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NEW ORLEANS – Bempedoic acid dramatically reduces low density lipoprotein (LDL) cholesterol in combination with maximally tolerated statins in patients with high cardiovascular risk, according to new research.
Patients treated with the experimental oral agent had a 15.1% reduction in the primary LDL cholesterol endpoint at 12 weeks, compared to a 2.4% increase for placebo (a difference placebo-corrected 17.4%; P <0.001) in the CLEAR Wisdom study.
Oral bempedoic acid also significantly reduced non-HDL cholesterol, total cholesterol, apolipoprotein B and C-reactive protein levels.
Although not being a test of results, the one-year results showed a 2% reduction in the number of non-fatal cardiovascular deaths, non-fatal myocardial infarction, and cerebrovascular accidents. evaluated with bempedic acid compared to placebo (2.7% vs. 4.7%). The difference of 2% persisted when the composite endpoint included coronary revascularization (5.7% vs. 7.8%) and hospitalization for unstable angina (6.1% vs. 8.2%). %).
"I think the supplement [LDL] Anne Goldberg, MD, Faculty of Medicine at the University of Washington in St. Louis, said during a session of last-minute clinical trials at the 68th Annual Scientific Session of the American College of Cardiology (ACC.19 ).
The results corroborate those published a few days earlier in the New England Journal of Medicine in a similar group of 2230 patients participating in the CLEAR Harmony study, in which Bempedoic acid reduced LDL cholesterol at 12 weeks of 19.2 mg / dL, a difference of 18.1% per compared to placebo (P <0.001).
Talk with theheart.org | Medscape CardiologyValentine Fuster, MD, Mount Sinai Medical School Icahn in New York, said: "This is an open door to a new pharmacological strategy," but added that he was surprised by the modest decrease in LDL because bempedoic acid works by blocking ATP. enzyme lyase upstream of statins in the same cholesterol synthesis pathway.
Nevertheless, "when ezetimibe appeared on the market, it had the same decrease in LDL cholesterol, it was not very striking," he said. "But when the badysis was done, the number of [subsequent cardiovascular] events that are actually diminished, then the results become more significant. "
During the session, presenter Donald Lloyd-Jones, MD, Feinberg School of Medicine, Northwestern University, Chicago, said: "We are all watching the development of this drug as it will be useful to have safer drugs. and more effective in our environment.armamentarium if it helps to reach the goal line. "
CLEAR Wisdom randomly badigned 779 patients with atherosclerotic cardiovascular disease (approximately 95%) and / or heterozygous familial hypercholesterolemia to bempedoic acid once daily at 180 mg or placebo for 52 weeks. Just over half of the patients received high-intensity statins; one third, statins of moderate intensity; and the rest, either a low-intensity diet or no statin. Two-thirds of the patients were men, almost all were white (94%), 84% were hypertensive and one-third were diabetic.
Mean LDL-C levels decreased in the bempedoic acid group from 119.4 mg / dL to 97.6 mg / dL at week 12, and the reduction was maintained at 1 year (99.6 mg / dL) said Goldberg. Levels of LDL-C in the placebo group remained constant at 122.4 mg / dL, 122.8 mg / dL and 116.9 mg / dL, respectively.
It should be noted that LDL-C levels decreased further after 12 weeks with bempedoic acid in patients not taking statins than in those taking statins of low / moderate or high intensity (-24 , 6% vs -14.9% vs -14.4%).
During a press conference, Goldberg pointed out that the intention was to make bempedic acid an adjunctive treatment in patients with elevated LDL-C levels on lipid-lowering drugs and not to replace statins as first-line therapy.
"Not all people who do not know a low LDL with a statin or ezetimibe will actually be candidates for the addition of PCSK9 [proprotein convertase subtilisin/kexin type 9 inhibitors]so having other treatments would be beneficial, "she said.
Jones and Fuster both pointed out that it was essential to determine whether there was a similar relative reduction in LDL based on the initial state of LDL cholesterol, or whether there was a change Absolute set when adding bempedic acid to statins. Goldberg agreed that such a stratified badysis is necessary but added that it had not been carried out.
With respect to the safety of the drug, there were no significant differences between the bempedo acid and placebo groups in the incidence of adverse events (70.1% vs. 70%). , 8%), serious adverse events (20.3% vs. 18.7%) and due drug interruptions. adverse events (10.9% vs 8.6%)
The team examined the subgroup of diabetic patients and found no worsening of blood glucose readings, including a 12-week change in fasting blood glucose (-0.5 mg / dL) or hemoglobin A1C (-0.08%), nor the percentage of patients with blood glucose levels of at least 126 mg / dL (69.7% vs 75.3% for placebo).
CLEAR Harmony also showed no evidence of beginning or worsening diabetes between the bempedic acid and placebo groups (3.3% vs. 5.4%).
However, the incidence of gout (1.2% vs 0.3%) and increase of uric acid (0.73 mg / dL vs -0.6 mg / dL) were significantly higher. The authors, led by Kausik K. Ray, MD, MPhil, of Imperial College London, suggest that the latter factor might be related to the renal transporter's competition between the glucuronide metabolite of bempedic acid and uric acid.
Importantly, bempedic acid, compared to placebo, did not increase myalgia rates (6.0% vs. 6.1%), muscle spasm (4.2% vs. 2.7%), or muscle weakness (9 out of 4 events), according to Ray and his colleagues. Goldberg has not reported these findings, but noted that activated bempedoic acid is not present in skeletal muscle.
William White, MD, of the University of Connecticut's School of Medicine, Farmingham, responded that there were some patients who could not take statins or ezetimibe because of adverse effects , others who did not take a high enough dose of statins to reduce LDL and, finally, a costly and injectable inhibitor of PCSK9 might not please others.
"It's a vast world of people with high cholesterol and it's not necessarily a unique model," said White.
Deepak Bhatt, MD, Brigham and Women's Hospital, Boston, said it would be nervous to substitute bempedic acid for ezetimibe or PCSK9 inhibitors, given the results and results. available safety data for these drugs, and that it is unlikely that bortezoid acid is less expensive generic ezetimibe.
"I believe in the LDL hypothesis and I think that the test results [for bempedoic acid] will probably be positive but I would be a little cautious, "said Bhatt.
CLEAR Outcomes, the ongoing study on cardiovascular effects, is expected to be completed in the third quarter of 2019 and results are available by 2022. At the end of February, Esperion Therapeutics has submitted new drug applications to the US Food and Drug Administration. US for bempedoic acid and a combination tablet of bempedoic acid and ezetimibe. The European Medicines Agency is currently reviewing the applications of both drugs.
The trials were funded by Esperion Therapeutics. Goldberg reports g Rants / research support from Amgen, Amarin, Pfizer, Regeneron, Sanofi and IONIS, and fees from the National Lipid Association, Esperion, Novartis, AKCEA, Regeneron / Sanofi, 23andMe and Merck.
American College of Cardiology (ACC) 68th Annual Scientific Session: Abstract 409-08. Presented on March 18, 2019.
N Engl J Med. 2019; 380: 1022-1032. Abstract
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