Dr. Steve Nissen
SAN DIEGO, Calif. – A new analysis of a large trial of a novel lipid-lowering agent shows a particularly significant reduction in cardiovascular events in the primary prevention population enrolled in the study, of which two-thirds He also had a cardiovascular event. type 2 diabetesleading to calls for more attention to this group of patients.
Main results of the CLEAR Outcomes trial of bempedoic acid (Nekretol, Esperion) in a mixed secondary and primary prevention population of statin intolerance. report At the American College of Cardiology/World College of Cardiology 2023 Conference, a 13% relative risk reduction was demonstrated for the primary co-primary endpoint of cardiovascular death. myocardial infarction (MI), strokeor coronary revascularization.
This new analysis of 4,206 high-risk primary prevention patients in the study (67% of whom also had type 2 diabetes) showed a 30% reduction in relative risk for the same endpoint. rice field.
Similar or greater reductions were seen in other key endpoints, with a 36% relative risk reduction for cardiovascular death/stroke/myocardial infarction combined and a 39% relative risk reduction for cardiovascular death and myocardial infarction alone. was shown.
“These results are frankly surprising,” said lead investigator Dr. Steve Nissen. Medscape Medical News.
“These are really significant reductions. These results show that despite the fact that high-risk primary prevention patients have lower absolute event rates than secondary prevention patients, lipid-lowering therapy results in a relative reduction in major cardiovascular events. It shows that risk can be reduced very impressively,” he said.
But Nissen, chief academic officer of the Cardiovascular and Thoracic Institute at the Cleveland Clinic in Ohio, said this patient population is underserved.
“This is the problem. Less than half of high-risk primary prevention patients, not only in the United States, but in nearly every other developed country, are on cholesterol-lowering drugs. These patients tend to be ignored,” he said. emphasized.
When asked what advice he would give clinicians based on the current findings, Nissen said, “Patients, especially those at high risk of developing cardiovascular disease, should [type 2] If you have diabetes, you should take lipid-lowering drugs. ”
“If patients can tolerate statins, they should be the first choice. We know they work and they are cheap now. “These classes work by very similar mechanisms. The bottom line is that these patients just need to be treated,” he said.
“morning Call”
He said these new results “are a wake-up call to the medical community that they need to pay more attention to high-risk primary prevention patients.”
Nissen does not believe the effect is unique to bempedoic acid. Rather, it is more likely to be the effect of decline. low density lipoprotein cholesterol (LDL-C) level.
“This message is not specifically about bempedoic acid. Similar results have been seen in historical studies on statins, but they seem to be forgotten. It’s about lowering LDL in patients with high blood pressure.” Patients at high risk for a first cardiac event should be identified and given cholesterol-lowering drugs, but in most cases it will be a statin. “
Nissen presented a new analysis of the CLEAR OUTCOMES study at the American Diabetes Association’s (ADA) 83rd Scientific Session on June 24. publish online in the Journal of the American Medical Association (JAMA).
He noted that there have been no large clinical trials of lipid-lowering therapy in primary prevention populations for many years.
“All modern trials with lipid-lowering therapies are in secondary prevention patients only and often enroll post-treatment patients. acute coronary syndrome event.
“However, the CLEAR OUTCOMES trial included a significant amount of primary prevention patients, those with risk factors such as: [type 2] diabetes and high blood pressure People who are considered at high risk for developing cardiovascular disease,” he explained.
CLEAR OUTCOMES was a masked, randomized trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 patients with cardiovascular risk factors but no history of cardiovascular events (primary prevention group). These participants had a mean age of 68 years, 67% had diabetes, and 59% were female.
Treatment with bempedoic acid resulted in a 22% reduction in LDL-C compared to placebo, a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels also decreased by 0.56 mg/L (21.5%) from a median baseline of 2.4 mg/L.
Nissen said at a press conference at the ADA conference that he believes “a combination of lower LDL and lower CRP could have been a contributing factor.” [for the effects we saw in the trial]. Indeed, bempedoic acid lowers both. “
and he pointed out that Recent US Approvals new low dose Colchicine Widely indicated for use at 0.5 mg (Lodoco, Agepha Pharma) atherosclerotic cardiovascular disease (ASCVD) is an entirely new therapeutic approach that specifically targets the inflammation that causes inflammation. atherosclerosis.
Although bempedoic acid is a prodrug that works by the same pathway as statins, it does not cause muscle soreness, making many people intolerant to statins.bempedoic acid is first approved Approved by the U.S. Food and Drug Administration for the treatment of heterozygous adults in 2020 familial hypercholesterolemia or if ASCVD requiring additional LDL-C lowering is established.
What are the benefits of primary prevention?
In this primary prevention arm, 40 months of treatment with bempedoic acid occurred in 5.3% of the treatment arm for the primary endpoint (composite of cardiovascular death, non-fatal MI, non-fatal stroke, or coronary revascularization) was associated with a significantly reduced risk of 7.6% versus placebo (adjusted hazard ratio (HR), 0.70; P. = .002). This represents a 30% relative risk reduction in major cardiovascular events.
Other key secondary endpoints also showed significant declines.
The composite endpoint rate of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% in the bempedoic acid group (HR, 0.64; P. < .001); MI occurred in 2.2% vs. 1.4% (HR, 0.61), cardiovascular death in 3.1% vs. 1.8% (HR, 0.61), and all-cause mortality in 5.2% vs. 3.6% (HR, 0.73), respectively. bottom.
Side effects with bempedoic acid included a high incidence of: gout (2.6% vs. 2.0%), cholelithiasis (2.5% vs 1.1%), increased serum creatinineuric acid, liver enzyme levels.
Nissen believes that these results suggest that high-risk primary prevention patients may benefit more from lipid-lowering than secondary prevention patients.
“It may seem paradoxical, but there is history that it might be,” he said.
At the JUPITER trial, he Rosuvastatin The last major primary prevention trial of lipid-lowering agents in 2008 was stopped early 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 idea that the absolute risk reduction is very small.
“However, the analysis found an absolute risk reduction of 2.3% for the primary endpoint, which is the number needed to treat to prevent 1 in 43 events. That’s pretty good. It is,” he commented.
Trying to explain why more benefit is seen in the primary prevention population, Nissen suggested that these patients may have more vulnerable plaque.
“I think high-risk primary prevention patients probably have a lot of lipid-rich plaque. Some people call it ‘vulnerable’ plaque. We know that treatment with cholesterol-lowering drugs causes these plaques: the lipid core is delipidated, stabilizing the plaques,” he explained.
“In secondary prevention patients, to some extent, the horse may already be out of the barn and have advanced disease. There is likely to be.”
He admitted that the idea was just speculation. “But that’s a potential explanation for our observations.”
editorial cautious
and Accompanying editorialAlso posted on JAMADr. Durb S. Kazi of Beth Israel Deaconess Medical Center in Boston, Massachusetts, cautioned that the results came from one of many subgroup analyzes in a large trial. says it needs to be interpreted.
Professor Kaji also noted that the intervention and control survival curves separated immediately on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to emerge somewhat later. there is This supports the claim that it was an accidental discovery.
Kaji also cautioned clinicians that bempedoic acid should not be considered an alternative to statins and should remain a first-line therapy for primary prevention.
“The available evidence to date suggests that although bempedoic acid is not a complete replacement for statins, it may be a reasonable treatment option for the primary prevention of ASCVD events in high-risk, statin-intolerant patients. There are,” he concludes.
ADA 2023. Announced June 24, 2023.
jam. Published online on June 24, 203. full text, editorial
Follow us for more diabetes and endocrinology news. twitter and Facebook.
