Hyperlipidemias and Atherosclerotic Cardiovascular Disease ________________________________________
Adverse Effects Potential adverse effects associated with bempedoic acid include leukopenia, thrombocythemia, upper respiratory tract infection, and, most commonly, hyperuricemia and gout. Gout and hyperuricemia are more common at higher doses and related to inhibition of tubular OAT2, which may increase blood uric acid levels [109]. It usually develops within the first four weeks of treatment initiation and persists until cessation of administration. Rupture or injury of tendon has rarely (<1%) occurred, typically involving the rotator cuff, biceps tendon, or Achilles tendon [109]. Risk factors include age older than 60 years, concomitant use of corticosteroids or fluoroquinolones, kidney failure, and prior tendon disorders. Drug Interactions Bempedoic acid can increase the serum concentration of certain drugs metabolized by the liver, including elagolix, voxilaprevir, and asunaprevir and should be avoided in patients taking these medications [109]. It may also increase the serum levels of the statins simvastatin and lovastatin. If bempedoic acid is coadministered with these agents, the dose should be limited to no more than 20 mg daily for simvastatin or 40 mg daily for lovastatin [109; 239].
Aggregate data from randomized trials, case-control and cohort studies, and long-term animal feeding experiments indicate that the consumption of at least 5% to 10% of energy from omega-6 polyunsat- urated fatty acids reduces the risk of CHD relative to lower intakes. The data also suggest that higher intakes appear to be safe and may be even more ben- eficial (as part of a low-saturated-fat, low-cholesterol diet). In summary, the AHA supports an omega-6 polyunsaturated fatty acid intake of at least 5% to 10% of energy in the context of other AHA lifestyle and dietary recommendations. To reduce omega-6 polyunsaturated fatty acid intakes from their cur- rent levels would be more likely to increase than to decrease risk for CHD. Adverse Effects No serious side effects have been reported with omega-6 fatty acids. Some minor gastrointestinal effects may resemble those described for the omega-3 polyunsaturated fatty acids. Plant sterols and stanols lower plasma levels of beta-carotene by 25% and vitamin E by 8% [201]. Drug Interactions Bile acid sequestrants and additives and drugs that impair the absorption of fat and soluble nutrients, such as olestra and orlistat, have the potential to significantly impair absorption of omega-3, 6, and 9 polyunsaturated fatty acids. ADENOSINE TRIPHOSPHATE-CITRATE LYASE (ACL) INHIBITOR Mechanism of Action and Clinical Pharmacology As noted, in 2020, the FDA approved bempedoic acid for the treatment of Heterozygous familial hypercholesterolemia or established ASCVD [233]. Bempedoic acid is the first in the class of adenosine triphosphate-citrate lyase (ACL) inhibitors. By inhibiting ACL, a hepatic enzyme involved in the synthesis of cholesterol, bempedoic acid decreases the conversion of mitochondrial-derived citrate to cytosolic ACL, creating less substrate for cholesterol and fatty acid synthesis. This ultimately decreases liver cholesterol synthesis and decreases serum LDL-C levels by upregulating LDL receptors [239]. Bempedoic acid is available as monotherapy and in a tablet with ezetimibe as combination therapy. It is an option to modify statin therapy or for patients who cannot tolerate statins. This combination has been demonstrated in clinical trials to lower LDL-C levels by 36% and, when given as monotherapy, bempedoic acid and ezetimibe have been respectively shown to lower LDL-C levels by 15% to 23% and by 13% to 20%, respectively [239]. The usual dose is 180 mg bempedoic acid and, if used, 10 mg ezetimibe once daily.
NOVEL PHARMACOTHERAPIES FOR HYPERLIPIDEMIAS
The discovery of lipid-lowering drugs has been a major contribution to the clinical management of hyperlipidemias and the prevention of ASCVD. However, the incidence of lipid disorders and resultant cardiovascular pathology continues to increase worldwide. Existing available therapies are generally effective. Statins are the most prescribed lipid-lowering drugs because of their therapeutic efficacy and beneficial effects on the prevention of ASCVD, although the potential for the occurrence of serious adverse effects in a small number of patients requires monitoring. Other therapies, including bile acid-binding resins, ezetimibe, fibrates, niacin, and omega-3 polyunsaturated fatty acids, either alone or co-administered with other lipid- lowering drugs, including statins, can further lower LDL and triglycerides or raise HDL. However, despite effectiveness of statins, there remain patients with severe lipid disorders (e.g., elevated apoprotein(a), remnant triglyceride-rich lipoproteins) and those intolerant to statins who may not achieve optimal risk reduction with conventional regimens. In fact, it is estimated that 10% of patients are not able or cannot tolerate available therapies to achieve recommended LDL goals [140]. So, continued research for globally effective pharmacotherapy is underway.
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