“Striking” benefit of lipid reduction in primary prevention

Dr Steve Nissen

SAN DIEGO, CA – A new analysis of a large-scale trial of a new lipid-lowering agent showed a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had Type 2 diabetesleading to calls for more attention to be given to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed population of secondary and primary prevention intolerant to statins, reported at the 2023 American College of Cardiology/World Congress of Cardiology meeting, showed a 13% relative risk reduction in the primary primary endpoint, a composite of cardiovascular death, myocardial infarction (MID), strokeor coronary revascularization.

This new analysis of the study’s 4,206 high-risk primary prevention patients – 67% of whom also had type 2 diabetes – showed a relative risk reduction of 30% for the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the CV death/stroke/MI composite showing a 36% relative risk reduction and a 39% relative risk reduction for CV death and IMs individually.

“These results are frankly striking,” said lead investigator Steve Nissen, MD. Medscape Medical News.

“These are really large reductions. These results tell us that high-risk patients in primary prevention, although their absolute event rate is lower than patients in secondary prevention, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Nissen, who is academic director at the Heart Vascular & Thoracic Institute at Cleveland Clinic, Ohio, pointed out that this patient population is not well treated.

“That’s the problem: less than half of high-risk patients in primary prevention in the United States, and virtually all other developed countries, receive cholesterol-lowering drugs. These patients tend to be ignored,” he pointed out.

Asked what advice he would give to clinicians based on current findings, Nissen said, “If a patient is at high risk of developing cardiovascular disease, especially those who have [type 2] diabetes, they need to take a lipid-lowering drug.”

“If patients can tolerate a statin, that should be the first choice. We know statins work, and they’re now inexpensive. They’re likely to give exactly the same benefit that we’ve shown in this study with the acid, because the two drugs work by very similar mechanisms. But if patients cannot tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.

“wake up call”

He said these new findings are “a wake-up call to the medical community that we need to pay much more attention to high-risk patients in primary prevention.”

Nissen does not believe the effect is specific to bempedoic acid; it is more of a lowering effect low density lipoprotein cholesterol (LDL-C).

“This message is not about bempedoic acid specifically. We have seen similar results in historical studies with statins, but that seems to have been overlooked. The message is about lowering LDL in patients at high risk of having We need to identify patients at high risk for a first cardiac event and put them on a cholesterol-lowering drug – and in most cases that will be a statin.

Nissen presented the new analysis from the CLEAR OUTCOMES trial here at the American Diabetes Association (ADA) 83rd Scientific Session on June 24. published online in the Journal of the American Medical Association (JAMA).

He pointed out that large trials of lipid-lowering treatment in the primary prevention population have not been done for many years.

“All contemporary trials of lipid-lowering therapies have only included patients in secondary prevention and they often enroll patients after a acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant number of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a blinded, randomized trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of these patients with risk factors for heart disease but no previous cardiovascular event – the primary prevention group. The average age of these participants was 68, 67% had diabetes and 59% were women.

Bempedoic acid treatment showed a 22% reduction in LDL-C compared to placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), compared to a median baseline of 2.4 mg/L.

Nissen said in a press briefing at the ADA meeting that he believes “it’s the combination of lower LDL and lower CRP that could have been the driving force.” [for the effects we saw in the trial]. Certainly bempedoic acid lowers both.”

And he noted the recent US approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents an entirely new treatment approach, specifically targeting inflammation as a atherosclerosis.

Bempedoic acid is a prodrug that acts on the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the US Food and Drug Administration in 2020 for the treatment of heterozygous adults familial hypercholesterolemia or established ASCVD that require further LDL-C reduction.

More advantages in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant reduction in risk for the primary endpoint – a composite of cardiovascular death, non-fatal MI, non-fatal stroke. death or coronary revascularization – which occurred in 5.3% of the treatment group. versus 7.6% in the placebo group (adjusted relative risk (HR), 0.70; P = .002). This represents a 30% reduction in the relative risk of major cardiovascular events.

Other key secondary parameters also showed impressive reductions.

The composite endpoint rate of cardiovascular death, MI or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P <0.001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5, 2% versus 3.6% (HR, 0.73), respectively.

Adverse effects of bempedoic acid included a higher incidence of drop (2.6% versus 2.0%), cholelithiasis (2.5% vs. 1.1%) and increased serum concentration creatinineuric acid and liver enzymes.

Nissen believes that these results suggest that there may be a greater benefit of lipid reduction in high-risk patients in primary prevention than in the population in secondary prevention.

“It may sound paradoxical, but there’s actually some history that it may be the case,” he said.

He pointed out that the JUPITER trial of Rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering drug, which was stopped prematurely with a 44% reduction in the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 in 43 events. That’s pretty good,” said he commented.

Trying to explain why there might be more benefit in the primary prevention population, Nissen suggested that these patients might have more vulnerable plaques.

“I think high-risk patients in primary prevention probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. It’s softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering drugs cause these plaques. The lipid core is delipidated and the plaque stabilizes,” he explained.

“It may be that in secondary prevention patients, to some extent the horse is already out of the stable – they have advanced disease. But primary prevention patients may have plaques that are more likely to be modified by lowering cholesterol.

He admitted the idea was just speculation. “But it is a potential explanation for our observations.”

Prudent Editorial

In a accompanying editorialalso published in JAMADhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, says the results should be interpreted with caution because they come from one of several subgroup analyzes of a larger trial.

Kazi also points out that the survival curves of intervention and control separate immediately, on the first day of follow-up, when the true effect of lipid-lowering treatment for primary prevention would be expected to have some onset. bit delayed, an observation he says supports the argument that it is a chance finding.

Kazi also reminds clinicians that bempedoic acid should not be considered a substitute for statins, which should remain the first-line treatment in primary prevention.

“At this time, the available evidence suggests that although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for the primary prevention of ASCVD events in high-risk, drug-intolerant patients. statins,” he concludes.

ADA 2023. Presented June 24, 2023.

JAMA. Published online June 24, 203. Full Text, Editorial

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