This article discusses the findings of the CLEAR Outcomes trial, which showed that bempedoic acid, a novel lipid-lowering medication, can significantly reduce the risk of major cardiovascular events in high-risk primary prevention patients, particularly those with type 2 diabetes.

The CLEAR outcomes trial

There have been calls for more focus on the primary prevention population who participated in a large-scale trial of a novel lipid-lowering agent and showed a particularly large reduction in cardiovascular events. About two-thirds of these participants also had type 2 diabetes.

At the American College of Cardiology/World Congress of Cardiology 2023 meeting, researchers reported the primary results of the CLEAR Outcomes trial of bempedoic acid in a mixed secondary and primary prevention population intolerant to statins.

1. It shows a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction (MI), stroke, or coronary revascularisation.
2. 30% relative risk reduction in the same endpoint was found in a new analysis of the study's 4,206 high-risk primary prevention participants, 67% of whom also had type 2 diabetes.
3. Relative risk was decreased by 36% for the combined endpoint of cardiovascular death, stroke, and myocardial infarction, and by 39% for cardiovascular death and MI separately.

These outcomes are quite astounding. These findings suggest that lipid-lowering medication may significantly reduce the relative risk of major cardiovascular events in high-risk primary prevention patients, despite the fact that their absolute risk of an incident is lower than that of secondary prevention patients.

Since the two groups of drugs function via very similar pathways, they are expected to provide the same benefit as we have demonstrated here with bempedoic acid. Bempedoic acid should be used instead of statins in people who cannot take them. The basic issue is that those individuals just must be treated.

Insights

1. These new findings serve as an urgent reminder to the medical community, indicating that we must pay significantly more attention to primary prevention patients with high risk.
2. A decrease in low-density lipoprotein cholesterol (LDL-C) levels is thought to be responsible for the observed benefit, rather than bempedoic acid per se.
3. Bempedoic acid is not the focus of this piece of writing. Statins have shown comparable results in the past, but this appears to have been forgotten.
4. In people at high risk for a first cardiovascular incident, the recommendation is to reduce LDL. Patients at high risk for a first cardiac attack should be identified and started on a medicine to decrease cholesterol, most likely statin.

Why this trial is important?

1. There haven't been any significant studies of lipid-lowering treatment in the community using primary prevention for a long time.
2. Only secondary prevention patients have been included in all current lipid-lowering treatment studies, and individuals are often added after an acute coronary syndrome incident.
3. However, investigators included a considerable number of primary prevention patients in the CLEAR OUTCOMES study, meaning individuals with risk factors like [type 2] diabetes and hypertension who are thought to be at high risk of developing cardiovascular disease.
4. 13,970 statin-intolerant individuals were included in the randomised, blinded CLEAR OUTCOMES study. The primary prevention group, which consisted of 4206 individuals with risk indicators for heart disease but no past cardiovascular incident, was included in the current research. These individuals had a mean age of 68, had a diabetes prevalence of 67%, and were 59% female.
5. When compared to placebo, bempedoic acid treatment reduced LDL-C by 22%, or 30.2 mg/dL, from a mean baseline of 142.5 mg/dL. From a median baseline of 2.4 mg/L, high-sensitivity C-reactive protein (CRP) levels were also decreased by 0.56 mg/L (21.5%).
6. The author thinks that the combination of decreased LDL and lower CRP may have been the cause. Undoubtedly, bempedoic acid reduces both.
7. Recent US clearance of a new low dosage of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a wide indication for use in atherosclerotic cardiovascular disease (ASCVD) is a fundamentally new strategy for treatment that focuses on inflammation as the primary cause of atherosclerosis.
8. Despite not causing muscular soreness, which is a common side effect of statins and renders many individuals sensitive to them, bempedoic acid is a prodrug that functions along the same routes. For the treatment of people with established ASCVD or heterozygous familial hypercholesterolemia who need further LDL-C reduction, bempedoic acid was initially licensed by the US Food and Drug Administration in 2020.

More gain from primary preventative measures?

1. The primary endpoint in this primary prevention group was a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularisation, which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio (HR), 0.70; P =.002). Treatment with bempedoic acid for 40 months was associated with a significant risk reduction for this endpoint. This translates into a relative risk decrease of 30% for significant cardiovascular events.
2. Impressive decreases were also seen in several important secondary endpoints. Bempedoic acid reduced the rate of the composite endpoint of cardiovascular death, MI, or stroke from 6.4% to 4.0% (HR, 0.64; P .001); MI occurred in 2.2% of cases versus 1.4% (HR, 0.61), cardiovascular death in 3.1% of cases versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% of cases versus 3.6% (HR, 0.73).
3. A greater incidence of gout (2.6% vs. 2.0%), cholelithiasis (2.5% vs. 1.1%), and elevations in blood creatinine, uric acid, and hepatic enzyme levels were some of the negative consequences of bempedoic acid.
4. According to the author, these findings imply that cholesterol reduction may help high-risk primary prevention patients more than the secondary prevention group.
5. The last significant primary prevention study of lipid-lowering medication, the JUPITER trial of rosuvastatin in 2008, was terminated early due to a 44% drop in the main outcome.
6. The notion that absolute risk reductions are very small is one of the reasons against the use of statins in primary prevention.
7. However, for the main endpoint of our investigation, we discovered an absolute risk decrease of 2.3%. To cure that many people would avert one out of every 43 events. That's very excellent.
8. Researchers proposed that these individuals may have more susceptible plaques in an effort to explain why there may be a greater effect in the primary prevention cohort. Patients who are at high risk for primary prevention often have a lot of lipid-rich plaque; some refer to this plaque as "vulnerable." These plaques are softer and high in cholesterol. We are aware that taking medicine to decrease cholesterol results in the plaques becoming smaller. The plaque stabilises when the lipid core is delipidated.
9. It's possible that secondary prevention patients' diseases have progressed to some level and that the horse has already left the stable. However, people who have undergone primary prevention may have plaques that are more susceptible to change by decreasing cholesterol.

Cautions to be kept in mind

Some experts claim that since the results are from one of many subgroup analyses of a bigger study, they should be viewed with care. Additionally, it should be kept in mind that bempedoic acid shouldn't be used in place of statins, which should still be the first-line treatment for primary prevention.

Essential question- Does bempedoic acid lessen significant adverse cardiovascular events in primary prevention individuals at high cardiovascular risk who are intolerant to statins?

The results- 4206 people with high cardiovascular risk but no history of a cardiovascular incident were included in this randomised study of 13 970 patients. Treatment with 180 mg/day of bempedoic acid was linked to a substantial decrease in major cardiovascular events in this subgroup (hazard ratio, 0.70).

Implications- These results imply that bempedoic acid therapy in primary prevention patients may minimise severe adverse cardiovascular events.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.