Meta-analysis: Intensive lipid lowering only beneficial at higher LDL levels
Intensive lipid-lowering therapy significantly reduces all-cause and cardiovascular mortality—but only for patients with low-density lipoprotein cholesterol (LDL-C) levels above 100 mg/dL, according to a meta-analysis published April 17 in JAMA.
This finding may help explain why some recent lipid-lowering trials that enrolled patients with lower LDL-C levels weren’t able to show a significant mortality benefit, wrote lead author Eliano P. Navarese, MD, PhD, and colleagues.
The researchers pooled data from 34 randomized clinical trials including more than 270,000 participants. The trials included the uses of statins, ezetimibe and PCSK9 inhibitors—sometimes in combination with each other—and were evaluated as more intensive (most potent pharmacological arm) and less intensive (control group).
More intensive lipid-lowering was associated with a 9 percent reduction in total mortality for each 40 mg/dL increase in LDL-C at baseline. However, this relationship was no longer present when baseline LDL levels dipped below 100. Cardiovascular mortality dropped by an additional 14 percent with intensive therapy for each 40 mg/dL increase in LDL, but that effect also only existed when baseline levels were above 100.
“If additional LDL-C–lowering therapies are considered in statin-treated patients, nonstatin LDL-C–lowering therapies shown to reduce cardiovascular disease events are recommended,” Navarese and coauthors wrote. “This analysis further supports individualizing estimates of the potential for a cardiovascular risk reduction benefit from LDL-C–lowering therapy based on consideration of not only a patient’s absolute risk and current LDL-C level but also an individualized estimate of the risk reduction based on current LDL-C level and the outcomes desired.”
The researchers also noted progressively higher LDL levels were associated with greater risk reductions for myocardial infarction and revascularization, but not for stroke. They suggested the equitable stroke outcomes for intensive versus less-intensive therapy may be due to a see-saw relationship between ischemic and hemorrhagic strokes.
“It could be hypothesized that a greater reduction in risk of ischemic stroke might be counterbalanced by an increase in hemorrhagic stroke with increasing magnitude of LDL-C lowering,” they wrote. “Although consistent reductions in ischemic stroke risk of 21 percent were found in a sensitivity analysis, too few trials reported hemorrhagic stroke rates for a definite conclusion.”
In a related editorial, two Duke University researchers described the meta-analysis as “quite provocative” and potentially game-changing for clinical practice.
“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,” wrote Ann Marie Navar, MD, PhD, and Eric D. Peterson, MD, MPH.
But applying these findings to individual patients is precisely the problem with meta-analyses, the editorialists said. Different trials included used separate treatments and potencies, had various follow-up durations, definitions of clinical events and patient adherence to medications, and may have had drug therapy titrated to different targets. Also, the mortality rates of the earliest trials—from two decades ago—were higher than those of more recent ones, likely because secondary prevention and treatments for heart attacks and other conditions have improved drastically over the past 20-plus years.
“Moving forward, an updated individual-participant analysis of all the major lipid-lowering trials would help determine whether the association between baseline LDL-C level and the benefits of lipid lowering represents a true biological phenomenon or is an artifact of the ecology of the trials,” Navar and Peterson wrote.
Daniel joined TriMed’s Chicago editorial team in 2017 as a Cardiovascular Business writer. He previously worked as a writer for daily newspapers in North Dakota and Indiana.