Starting Low and Going Lower: Some Benefit to Very Low LDL Levels

Further lowering LDL cholesterol in patients who have levels once considered ideal reduces the risk of major vascular events and does not appear to be associated with excess risk, according to results of a new meta-analysis.

For individuals with baseline LDL cholesterol levels of 70 mg/dL or less, lowering LDL cholesterol another 38.7 mg/dL, or approximately 1 mmol/L, results in a 21% reduction in major cardiovascular events, a relative reduction in line with that observed in the Cholesterol Treatment Trialists’ Collaboration (CTTC), where baseline LDL cholesterol levels were roughly twice as high.

Importantly, taking LDL cholesterol down further in these patients was not associated with increased risks of myalgia/myopathy, new-onset diabetes, hemorrhagic stroke, or cancer.  

“If we think back, the initial statin trials studied patients with elevated LDL cholesterol, patients in the 160 or 170 mg/dL range, and showed a benefit of lowering,” senior investigator Marc Sabatine, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “We and others have done trials studying patients with average LDL cholesterol and also showed a benefit. That has begged the question of how low should we go in terms of LDL cholesterol? And I think the answer is that you can’t be too low.”

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of cholesterol do not currently recommend a treatment target for LDL cholesterol, instead advising physicians to use moderate- or high-intensity statins based on patient risk. However, prior to the 2013 guidelines, the National Cholesterol Education Program recommended intensifying therapy in very high-risk patients if LDL cholesterol levels exceeded 70 mg/dL. The most recent European Society of Cardiology guidelines for the treatment of dyslipidemias retain treatment targets and recommend a goal of less than 70 mg/dL in very high-risk patients, consistent with recommendations from the National Lipid Association (NLA).

Start Low, Go Even Lower

The new analysis, published online August 1, 2018, ahead of print in JAMA Cardiology, includes a subset of patients in the CTTC starting with LDL cholesterol levels of less than 70 mg/dL (mean 65.7 mg/dL). Researchers also included three randomized, double-blind, placebo-controlled trials (IMPROVE-IT, FOURIER, and REVEAL) of LDL-cholesterol lowering with nonstatin therapy. All three studies were secondary prevention trials and tested ezetimibe, evolocumab (Repatha; Amgen), and the commercially abandoned anacetrapib, respectively.

The median LDL cholesterol levels in the control arms of IMPROVE-IT and REVEAL were 70 mg/dL and 63 mg/dL, respectively. In the present analysis, researchers included a subset of patients from the FOURIER trial in which the median baseline LDL cholesterol level was 66 mg/dL.

I think the answer is that you can’t be too low. Marc Sabatine

In the CTTC subset of patients with low starting LDL levels, each 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol with statin therapy resulted in a 22% reduction in major vascular events. Similar reductions in major vascular events also were observed in IMPROVE-IT, FOURIER, and REVEAL. Overall, treatment with statins and nonstatin therapy reduced the risk of major events 21% with each 1-mmol/L reduction in LDL cholesterol. The risks of coronary heart disease mortality, MI, and coronary revascularization were reduced 18%, 36%, and 21%, respectively, with each 1-mmol/L reduction in LDL cholesterol.    

“We found that whether it was with statin therapy, or adding ezetimibe or a PCSK9 inhibitor to a statin, all of them reduced vascular risk, even in these patients that started with low levels of LDL cholesterol,” said Sabatine. “The magnitude of benefit is entirely consistent with what has been seen in other trials. In older statin trials, there was about a 20% reduction in risk for each 1-mmol/L reduction in LDL cholesterol.”

The bottom line, said Sabatine, is that there doesn’t appear to be any attenuation in vascular benefit in patients with lower baseline LDL cholesterol levels treated with additional lipid-lowering therapies.

To TCTMD, Sabatine said that if a secondary-prevention patient presents with an LDL cholesterol of 65 mg/dL, there should be an attempt to further lower cholesterol given the benefits and absence of harm. He added that further reducing LDL cholesterol levels would apply across the board in the secondary-prevention setting. For example, there are no specific risk factors or patient characteristics that he would look for to determine if such an aggressive push might be warranted.

“If you had someone who smoked and smoked three packs per day and they got down to one pack per day, none of us would say, ‘Well, before we push them to get down even lower, do they really have enough risk factors to warrant this?’” said Sabatine. “We’d say, ‘Of course, let’s get them down.’”

Absolute Reduction in LDL Cholesterol an Important Factor

James Underberg, MD (NYU Langone Medical Center, New York, NY), who was not involved in the analysis, said the results showing that treating patients to very low LDL cholesterol levels is safe and effective aren’t surprising. Earlier this summer, Underberg published a review summarizing available evidence and concluded that very low LDL cholesterol levels are associated with a cardiovascular benefit. The benefit, however, was dependent on the patient’s risk profile and the absolute change in LDL cholesterol with pharmacologic therapy.

All other risk factors being equal, taking a patient from 200 to 100 mg/dL likely achieves a greater clinical benefit than lowering a patient’s LDL cholesterol from 100 to 50 mg/dL, he said. While both reduce LDL cholesterol 50% from baseline, the larger absolute risk reduction will translate into a larger reduction in cardiovascular events, said Underberg.

“It’s encouraging for us who treat patients at high risk and often do drive LDL cholesterol levels down with some of the newer medications,” said Underberg. “The important message is that lowering LDL beyond the lowest current targets is associated with further risk disease prevention and no offsetting safety risks. What it doesn’t mean, which is often misinterpreted, is that if somebody’s LDL cholesterol is 30 mg/dL, and you put them on a drug to make it 20 mg/dL, that has been shown to be beneficial.”

Underberg, a lipid specialist and past president of the NLA, said these data are good news for patients who need to be treated to lower goals than traditionally targeted, “but it’s important for practitioners to know that it doesn’t mean small changes at the low end of the scale might necessarily be worth using an [additional] drug.”

In clinic, if a patient has an LDL cholesterol level less than 70 mg/dL, and all other risk factors are treated adequately, Underberg said he might consider adding another agent. However, that’s “functioning outside the purview of the guidelines—it’s not something I would promote as standard care,” he said. “What this article tells us is that if LDL cholesterol is 73 mg/dL, and the patient has another event, and you drive the LDL cholesterol down to 20 mg/dL, that’s OK. You don’t need to worry about that.”

Stanley Hazen, MD, PhD (Cleveland Clinic, OH), told TCTMD they typically aim for lower than 70 mg/dL, often shooting to get some patients down to 40 or 50 mg/dL. He noted that up to 25% of patients in the trials testing PCSK9 inhibitors had subjects with LDL cholesterol levels less than 25 mg/dL.

“I think the economics of the situation are the major obstacle,” he said. “In general, broader and more widespread use of PCSK9 inhibitors on top of optimized tolerated statin therapy is supported by existing data for secondary prevention patients, and further reduction in LDL goals is reasonable. The number needed to treat becomes larger as the absolute risk becomes smaller so it becomes a cost-benefit decision. I personally think [PCSK9 inhibitors] should be available to a patient should they desire and have the means. I also wish the cost for PCSK9 inhibitor therapy were not so high.”  

In an editorial, Antonio Gotto, Jr, MD, DPhil (Weill Cornell Medicine, New York, NY), also finds the results encouraging, but notes it took 23 years before researchers and clinicians identified the association between statin use and risk of new-onset diabetes. As such, much longer follow-up will be needed with the PCSK9 inhibitors evolocumab and alirocumab (Praluent; Regeneron/Sanofi). The median follow-up in the ODYSSEY trial with alirocumab was just 2.8 years, while those treated with evolocumab in FOURIER were followed for 2.1 years.

That said, Gotto said he hopes the forthcoming update to the ACC/AHA cholesterol guidelines will provide some guidance on treatment targets rather than simply focusing on the intensity of treatment, particularly since some of the new agents are capable of lowering LDL cholesterol to levels that are as foreign to physicians as “travel to outer space.”