The CLEAR Outcomes trial was a double-blind, randomized, placebo-controlled trial involving patients who were “statin-intolerant” and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. Dr. Steven Nissen (Heart, Vascular and Thoracic Institute, Cleveland Clinic Center for Clinical Research, Cleveland, OH, USA) discusses the CLEAR Outcomes study, including likely clinical impacts, and future directions following these findings.
The abstract entitled ‘Cholesterol Lowering Drug Shown to Cut Major Heart-Related Events and Risk of Death from Heart Disease by One-Third for Statin-Intolerant Patients’ was presented at the 83rd American Diabetes Association Scientific Session, June 23-26, 2023.
- Could you describe the incidence and risk of coronary artery disease (CAD) and high cholesterol in people with diabetes? (0:19)
- What is the rationale for using a non-statin cholesterol-lowering drug to improve cardiovascular outcomes for these patients? (0:45)
- What were the aims, design, and eligibility criteria of the CLEAR Outcomes trial? (1:34)
- Can you outline the primary and secondary endpoints, and how well were these achieved? (2:17)
- In your opinion, will the likely clinical impact of these findings be, and what further work should be done? (3:49)
Disclosures: Steven Nissen is a consultant for Abbvie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics.
Support: Interview and filming supported by Touch Medical Media. Interview conducted by Zoe Sidwell.
Filmed as a highlight of ADA 2023.
I’m Dr Steven Nissen and I am the chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic.
Could you describe the incidence and risk of coronary artery disease (CAD) and high cholesterol in people with diabetes?
The leading cause of death in people with diabetes is cardiovascular disease. It accounts for about two-thirds of all the mortality in patients with diabetes. So we tend to say that diabetes is a cardiovascular disease because it leads to many adverse cardiovascular outcomes.
What is the rationale for using a non-statin cholesterol-lowering drug to improve cardiovascular outcomes for these patients?
Well, first of all, statins are the gold standard. We would consider statins as always the first line drug. We have data from hundreds of thousands of patients showing benefits, particularly in diabetic patients for statins, but, We know that about ten to fifteen percent of patients can’t tolerate statins typically due to muscle-related adverse effects, and those people are not getting the benefit of cholesterol-lowering with statins. And so we need an alternative. That’s why we’ve been involved in the development of Bempedoic acid because it is a drug that can be taken by people who are statin-intolerant.
What were the aims, design, and eligibility criteria of the CLEAR Outcomes trial?
So to get into the clear outcomes trial, you had to have one of two criteria met, either you had to have pre-existing cardiovascular disease. That was seventy percent of patients. Or you had to have risk factors for cardiovascular disease, and that was thirty percent of the patients. It turns out that the most common risk factor that allowed people to enter the trial was diabetes. The other criterion that was really important is you add to have an LDL cholesterol of greater than one hundred milligrams per deciliter.
Can you outline the primary and secondary endpoints, and how well were these achieved?
So in the overall clear outcomes trial, the primary endpoint had showed was the composite of cardiovascular death, stroke, myocardial infarction, or coronary revascularization. That four component endpoint had a hazard ratio of 0.87. There was however series of key secondary endpoints that were studied. The first of these was three components. Major adverse cardiovascular events. That was just cardiovascular death, non fatal MI or non fatal stroke. That was a hazard ratio of 0.85, a fifteen percent reduction. There was also a reduction in myocardial infarction. The hazard ratio was 0.77. That’s a twenty three percent reduction in the risk of myocardial infarction and then the fourth component was need for cardiovascular coronary revascularization. And that hazard ratio was 0.81, a nineteen percent reduction. Those primary and the three additional secondary endpoints were all statistically significant, hazard reported in the main management.
In your opinion, will the likely clinical impact of these findings be, and what further work should be done?
From our point of view, what we’ve established is that Bempedoic acid can be added to the group of medications that lower LDL cholesterol and improve cardiovascular outcomes. However, we studied Bempedoic acid alone and Bempedoic acid alone only produces about a twenty two percent reduction in LDL cholesterol. Fortunately, the product is available as a fixed dose combination with the cholesterol absorption inhibitor is edomite, and that fixed dose combination can lower LDL cholesterol by between thirty five percent and forty percent about the same amount as a moderate intensity statin. So we think that in statin intolerant patients, this will be a go-to therapy, the combination fixed dose combination of Bempedoic acid with Azetamide, which produces similar LDL reduction to a moderate intensity statin.
Subtitles and transcript are autogenerated.
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