at all. They're simply saying that people who start the day not just at high risk, but at higher LDL, are going to get much more benefit from treatment than those who are high risk but have a much lower LDL," Neil J Stone, MD, Northwestern Feinberg School of Medicine, Chicago, Illinois, who was not involved in the research, said in an interview.

"And likewise, if one's LDL is above 100, and you're really at very low risk, that doesn't mean you should be on a statin. You always start by assessing their risk," he said.

Patients with LDL greater than 100 mg/dL who are at very high risk "are a group that will get a very strong benefit from LDL-lowering therapy, and that's probably good for doctors to be able to say to patients."

If anything, Stone said, the analysis provides encouragement for physicians to assess each patient individually for overall CV risk as well as LDL levels, and treat without undue reliance on specific LDL targets.

It provides doctors — given the patient's CV risk status, LDL-C, and current therapy — insight into "what their benefit could be if they increased the intensity of their therapy. I think that's really the take-home point, that patients should try to understand what the benefit is, if they're going to pursue more aggressive therapy."

A Message With Limitations

Stone, however, pointed to a prominent limitation of the meta-analysis: that its findings are based on trial-level rather than more granular patient-level data. That limitation was a focus of an accompanying editorial.

"If the authors' trial-level conclusions are confirmed to apply to individual patients, clinicians (and payers) may have a strong biological basis for limiting therapy and access to potent but costly lipid-lowering drugs such as PCSK9 inhibitors to patients with LDL-C levels above certain thresholds," write Ann Marie Navar, MD, PhD, and Eric D. Peterson, MD, MPH, from Duke University, Durham, North Carolina.

"However, because the individual-level data were not analyzed, the study cannot say definitively whether the observed treatment differences were attributable to effect modification by baseline LDL-C level or whether this association is confounded by other trial-related differences."

Such confounders likely include plunging mortality in ischemic heart disease due to treatment advances throughout the decades covered by the meta-analysis, they write. The included trials also varied in methods, end point definitions, follow-up times, and other ways.

Attempts to adjust for potential confounders were limited in being based on trial-level averages rather than patient-level data, Navar and Peterson note.

The meta-analysis does suggest, however, that "When selecting patients for more intensive lipid-lowering therapies, clinicians should consider both a patient's initial LDL-C level but also the patient's overall risk for CVD events," they write.

"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-C levels."

Fixed or Varying Clinical Benefits?

The current findings, Robinson and her colleagues note, to some extent question the applicability of a Cholesterol Treatment Trialists' Collaboration (CTT) meta-analysis in 2010 that famously saw a significant 22% decline in MACE risk for every 39-mg/dL (1-mmol/L) drop in baseline LDL-C.

That observation, according to the CTT authors, was true regardless of initial LDL levels and applied to achieved LDL levels below conventional targets.

In contrast, Robinson said in an interview, "We found that the risk reduction isn't fixed. It's less than 22% when baseline LDL levels are low and it's more than 22% when LDL levels are high."

Therefore, she and her colleagues write, the 22% reduction in MACE risk in the CTT analysis "may not be generalizable to populations with baseline LDL-C levels higher or lower than the mean LDL-C of 120 mg/dL in the meta-analysis, or to composite end points other than MACE."

On the other hand, the CTT meta-analysis included patients who were at increased CV risk, so its implications are likely different for those at lower risk.

"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," lead author, Colin Baigent, BM, BCh, University of Oxford, United Kingdom, told theheart.org | Medscape Cardiology at that time, in coverage of the earlier meta-analysis.

"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," Baigent said.

The meta-analysis from Robinson and colleagues looked at multicenter trials of lipid-lowering agents that randomly assigned 1000 or more patients who were treated for at least 48 weeks and followed by intention to treat. In the 34 trials, 136,299 patients received more intensive treatment and 133,989 were in the control groups receiving less intensive therapy or placebo.

Eight trials were in primary prevention, 16 were in secondary prevention, and 10 were in both settings, the report notes; the mean follow-up was 3.9 years.

Outcomes varied by LDL-C levels. In general, the greatest risk reductions for all-cause and CV mortality and other endpoints on more intensive therapy were in patients who started at an LDL-C of at least 160 mg/dL.

All-cause and CV mortality were significantly reduced in the more intensive therapy groups for all initial LDL concentrations down to 100 mg/dL, but not at lower LDL levels.

Risk reductions for MI, revascularization, and MACE with more intensive therapy were significant at all initial LDL levels.

Table. Rate Ratios for Outcomes: More Intensive vs Less Intensive Therapy by Initial LDL Levels in Meta-Analysis of Lipid-Lowering Trials

Endpoints LDL <100 mg/dL LDL 100 - 129 mg/dL LDL 130 - 159 mg/dL LDL ≥160 mg/dL Overall
All-cause mortality 1.00 (0.95 - 1.06) 0.88 (0.79 - 0.98) 0.91 (0.86 - 0.96) 0.72 (0.62 - 0.84) 0.92 (0.88 - 0.96)
CV mortality 0.99 (0.92 - 1.06) 0.81 (0.68 - 0.95) 0.82 (0.78 - 0.87) 0.65 (0.54 - 0.77) 0.84 (0.79 - 0.89)
MI 0.84 (0.76 - 0.92) 0.76 (0.65 - 0.88) 0.74 (0.69 - 0.80) 0.64 (0.53 - 0.78) 0.76 (0.72 - 0.80)
Ischemic stroke 0.81 (0.73 - 0.90) 0.72 (0.59 - 0.86) 0.80 (0.73 - 0.87) 0.57 (0.37 - 0.89) 0.79 (0.74 - 0.84)
Revascularization 0.85 (0.75 - 0.96) 0.79 (0.71 - 0.88) 0.78 (0.74 - 0.83) 0.64 (0.56 - 0.74) 0.78 (0.74 - 0.83)
MACE 0.90 (0.85 - 0.96) 0.78 (0.70 - 0.86) 0.80 (0.78 - 0.83) 0.70 (0.63 - 0.79) 0.81 (0.78 - 0.85)


"I think payers have told us that they're willing to spend only so much money on PCSK9 inhibitors, and I rather see them get the biggest bang for their buck," said Robinson.

This probably means, rather than using those agents routinely to push LDL down to a target level, focusing them on "ideally the very high-risk people with high LDL levels. Basically that's people with familial hypercholesterolemia or statin-intolerant patients with cardiovascular disease and other high-risk characteristics."

Her group's meta-analysis, she said, should help with that in providing guidance on which patients should receive costly treatments like the PCSK9 inhibitors.

Robinson discloses receiving research grants from Acasti, Amarin, Amgen, AstraZeneca, Esai, Esperion, Merck, Pfizer, Regeneron, Sanofi, and Takeda and receiving fees from Akcea/Ioinis, Dr Reddy Laboratories, Eli Lilly, Esperion, Pfizer, Regeneron, and Sanofi. Disclosures for the other authors are in the report. N avar discloses receiving grants and fees from Regeneron, Sanofi, and Amgen. Peterson discloses receiving grants and personal fees from Merck, AstraZeneca, Amgen, and Sanofi and a grant from Regeneron. Stone had no disclosures.

JAMA. Published online April 17, 2018. Abstract, Editorial

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