endocrine and metabolic disorders
Dyslipidemia
Treatment of Dyslipidemia
Lifestyle changes (eg, exercise, dietary modification) For high LDL-C, statins, bile acid sequestrants,ezetimibe,bempedoic acid, and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors For high TG, fibrates, omega-3 fatty acids, and sometimes other measures The main goal for dyslipidemia treatment is prevention of atherosclerotic cardiovascular disease (ASCVD), including Overview of Acute Coronary Syndromes (ACS) , Treatment of children is controversial because there is no evidence that lowering lipid levels in childhood effectively prevents heart disease in adulthood. Moreover, the safety and effectiveness of long-term lipid-lowering treatment in children are unknown. Nevertheless, the American Academy of Pediatrics (AAP) recommends treatment for some Elevated LDL-C in children levels. Children with heterozygous familial hypercholesterolemia should be treated beginning at age 8 to 10 years. Children with homozygous familial hypercholesterolemia require diet, medications, and often LDL apheresis to prevent premature death; treatment is begun when the diagnosis is made. Treatment options depend on the specific lipid abnormality, although different lipid abnormalities often coexist. In some patients, a single abnormality may require several therapies; in others, a single treatment may be adequate for several abnormalities. Treatment should always include treatment of Treatment and For all individuals, the prevention of ASCVD requires an emphasis on a heart-healthy lifestyle, particularly diet and exercise. Other options to lower LDL-C in all age groups include medications, dietary supplements, and procedural interventions. Many of these options are also effective for treating other lipid abnormalities. Dietary changeshelp to maintain ideal body weight and provide other benefits. These changes include Decreasing intake of saturated fats and cholesterol Increasing the proportion of dietary fiber and complex carbohydrates Referral to a dietitian is often useful. Exerciselowers LDL-C in some people and also helps maintain ideal body weight. Dietary changes and exercise should be used whenever feasible, but American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend also using drug therapy for certain groups of patients after discussion of the risks and benefits of statin therapy ( Treatment references ). Fordrug therapy in adults,the AHA/ACC Guidelines recommend treatment with a statin for 4 groups of patients, comprised of those with any of the following: Clinical ASCVD LDL-C ≥ 190 mg/dL (≥ 4.9 mmol/L) Age 40 to 75 years, with diabetes and LDL-C 70 to 189 mg/dL (1.8 to 4.9 mmol/L) Age 40 to 75 years, with LDL-C 70 to 189 mg/dL (1.8 to 4.9 mmol/L), and an estimated 10-year risk of ASCVD ≥ 7.5% Risk of ASCVDis estimated using the pooled cohort risk assessment equations. This riskis based on sex, age, race, total and HDL-C, systolic and diastolic blood pressure, diabetes and smoking status, and use of antihypertensives or statins. Increased lifetime risk (identified using the AHA/ACC risk calculator) is relevant because 10-year risk may be low in younger patients, in whom longer-term risk should be taken into account. When considering whether to give a statin, clinicians may also take into account other factors, including LDL-C ≥ 160 mg/dL (4.1 mmol/L) Family history of premature ASCVD (ie, age of onset < 55 years in a male first-degree relative, or < 65 years in a female first-degree relative) High-sensitivity C-reactive protein ≥ 2 mg/L (≥ 19 nmol/L) Coronary artery calcium score ≥ 300 Agatston units (or ≥ 75th percentile for the patient's demographic) Ankle-brachial index < 0.9 Increased lifetime risk are the treatment of choice for LDL-C reduction because evidence has demonstrated that they reduce cardiovascular morbidity and mortality ( Treatment references ). Other classes of lipid-lowering drugs are not the first choice for treating elevated LDL-C because they have not demonstrated equivalent efficacy for decreasing ASCVD. Statins inhibit hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis, leading to up-regulation of LDL receptors and increased LDL clearance. They reduce LDL-C by up to 60% and produce small increases in HDL-C and modest decreases in TGs. Statins also appear to decrease intra-arterial inflammation, systemic inflammation, or both by stimulating production of endothelial nitric oxide and may have other beneficial effects. Statin therapy is classified as high-, moderate-, or low-intensity and is given based on treatment group and age (see table). The choice of statin depends on the patient's co-morbidities, other drugs, risk factors for adverse events, statin intolerance, cost, and patient preference. Adverse effects with statins are uncommon but include liver enzyme elevations and myositis or Rhabdomyolysis . Liver enzyme elevations are uncommon, and serious liver toxicity is extremely rare. Symptoms or severe adverse effects involving muscle occur in up to 10% of patients taking statins and may be dose-dependent. Muscle symptoms can occur without muscle enzyme (eg, creatine kinase) elevation. Adverse effects are more common among older patients, patients with several disorders, and patients taking several drugs. In some patients, changing from one statin to another or lowering the dose (after temporarily discontinuing the drug) relieves the problem. Muscle toxicity seems to be most common when some of the statins are used with drugs that inhibit cytochrome P3A4 (eg, macrolide antibiotics, azole antifungals, In patients with ASCVD, risk reduction increases with decreasing LDL-C levels. Thus, initial treatment is a statin at maximally tolerated dose with the goal of lowering LDL-C by > 50% (high-intensity therapy). For very high-risk patients with ASCVD (eg, those with a recent Acute Myocardial Infarction (MI) or ). The 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies provides guidance to clinicians on the role of non-statin therapy in both primary and secondary prevention of ASCVD ( Treatment references ). Statins are generally first-line medications, but in patients with statin intolerance, or those who are not able to achieve target LDL-C levels despite statin use, non-statin medications are used. impairs cholesterol synthesis in the liver and increases LDL receptors. It lowers LDL-C by 15 to 17% ( Treatment references ). ) block intestinal bile acid reabsorption, forcing up-regulation of hepatic LDL receptors to recruit circulating cholesterol for bile synthesis. They have been shown to reduce cardiovascular mortality. Bile acid sequestrants are usually used with statins or with Low HDL-C to augment LDL-C reduction. They are the drugs of choice for women who are or are planning to become pregnant. Statins are contraindicated in pregnancy because they maybe teratogenic due to the interruption of cholesterol synthesis, which is essential in fetal development. Bile acid sequestrants are safe, but their use is limited by adverse effects of bloating, nausea, cramping, and constipation. They may also increase TGs, so their use is contraindicated in patients with hypertriglyceridemia. Thecholesterol absorption inhibitorezetimibeinhibits intestinal absorption of cholesterol and phytosterol.Ezetimibeusually lowers LDL-C by 15 to 20% and causes small increases in HDL-C and a mild decrease in triglycerides.Ezetimibecan be used as monotherapy in patients intolerant to statins or added to statins for patients taking maximum statin doses with persistent LDL-C elevation. Adverse effects are infrequent. showed a decrease in cardiovascular events in patients with prior atherosclerotic cardiovascular disease ( Treatment references ). SiRNA targeting PCSK9is given as a subcutaneous injection every 6 months.Inclisiraninhibits PCSK9 production in the liver, thereby prolonging activity of LDL receptors and lowering LDL-C levels. Although LDL-C is lowered, cardiovascular outcome trials withinclisiranare ongoing.Inclisirancan be used as an adjunct to diet and maximally tolerated statin therapy for patients with ASCVD or heterozygous familial hypercholesterolemia. Dietary supplementsthat lower LDL-C levels include fiber supplements and commercially available margarines and other products containing plant sterols (sitosterol, campesterol) or stanols. Fiber supplements decrease cholesterol levels in multiple ways, including decreased absorption and increased excretion. Oat-based fiber supplements can decrease total cholesterol by up to 18%. Plant sterols and stanols decrease cholesterol absorption by displacing cholesterol from intestinal micelles and can reduce LDL-C by up to 10% without affecting HDL-C or TGs. Cholesterylester transfer protein inhibitorsare a class of drugs that are under investigation and that may simultaneously raise HDL-C and lower LDL-C. Cholesterylester transfer protein (CETP) is a plasma glycoprotein produced in the liver and adipose tissue that circulates in the blood bound primarily to HDL, which mediates the transfer of cholesteryl esters from HDL to ApoB containing particles. Medications for homozygous familial hypercholesterolemia include PCSK9 inhibitors,lomitapide, andevinacumab.Lomitapideis an inhibitor of microsomal triglyceride transfer protein that interferes with the secretion of TG-rich lipoproteins in the liver and intestine. Dose is begun low and gradually titrated up about every 2 weeks. Patients must follow a diet with less than 20% of calories from fat.Lomitapidecan cause gastrointestinal adverse effects (eg, diarrhea, increased hepatic fat, elevated liver enzymes).Evinacumabis a recombinant human monoclonal antibody that binds to and inhibits angiopoietin-like protein 3, an inhibitor of LPL and endothelial lipase. It can decrease LDL-C (by 47%), TG, and HDL-C.Evinacumabis given by intravenous infusion once monthly. It can cause gout, influenza-like illness, and infusion reactions. Procedural approaches are reserved for patients with severe hyperlipidemia (LDL-C>300 mg/dL [> 7.74 mmol/L]) and no vascular disease. LDL apheresis may be done in patients with LDL-C > 200 mg/dL (> 5.16 mmol/L) and vascular disease that is refractory to conventional therapy, such as occurs with familial hypercholesterolemia. Options include LDL apheresis (in which LDL is removed by extracorporeal plasma exchange) and, rarely, ileal bypass (to block reabsorption of bile acids) and liver transplantation (which transplants LDL receptors). LDL apheresis is the procedure of choice in most instances when maximally tolerated therapy fails to lower LDL-C adequately. Apheresis is also the usual therapy in patients with the homozygous form of familial hypercholesterolemia who have limited or no response to drug therapy. Childhood risk factors besides family history and Diabetes Mellitus in Children and Adolescents include cigarette smoking, 110 mg/dL (> 2.8 mmol/L) ( Treatment references ). Drug therapy is recommended for children>8 years and with either of the following: Poor response to dietary therapy, LDL-C≥190 mg/dL (≥4.9 mmol/L), and no family history of premature cardiovascular disease LDL-C≥160 mg/dL (≥4.13 mmol/L) and a family history of premature cardiovascular disease or≥2 risk factors for premature cardiovascular disease Medications used in children include many of the statins. Children with familial hypercholesterolemia may require a second drug to achieve LDL-C reduction of at least 50%. Although it is unclear whether elevated TGs independently contribute to cardiovascular disease, they are associated with multiple metabolic abnormalities that contribute to coronary artery disease (eg, Diabetes Mellitus (DM) , is to first implement lifestyle changes, including exercise, weight loss, and avoidance of concentrated dietary sugar and alcohol. Intake of 2 to 4 servings/week of marine fish high in omega-3 fatty acids may be effective, but the amount of omega-3 fatty acids is often lower than needed; supplemental doses may be helpful. In patients with diabetes, glucose levels should be tightly controlled. If these measures are ineffective, lipid-lowering drugs should be considered. Patients with very high TG levels (> 1,000 mg/dL [> 11 mmol/L]) may need to begin drug therapy at diagnosis to more quickly reduce the risk of Acute Pancreatitis . reduce TGs by about 50%. They appear to stimulate endothelial lipoprotein lipase (LPL), leading to increased fatty acid oxidation in the liver and muscle and decreased hepatic VLDL synthesis. They also increase HDL-C by up to 20%. Fibrates can cause gastrointestinal adverse effects, including dyspepsia, abdominal pain, and elevated liver enzymes. They uncommonly cause Cholelithiasis . Fibrates may potentiate muscle toxicity when used with statins and potentiate the effects of Statinscan be used in patients with TGs<500 mg/dL (<5.65 mmol/L) if LDL-C elevations are also present; statins may reduce both LDL-C and TGs through reduction of VLDL. If only TGs are elevated, fibrates are the drug of choice. Omega-3 fatty acidsin high doses (1 to 6 g a day of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) can be effective in reducing TGs. The omega-3 fatty acids EPA and DHA are the active ingredients in marinefish oilor omega-3 capsules. Adverse effects include eructation and diarrhea. These effects may be decreased by giving thefish oilcapsules with meals in divided doses (eg, twice a day or 3 times a day). Omega-3 fatty acids can be a useful adjunct to other therapies. Prescription omega-3 fatty acid preparations are indicated for TG levels > 500 mg/dL (>5.65 mmol/L). TheApo CIII inhibitor(an antisense inhibitor of apo CIII), volanesorsen, is available in some countries. It lowers triglyceride levels in patients with severely elevated TG levels, including people with lipoprotein lipase deficiency. It is given as a weekly injection. 1.04 mmol/L]; the guidelines do not specify an HDL-C target level and recommend interventions to raise HDL-C only after LDL-C targets have been reached ( Treatment references ). Treatments for LDL-C and TG reduction often increase HDL-C, and the 3 objectives can sometimes be achieved simultaneously. No guidelines specifically address treatment of low HDL-C in children. Although higher HDL-C levels predict lower cardiovascular risk, it is not clear whether treatments to increase HDL-C levels decrease risk of cardiovascular events or death. Treatment includeslifestyle changessuch as an increase in exercise and weight loss. Alcohol raises HDL-C but is not routinely recommended as a therapy because of its many other adverse effects. Drugs may be successful in raising levels when lifestyle changes alone are insufficient, but it is uncertain whether raising HDL-C levels reduces mortality. resistance, and hyperuricemia and gout. It may also Hyperhomocysteinemia . The combination of high doses of Fibratesincrease HDL-C. Fibrates may decrease cardiovascular risk in patients with TGs > 200 mg/dL (> 2.26 mmol/L) and HDL-C < 40 mg/dL (<1.04 mmol/L). The usual approach in patients with elevated Lp(a) is to lower LDL-C aggressively. LDL apheresis has been used to lower Lp(a) in patients with high Lp(a) levels and progressive vascular disease. The upper limit of normal for Lp(a) is about 30 mg/dL (75 nmol/L), but values in African Americans tend to be higher. Few data exist to guide the treatment of elevated Lp(a) or to establish treatment efficacy.Niacinis the only drug that directly decreases Lp(a); it can lower Lp(a) by > 20% at higher doses. There are several RNA-based therapies that lower Lp(a) levels in clinical development. Treatment of diabetic dyslipidemia should always involve lifestyle changes and statins to reduce LDL-C. To decrease the risk of pancreatitis, fibrates can be used to decrease TGs when levels are > 500 mg/dL (>5.65 mmol/L).Metforminlowers TGs, which may be a reason to choose it over other oral antihyperglycemic drugs when treating diabetes. Some thiazolidinediones (TZDs) increase both HDL-C and LDL-C. Some TZDs also decrease TGs. These antihyperglycemic drugs should not be chosen over lipid-lowering drugs to treat lipid abnormalities in patients with diabetes but may be useful adjuncts. Patients with very high TG levels and less than optimally controlled diabetes may have a better response toinsulinthan to oral antihyperglycemic drugs. Treatment of dyslipidemia in patients with Hypothyroidism , Lipid levels should be monitored periodically after starting treatment. No data support specific monitoring intervals, but measuring lipid levels 2 to 3 months after starting or changing therapies and once or twice yearly after lipid levels are stabilized is common practice. Liver and severe muscle toxicity with statin use occurs in 0.5 to 2% of all users. Routine monitoring of liver enzyme levels is not necessary, and routine measurement of creatine kinase (CK) is not useful to predict the onset of Rhabdomyolysis . Muscle enzyme levels need not be checked regularly unless patients develop myalgias or other muscle symptoms. If statin-induced muscle damage is suspected, statin use is stopped and CK may be measured. When muscle symptoms subside, a lower dose or a different statin can be tried. 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