Major Concepts in Treatment with Bempedoic Acid and Inclisiran that Clinicians Need To Know.

PURPOSE OF REVIEW: There have been recent developments of novel therapeutic agents for lipid lowering. This article reviews treatment concepts for two of the newest lipid-lowering medications. RECENT FINDINGS: Bempedoic acid inhibits adenosine citrate lyase, decreasing intracellular lipogenesis. This oral medication is a prodrug and requires activation by enzymes present in hepatocytes but absent in the skeletal muscle. Clinical trials demonstrated additive benefit with statin therapy, and it was well tolerated in statin-intolerant populations. Inclisiran uses RNA interference to prevent translation of PCSK9 mRNA. Due to its stability, it can be given as an injection every 6 months and produces consistent, durable, and potent cholesterol lowering. Bempedoic acid and inclisiran represent new avenues of treatment for the prevention and treatment of cardiovascular disease. This will allow for more comprehensive care by addressing challenges with medication adherence, such as adverse effects to prior medications as well as ease of dosing.

Management of patients with statin intolerance.

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality, and statins have become a cornerstone in its treatment and prevention. Despite the well-documented benefits of statins, many patients stop taking them, with adverse muscle symptoms being a commonly cited reason. Although some statin-associated adverse muscle effects are real, some can be attributed to the nocebo effect, which is the patient's perception of harm. The purpose of this article is to review the literature on statin safety, particularly that related to muscle, to analyze adverse effects, and to propose various treatment strategies for the statin intolerant patient.

Review of recent clinical trials and their impact on the treatment of hypercholesterolemia.

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death in the United States with incidence expected to increase in the coming decades. Recent years have produced a variety of new and novel therapeutics aimed at reducing the global burden of cardiovascular disease. This review highlights these recent advancements. RECENT FINDINGS: In addition to more rigorous therapeutic thresholds for traditional LDL lowering agents such as statins, recent studies have developed new pathways of lipid lowering for both typical cardiovascular disease and complex, genetic lipid disorders. This includes inhibition of the cholesterol synthesis enzyme ATP citrate lyase with bempedoic acid, prevention of PCSK9 mRNA translation with inclisiran, inhibition of the lipoprotein lipase inhibitor angiopoetin like 3 protein with evinacumab and the use of anti-sense oligonucleotides to lower lipoprotein(a) levels. Icosapent ethyl, while remaining a topic of debate and controversy, demonstrates efficacy in cardiovascular risk reduction when all available data are examined. Lastly fibrate therapy continues to produce negative results in terms of cardiovascular disease reduction. SUMMARY: Recent years have yielded breadth and depth to cardiovascular treatments. This expanded armamentarium will allow for more effective and more consistent treatment and prevention of cardiovascular disease.

The use of fibric Acid derivatives in cardiovascular prevention.

OPINION STATEMENT: Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol-lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.

Mipomersen and its use in familial hypercholesterolemia.

INTRODUCTION: Familial Hypercholesterolemia (FH) is an inherited disorder characterized by a defect in the binding and internalization of low-density lipoprotein (LDL) particles, resulting in markedly elevated LDL levels and premature atherosclerosis. It is one of the most common inherited disorders of lipid metabolism. Many FH patients, especially those with homozygous FH do not reach LDL goals with traditional LDL therapies and may require additional, less often used, therapies. Areas covered: Mipomersen is an anti-sense oligonucleotide that prevents production of apolipoprotein B leading to decreased levels of very low-density lipoprotein (VLDL) and LDL. In this review the authors discuss the pharmacokinetics of the drug, the clinical trials evaluating its efficacy and safety, and risks and challenges associated with its clinical implementation. Its use as therapy for the treatment of FH is also discussed. Expert opinion: Mipomersen is approved for use only in homozygous FH. It has frequent adverse effects, such as injection site reactions, flu-like symptoms, and hepatoxicity. It is useful only in patients who have failed other therapies, and it faces competition from other medications that have more tolerable side effect profiles.

Cardiovascular risk reduction: the future of cholesterol lowering drugs.

Atherosclerotic cardiovascular disease is the leading cause of death in developed and developing countries. LDL lowering therapies have a major role in reduction of cardiovascular events. Statins have been the mainstay of LDL lowering therapies with 20-60% reductions in LDL cholesterol. Monoclonal antibodies to proprotein convertase subtilisin kexin type 9 (PCSK9) represent a new therapeutic option, reducing LDL cholesterol by an additional 40-70% on top of other lipid lowering therapies. This is likely to produce significant cardiovascular risk reduction, although clinical cardiovascular outcomes trials are still in progress. HDL cholesterol raising and triglyceride lowering therapies have not yet shown unequivocal benefits for cardiovascular risk reduction. New therapies in these areas are in development, and their future promise remains to be demonstrated.

Familial Hypercholesterolemia.

Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder.

Familial Hypercholesterolemia: Advances in Recognition and Therapy.

Familial hypercholesterolemia (FH) is an autosomal co-dominant genetic disorder characterized by elevated low-density lipoprotein cholesterol levels and increased risk for premature cardiovascular disease. It is under-diagnosed, yet early detection and treatment are critical to limit premature atherosclerotic disease. High-intensity statins are the mainstay of treatment, which should be started as early as possible in homozygous FH and as soon as the diagnosis of heterozygous FH is made in adults. Combination therapy is often necessary in FH patients and can include the addition of ezetimibe and bile acid sequestrants. Lipoprotein apheresis is used when pharmacotherapy is inadequate, especially for those with homozygous FH and some patients with severe heterozygous FH. Mipomersen and lomitapide are also indicated for patients with homozygous FH. The recently approved PCSK9 inhibitors, alirocumab and evolocumab, are a promising treatment and outcome studies are ongoing. This article reviews the pathophysiology, diagnosis, and management of FH.

Familial hypercholesterolemia.

Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder.

Lipid lowering in liver and chronic kidney disease.

Lipid lowering, particularly with HMG CoA reductase inhibitors ("statins"), reduces the risk of cardiovascular disease. Patients with chronic liver and kidney disease present challenges to the use of lipid medications. In the case of most liver disorders, the concern has been one of safety. There is evidence that most lipid-lowering medications can be used safely in many situations, although large outcomes trials are not available. In contrast, in chronic kidney disease, dosing of lipid medications may require substantial modification depending on creatinine clearance. There are significant alterations in lipid metabolism in chronic kidney disease with concomitant increases in cardiovascular risk. Some data are available on cardiovascular outcomes with dyslipidemia treatment in renal patients. This review will examine lipid physiology and cardiovascular risk in specific liver and kidney diseases and review the evidence for lipid lowering and the use of statin and non-statin therapies in chronic liver and kidney disease.

Novel therapies and new targets of treatment for familial hypercholesterolemia.

Patients with familial hypercholesterolemia (FH) are not always able to achieve target levels of low-density lipoprotein (LDL) cholesterol with currently available medications. A number of novel pharmaceutical approaches to LDL cholesterol-lowering have been in development. Antisense oligonucleotides are molecules that are injected subcutaneously and cause decreased release of apolipoprotein B-containing lipoproteins from the liver. Microsomal transfer protein inhibitors block the accumulation of triglyceride into apolipoprotein B precursors. Squalene synthase inhibitors partially block a late step in cholesterol biosynthesis. Proprotein convertase subtilisin kexin type 9 inhibitors can lead to increased LDL cholesterol receptor functioning and thereby decrease LDL cholesterol levels. Thyroid hormone analogues lower LDL cholesterol and other lipoproteins by a selective effect on certain thyroid hormone receptors, avoiding the adverse effects of excessive thyroid hormone levels. Several of these classes of lipid-modifying agents are currently in clinical trials. Long-term safety data will be needed before any are available to be used clinically, but some hold significant potential for improving treatment options for patients with FH.

Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety.

Statins, ezetimibe, and bile acid-binding resins can be used individually or in combination for lowering low-density lipoprotein cholesterol (LDL-C) levels. Statins are the most potent drugs for lowering LDL-C and are well tolerated in most patients. The addition of a bile acid sequestrant or ezetimibe to a statin produces additional LDL-C reduction allowing many patients to reach LDL-C targets. This article discusses the efficacy and safety of available statins, bile acid sequestrants, and ezetimibe in the treatment of hyperlipidemia.

A case of severe neuropathy associated with hypertriglyceridemia.

OBJECTIVE: To describe a case of severe neuropathy associated with hypertriglyceridemia. METHODS: We describe the clinical and laboratory findings of the study patient and review the relevant literature. RESULTS: A 45-year-old woman presented to the emergency department with recurrent abdominal pain and severe peripheral neuropathy. Her laboratory data revealed elevated lipase and a very high triglyceride concentration (>10,000 mg/dL), consistent with a diagnosis of recurrent hypertriglyceridemia-induced pancreatitis. Workup for peripheral neuropathy showed normal concentrations of thyrotropin, fasting blood glucose, vitamin B(12), and creatinine, as well as a normal hemoglobin A(1c) level, serum protein electrophoresis, and urine protein electrophoresis. Rapid plasma reagin antibodies, antinuclear antibodies, and lyme antibodies were not detected. In the absence of other identifiable causes, hypertriglyceridemia was deemed the likely etiology of severe neuropathy in this patient. CONCLUSIONS: Peripheral nerve conduction abnormalities can be identified in patients with mild hypertriglyceridemia in the absence of symptoms. Early recognition and aggressive management of hypertriglyceridemia may prevent the complications of severe peripheral neuropathy.

Combination therapy of dyslipidemia.

Clinical trials have demonstrated the benefit of low-density lipoprotein (LDL) cholesterol reduction and, with less robust evidence, reduction of triglyceride levels and increased high-density lipoprotein (HDL) cholesterol in the prevention of atherosclerotic cardiovascular disease. Although the statins are the cornerstone of lipid-lowering therapy, they may not be adequate to accomplish all of the changes in lipid and lipoprotein levels called for in current guidelines. Combinations of one or more lipid-modifying drugs in addition to lifestyle changes are now part of clinical guidelines and are being used extensively in practice. Clinicians need to be familiar with the individual drugs and how they interact. There is also a need for outcome data with combination therapy, especially for statin-fibrate and statin-niacin combinations. Several clinical trials are underway and should provide further evidence for the benefit of combination therapy of dyslipidemia. New drug classes have the potential to provide additive effects with currently available medications to provide substantial LDL reduction and increased HDL level that may lead to a substantial reduction in the burden of atherosclerotic vascular disease.

Clinical implications of statin event trials.

Event trials using statin therapy have shown a beneficial effect on rates of cardiovascular events. The three statins that have been used in long-term trials have shown generally similar effects on rates of myocardial infarction, stroke, revascularizations, and mortality. Safety data appear to be comparable for lovastatin, pravastatin, and simvastatin. Long-term trials of other statins are in progress or pending. The question of how much low-density lipoprotein cholesterol should be lowered may be answered by studies currently in progress.