PHM 1.03 - Agents Used in Dyslipidemia PDF

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 210 attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2-3 months after starting therapy OUTLINE Introduction Pathophys...

PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 210 attributable chiefly to mitigation of the inflammatory activity of macrophages and is evident within 2-3 months after starting therapy OUTLINE Introduction Pathophysiology of Hyperlipoproteinemia Dietary Management of Hyperlipoproteinemia Basic and Clinical Pharmacology of drugs used in Hyperlipoproteinemia Introduction Plasma lipids are transported in complexes called lipoproteins Hyperlipoproteinemias or hyperlipidemias Metabolic disorders that involve elevations in any lipoprotein species Hyperlipemia Denotes increased levels of triglycerides Major clinical sequelae of hyperlipidemias are acute pancreatitis (occurs in patient with hyperlipidemia) and atherosclerosis In Dyslipidemia, atherosclerosis is the leading cause of death for both genders in the USA and other Western countries,” also holds true for the Asian countries and the Philippines” Lipoproteins that contain apolipoprotein (apo) B-100 convey lipid to the arterial wall Transport Low density lipoproteins (LDL), Very low density (VLDL), and Lipoprotein (a)[LP(a)] Remnant lipoprotein formed during the catabolism of chylomicrons that contain the B-48 protein (apo B-48) can also enter the artery wall, contributing to atherosclerosis Cellular components in atherosclerosis macrophages, and smooth muscle cells filled with cholesteryl esters (result from endocytosis of modified lipoprotein via at least four species of scavenger receptors) PROGRESSION: Chemical modification of lipoproteins by radicals create ligands of these receptors free The atheroma grows with accumulation of foam cells, collagen, fibrin, and frequently calcium Lesions can slow occlude coronary vessels Clinical symptoms are more frequently precipitated by rupture of unstable atheromatous plaques Activation of platelets and formation of occlusive thrombi Although treatment of hyperlipidemia can cause slow physical regression of plaques, the welldocumented reduction in acute coronary events that follows vigorous lipid-lowering treatment is 1 | Page PHARMACOLOGY “hindi talaga siya directly correlated, yung benefit niya doon sa pagbaba ng cholesterol but it rather acts to prevent the further inflammation of endothelium” High Density Lipoproteins (HDL) Exert several antiatherogenic effects Participate in the retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins Low level of HDL (hypoalphalipoproteinemia) are an independent risk for atherosclerotic disease and thus are a potential target for intervention Cigarette smoking is a major risk factor for coronary disease Associated with reduced levels of HDL, impairment of cholesterol retrieval, cytotoxic effects on the endothelium, increased oxidation of lipoproteins and stimulation of thrombogenesis Diabetes- major risk (source of oxidative stress) Normal coronary arteries can dilate in response to ischemia, increasing delivery of oxygen to the myocardium (mediated by nitric oxide, acting on smooth muscle cells of the arterial media) Release of nitric oxide from the vascular endothelium is impaired by atherogenic lipoproteins Reducing levels of atherogenic lipoproteins and inhibiting the oxidation restores endothelial function Atherogenesis – multifactorial (therapy should be directed toward all modifiable risk factors) PATHOPHYSIOLOGY OF HYPERLIPOPROTEINEMIA NORMAL LIPOPROTEIN METABOLISM STRUCTURE Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by un-esterified cholesterol, phospholipids, and apoproteins Certain lipoproteins contain very high- molecular weight B proteins that exist in two forms: a) B-48: formed in the intestine and found in chylomicrons and their remnants b) B-100: synthesized in liver and found in VDL, VLDL, remnants (IDL), LDL (formed from VLDL), and Lp (a) lipoproteins HDL consist of at least 20 discrete molecular species containing apolipoproteins A-I (apo A-I) About 100 other proteins are known to be distributed variously among the HDL species LIPO-B “B”-BAD lipoproteins Apo-A “A”-ANGEL because they do good Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 PHARMACOLOGY - SYNTHESIS AND CATABOLISM A. CHYLOMICRONS formed in the intestines and carry triglycerides of dietary origin, un-esterified cholesterol, and cholesteryl esters Transit the thoracic duct to the bloodstream Triglycerides are removed from the chylomicrons in extrahepatic tissues through a pathway shared with VLDL that involves hydrolysis by the lipoprotein lipase (LPL) system Decrease in particle diameter occur as triglycerides are depleted Surface lipids and small apoproteins are transferred to HDL > resultant chylomicrons remnant is taken up by receptor- mediated endocytosis into hepatocytes B. VERY-LOW DENSITY LIPOPROTEINS Secreted by liver and export triglycerides to peripheral tissues VLDL triglycerides are hydrolyzed by LDL, yielding free fatty acids for storage in adipose tissue and for oxidant in tissues such as cardiac and skeletal muscle Depletion of triglycerides produces remnants (IDL), some of which undergo endocytosis directly into hepatocytes Remainder are converted to LDL further removal of triglycerides mediated by hepatic lipase This process explains the “beta shift” phenomenon, the increase of LDL (betalipoprotein) in serum as hypertriglyceridemia subsides C. LOW DENSITY LIPOPROTEINS Catabolized chiefly in hepatocytes and other cells after receptor mediated endocytosis Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid and HMG-CoA reductase Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell Normally about 70% of LDL, is removed from plasma by hepatocytes Even more cholesterol is delivered to the liver via IDL and chylomicrons Unlike other cells, hepatocytes can eliminate cholesterol by secretion in bile and by conversion to bile acids D. - 210homologous with The (a) protein is highly plasminogen but is not activated by tissue plasminogen activator Lp(a) is found in atherosclerotic plaques and contributes to coronary disease by inhibiting thrombolysis Associated with aortic stenosis E. HIGH DENSITY LIPOPROTEINS Apoproteins of HDL are secreted largely by the liver and intestine Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis HDL also acquires cholesterol from peripheral tissues, protecting the cholesterol homeostasis of cells Free cholesterol is chiefly exported from the cell membrane by a transporter, ABCA1, acquired by a small particle termed prebeta1 HDL, and then esterified by lecithincholesterol acyltransferase (LCAT), leading to the formation of larger HDL species At the population level, HDL cholesterol (HDLC) levels relate inversely to atherosclerosis risk LIPOPROTEIN DISORDERS Detected by measuring lipids in serum after a 10hour fast Risk of heart disease increases with concentrations of the atherogenic lipoproteins, is inversely related levels of HDL-C, and is modified by other risk factors Higher LDL= higher risk for heart disease (direct relationship) Lower HDL= higher risk for heart disease (inverse relationship) Clinical trials suggest that an LDL cholesterol (LDLC) level of 50-60mg/dL is optimal for patients with coronary disease Ideally, triglycerides should be below 120mg/dL but current studies show that we do not need to treat triglycerides unless they are more than 500mg/dL Although LDL-C is still the primary target of treatment, reducing the levels of VLDL and IDL also is important Differentiation of the disorders requires identification of the lipoproteins involved Diagnosis of primary disorder usually requires further clinical and genetic data as well as ruling our secondary hyperlipidemias Lp(a) LIPOPROTEIN Lp (a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bond 2 | Page Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 PHARMACOLOGY 210 xanthomas, Patients may have eruptive hepatosplenomegaly, hypersplenism, and lipidladen foam cells in bone marrow, liver, and spleen The lipemia is aggravated by estrogens because they stimulate VLDL production, and pregnancy may cause marked increase in triglycerides despite strict dietary control Although these patients have a predominant chylomicronemia, they may also have moderately elevated VLDL, presenting with a pattern called Mixed Lipemia (fasting chylomicronemia and elevated VLDL) A presumptive diagnosis is demonstrating a pronounced decrease in triglycerides 72 hours after elimination of daily dietary fat Marked restriction of total dietary fat and abstention from alcohol are the basis of effective long-term treatment Niacin, a fibrate, or marine omega 3-fatty acids may be of some benefit if VLDL levels are increased FAMILIAL HYPERTRIGLYCERIDEMIA THE PRIMARY HYPERTRIGLYCERIDEMIAS HYPERTRIGLYCERIDEMIA Associated with increased risk of coronary disease Chylomicrons, VLDL, and IDL are found in atherosclerotic plaques Patients tend to have cholesterol-rich VLDL of small particle diameter and small, dense LDL Patients with triglycerides above 700mg/dL should be treated to prevent acute pancreatitis because the LPL clearance mechanism is saturated at about this level Hypertriglyceridemia is an important component of the metabolic syndrome, which also includes insulin resistance, hypertension, and abdominal obesity Reduced levels of HDL-C are usually observed due to transfer of cholesteryl esters to the triglyceriderich lipoprotein particles Management of these patients frequently requires, in addition to fibrate, the use of METFORMIN, another antidiabetic agent, or both (the severity of hypertriglyceridemia of any cause is increased in the presence of the metabolic syndrome or type 2 diabetes) PRIMARY CHYLOMICRONEMIA Chylomicrons are not present in the serum of normal individuals who have fasted 10hours. The recessive traits of deficiency of LPL, its cofactor apo C-II, the LMF1 or GPIHBP1 proteins, or ANGPTL4 and Apo A-V, are usually associated with severe lipemia (2000 mg/dL of triglycerides or higher when the patient is consuming a typical American diet) These disorders might not be diagnosed until an attack of acute pancreatitis occurs 3 | Page Patients have centripetal obesity with insulin resistance Other factors, including alcohol and estrogens, that increase secretion of VLDL can result in mixed lipemia Eruptive xanthomas, lipemia retinalis, epigastric pain, and pancreatitis are variably present depending on the severity of the lipemia Treatment is primarily dietary, with restriction of total fat, avoidance of alcohol and exogenous estrogens, weight reduction, exercise and supplementation with marine omega 3-fatty acids Most patients also require treatment with a fibrate FAMILIAL COMBINED HYPERLIPOPROTEINEMIA (FCH) Common disorder Associated with an increased incidence of coronary disease, individuals may have elevated levels of VLDL, LDL, or both, and the pattern may change with time Involves a approximate doubling in VLDL secretion and appears to be transmitted as a dominant trait Triglycerides can be increased Elevation of cholesterol and triglycerides are generally moderate, and xanthomas are absent Diet alone does not normalize lipid levels A reductase inhibitor alone, or in combination with niacin or fenofibrate, is usually required to treat these patients When fenofibrate is combined with a reductase inhibitor, either PRAVASTATIN or ROSUVASTATIN is recommended because neither is metabolized via CYP2A4 Marine omega 3-fatty acids may be useful Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 FAMILIAL DYSBETALIPOPROTEINEMIA Remnants of chylomicrons and VLDL accumulate and levels of LDL are decreased Because remnants are rich in cholesteryl esters, the level of total cholesterol may be as high as that of triglycerides Diagnosis is confirmed by the absence of the ε3 and ε4 alleles of apo E, the ε2/ ε2 genotype Patients often develop tuberous or tuberoeruptive xanthomas, or characteristics planar xanthomas of the palmar creases Tend to be obese, and some have impaired glucose tolerance Other factors e.g. hypothyroidism: can aggravate the lipemia Coronary and peripheral atherosclerosis occurs with increased frequency Weight loss, together with decreased fat, cholesterol and alcohol consumption, may be sufficient, but a fibrate or niacin is usually needed to control the condition Reductase inhibitors are also effective because they increase hepatic LDL receptors that participate in remnant removal THE PRIMARY HYPERCHOLESTEROLEMIAS LDL RECEPTOR DEFICIENT FAMILIAL HYPERCHOLESTEROLEMIA (FH) PHARMACOLOGY 210 transfer protein (MTP), and monoclonal antibodies directed at PCSK9 FAMILIAL LIGAND-DEFECTIVE APOLIPOPROTEIN B-100 Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity Tendon xanthomas may occur Response to reductase inhibitors is variable Upregulation of LDL receptors in liver increase endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles Fibrates or Niacin may have beneficial effects by reducing VLDL production FAMILIAL COMBINED HYPERLIPOPROTEINEMIA (FCH) Some persons with familial combined hyperlipoproteinemia have only an elevation in LDL Serum cholesterol is often less than 350mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated It may necessary to add Niacin or EZETIMIBE to normalize LDL Lp(a) HYPERLIPOPROTEINEMIA Autosomal dominant trait In most heterozygotes, cholesterol levels range from 260-500 mg/dL Triglycerides are usually normal Tendon xanthomas are often present Arcus comeae and xanthomas may appear in the third decade Coronary disease tends to occur prematurely In homozygous familial hypercholesterolemia, which can lead to coronary disease in childhood, levels of cholesterol often exceed 1000mg/dL and early tuberous and tendinous xanthomas occur Patients may also develop elevated plaque- like xanthomas of the aortic valve, digital webs, buttocks and extremities Some individuals have combined heterozygosity for alleles producing non- functional and kinetically impaired receptors In heterozygous patients, LDL can be normalized with reductase inhibitors or combined drug regimens Homozygotes and those with combined heterozygosity whose receptors retain even minimal function may be partially respond to niacin, exetimibe, and reductase inhibitors Emerging therapies for these patients include MIPOMERSEN, employing an antisense strategy targeted at apo B-100 and LOMITAPIDE, a small molecule inhibitor of microsomal triglyceride 4 | Page Associate with increased atherogenesis and arterial thrombus formation Determined chiefly by alleles that dictate increased production of the (a) protein moiety Lp(a) can be secondarily elevated in patients with severe nephrosis and certain other inflammatory states Niacin reduces levels of Lp(a) in many patients ❖ Reduction of levels of LDL-C below 100mg/dL decreases the risk attributable to Lp(a), as does the administration of low-dose ASPIRIN PCSK9 monoclonal antibodies also reduce levels of Lp(a) by about 25% CHOLESTERYL ESTER STORAGE DISEASE Individuals lacking activity of lysosomal acid lipase (LAL) accumulate cholesteryl esters in liver and certain other cell types leading to hepatomegaly with subsequent fibrosis, elevated levels of LDL-C, low levels of HDL-C, and often modest hypertriglyceridemia A recombinant replacement enzyme therapy, sebelipase alfa, effectively restores the hydrolysis of cholesteryl esters in liver, normalizing plasma lipoprotein levels OTHER DISORDERS Deficiency of cholesterol 7α-hydroxylase can increase LDL in the heterozygous state Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 Homozygotes also can have elevated triglycerides, resistance to reductase inhibitors as a single agent, and increased risk of gallstones and coronary disease A combination of Niacin with a reductase inhibitor appears to be effective Autosomal recessive hypercholesterolemia (ARH) is due to mutations in a protein that normally assists in endocytosis of LDL High-dose reductase EZETIMIBE is effective the receptor chaperon conducts the receptor to the lysosome for degradation gain-of-function mutations in PCSK9 are associated with elevated levels of LDL-C and could be managed with a PCSK9 antibody the ABCG5 and ABCG8 half-transporters act together in enterocytes and hepatocytes to export phytosterols into the intestinal lumen and bile, respectively homozygous or combined heterozygous ablative mutations in either transporter result in elevated levels of LDL enriched in phytosterols, tendon and tuberous xanthomas, and accelerated atherosclerosis EZETIMIBE is a specific therapeutic for this disorder PHARMACOLOGY 210 THE SECONDARY HYPERTRIGLYCERIDIMIAS Before primary disorders can be diagnosed, secondary causes of the phenotype must be considered The lipoprotein abnormality usually resolves if the underlying disorder can be treated successfully These secondary disorders can also aggravate primary genetic disorder DIETARY MANAGEMENT OF HYPERLIPOPROTEINEMIA HDL DEFICIENCY rare genetic disorders, including Tangier disease and LCAT (lecithin, cholesterol acyltransferase) deficiency associated with extremely low levels of HDL familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45mg/dL in women patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor management should include special attention to avoidance or treatment of other risk factors Niacin increases HDL in many of these patients but the effect on outcome is unknown Reductase inhibitors and fibric acid derivatives exert lesser effects aggressive LDL reduction is indicated In the presence hypertriglyceridemia, HDL cholesterol is low because of exchange of cholesteryl esters from HDL into triglyceride- rich lipoprotein Treatment of hypertriglyceridemia increases the HDL-C level 5 | Page Dietary measures are initiated first—unless the patient has evident coronary or peripheral vascular disease—and may obviate the need for drugs Patients with the familial hypercholesterolemia always require drug therapy in addition to diet Cholesterol and saturated and trans-fats are the principal factors that increase LDL Total fat, sucrose, and especially fructose increased VLDL Alcohol can cause significant hypertriglyceridemia by increasing hepatic secretion of VLDL Synthesis and secretion of VLDL are increased by excess calories During weight loss, LDL and VLDL levels may be much lower than can be maintained during neutral caloric balance The conclusion that diet suffices for management can be made only after weight loss stabilized for at least 1 month General recommendations include limiting total calories forms fat to 20-25% of daily intake, saturated fats to less than 7%, and cholesterol to less than 200mg/dL (reductions in serum cholesterol range from 10% to 20% on this regimen) Use of complex carbohydrates and fiber is recommended, and cis-monounsaturated fats should predominate Weight reduction, caloric restriction, and avoidance of alcohol are especially important for patients with elevated triglycerides The effect of dietary fats on hypertriglyceridemia is dependent on the disposition of double bonds in the fatty acid Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 Omega 3 fatty acids found in fish oils, but not those from plant sources, activate peroxisome proliferator-activated receptor-alpha (PPAR-α) and can induce profound reduction of triglycerides in some patients They also have anti-inflammatory and antiarrhythmic activities It is necessary to determine the content of Docosahexaenoic Acid and Eicosapentaenoic Acid in over-the-counter preparations Appropriate amounts should be taken to provide up to 3-4g of these fatty acids (combined) daily The omega-6 fatty acids present in vegetable oil cause triglycerides to increase Homocysteine, which initiates proatherogenic changes in endothelium, can be reduced in many patients by restriction of total protein intake to the amount required for amino acid replacement Supplementation with folic acid plus other B vitamins, and administration of betaine, is indicated in severe homocysteinemia Reduction of high levels of homocysteine is especially important in individuals with elevated levels of Lp(a) Consumption of red meat should be minimized to reduce the production by the intestinal biome of tetramethyl amine oxide, a compound injurious to arteries BASIC & CLINICAL PHARMACOLOGY OF DRUGS USED IN HYPERLIPIDEMIA The decision to use drug therapy for hyperlipidemia is based on ano yung risk ng patient and what specific metabolic defect you are treating and its potential for causing atherosclerosis or pancreatitis. Diet should be continued to achieve the full potential of the drug regimen. Diet should be initiated as a first line therapy and magdagdag if it dictates kung ano yung mga gamot na kailangan. IMPORTANT! These drugs should be avoided in pregnant and lactating women and those likely to become pregnant. Children with heterozygous familial hypercholesterolemia may be treated with a resin or reductase inhibitor if it is indicated, usually after 7 or 8 years of age, when myelination of the central nervous system is essentially complete. Children should not be given with lipid lowering drugs unless the child is a very high risk or the management indicates na kailangan mo talagang gamitin. If no risk factors, it is not usually given to children. The decision to treat a child should be based on the level of LDL, other risk factors, the family history, and the child’s age. 6 | Page PHARMACOLOGY 210 age 16 in the Drugs are usually not indicated before absence of multiple risk factors or compound genetic dyslipidemias. COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE (REDUCTASE INHIBITORS: “STATINS”) ATORVASTATIN | FLUVASTATIN | PRAVASTATIN | SIMVASTATIN | ROSUVASTATIN | PITAVASTATIN | LOVASTATIN (not available in PH) These compounds are structural analogs of HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A). Most effective in reducing LDL Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions Has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels. A. CHEMISTRY & PHARMACOKINETICS Lovastatin and Simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives. Pravastatin has an open, active lactone ring Atorvastatin, Fluvastatin, and Rosuvastatin are fluorine-containing congeners that are active as given. Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% (it depends on what statins they are taking) with the exception of Fluvastatin, which is almost completely absorbed. All have high first-pass extraction by the liver. IMPORTANT: For patients with hepatic derangement or liver problems, you have to monitor these patients especially when you start giving your statins Plasma half-lives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours). Given once a day B. MECHANISM OF ACTION HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins, so hindi niya mapupuntahan yung last step to the formation of your LDL Induce an increase in high-affinity LDL receptors Effect increases both the fractional catabolic rate of LDL and the liver’s extraction of LDL precursors (VLDL remnants) from the blood, thus reducing LDL Because of marked first-pass hepatic extraction, the major effect is on the liver. Preferential activity in liver of some congeners appears to be attributable to tissue-specific differences in uptake. Modest decreases in plasma triglycerides and small increases in HDL also occur, especially in Pravastatin and Rosuvastatin Clinical trials They prevent or contribute to the reduction of recurrence of end-organ damages and heart attack, stroke, etc. Demonstrated significant reduction of new coronary events and atherothrombotic stroke. Mechanisms other than reduction of lipoprotein levels appear to be involved. The observation that reduction in new coronary events occurs more rapidly than changes in morphology of arterial plaques suggests that these pleiotropic effects may be important. PHARMACOLOGY 210 C. THERAPEUTIC DOSES AND DOSAGE It depends on what statin you are using Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL. Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be given these agents. NOTE: - - Because cholesterol synthesis occurs predominantly at night, reductase inhibitors — except atorvastatin, rosuvastatin, and pitavastatin—should be given in the evening. Absorption generally (with the exception of pravastatin and pitavastatin) is enhanced by food. Daily doses of lovastatin vary from 10 to 80 mg. Use in children is restricted to selected patients with familial hypercholesterolemias. Simvastatin is twice as potent and is given in doses of 5–80 mg daily. The most commonly used before because this was the first marketed extensively. Because of increased risk of myopathy with the 80-mg/d dose, the U.S. Food and Drug Administration (FDA) issued labeling for scaled dosing of simvastatin and combined ezetimibe/simvastatin in 2011 When you reach 80 mg, the chances of having myopathy are high kase pati yung fat na nasa skeletal muscle mo dinedegrade niya. It may cause myopathy especially in elderly. Pitavastatin is given in doses of 1–4 mg daily. Fluvastatin appears to be about half as potent as lovastatin on a mass basis and is given in doses of 10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and Rosuvastatin at 5–40 mg/d but the highest dosage that is usually used is 20 mg. The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage range in patients with moderate to severe hypercholesterolemia. D. TOXICITY PATHWAY Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Lowdensity lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low- density lipoproteins; R, LDL receptor. The Acetyl-CoA gets acted by the HMG-CoA and the reductase inhibitors prevents the formation of cholesterol and also prevents the acetylation of LDL, VLDL, and everything. These drugs usually pass your liver so ang toxicity niya is usually hepatic in nature ► tataas yung transaminases, elevation of SGPT and SGOT Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. Therapy may be continued in such patients in the absence of symptoms if aminotransferase levels are monitored and stable (kung hindi 3x normal, you can continue) 7 | Page Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. -the transaminases are three times than normal This finding portends more severe hepatic toxicity, you have to discontinue the medications These patients may present with malaise, anorexia, and precipitous decreases in LDL. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than three times the upper limit of normal. PHARMACOLOGY 210 kapag may ibang problems that may aggravate the myopathy elevated kahit na discontinue these NOTE: The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4 whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin, is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, north Asians, and the elderly Severe hepatic disease may preclude their use. Although the occurrence of myopathy is relatively uncommon especially even if you have hydro statins kapag may ibang problems that may aggravate the myopathy these can happen Kung more than three times asymptomatic, you have to medications NOTE: ▬ In general, aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months (if stable). ▬ Monitoring of liver enzymes should be more frequent if the patient is taking other drugs that have potential interactions with the statin. Excess intake of alcohol tends to aggravate hepatotoxic effects of statins. Statins are contraindicated to alcohol, makes the patient high risk of hepatic problems Fasting plasma glucose levels tend to increase 5– 7 mg/dL with statin treatment. Long-term studies have shown a small but significant increase in the incidence of type 2 diabetes in statin-treated patients, most of whom had findings of prediabetes before treatment. Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is NOT discontinued, myoglobinuria can occur, leading to renal injury. -kasi maiipon yung myoglobin, mastostock sa liver Myopathy may occur with monotherapy, but there is an increased incidence in patients also receiving certain other drugs. Myopathy is one of the concerns in statins because patients who are on monotherapy with this have also an increase incidence of having or receiving other drugs – kung nahalo yung gamut nila sa ibang drugs that potentiate the myopathy, this ma aggravate the myopathy that is carried by statins Although the occurrence of myopathy is relatively uncommon especially even if you have hydrostatins 8 | Page Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. Conversely, drugs such as phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma concentrations of the 3A4-dependent reductase inhibitors. Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of Fluvastatin and Rosuvastatin. Pravastatin and Rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group of antifungal agents, macrolides, and cyclosporine. Doses should be kept low and the patient monitored frequently. Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. All statins undergo glycosylation, thus creating an interaction with Gemfibrozil. Monitor the liver function Creatine kinase activity should be measured in patients receiving potentially interacting drug combinations. In all patients, CK should be measured at baseline If muscle pain, tenderness, or weakness appears, CK should be measured immediately and the drug discontinued if activity is elevated significantly over baseline. The myopathy usually reverses promptly upon cessation of therapy. Myopathy in the absence of elevated CK can occur. Rarely, hypersensitivity syndromes have been reported that include a lupus-like disorder, dermatomyositis, peripheral neuropathy, and autoimmune myopathy. Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 FIBRIC ACID DERIVATIVES PHARMACOLOGY Fenofibrate 145, 180, 200 210 mg tablet daily. D. TOXICITY GEMFIBROZIL | FENOFIBRATE Mainstay therapy for patients who hyperglyceridemia decrease levels of VLDL and, in some patients, LDL as well A. CHEMISTRY AND PHARMACOKINETICS  GEMFIBROZIL is absorbed quantitatively from the intestine and is tightly bound to plasma proteins. undergoes enterohepatic circulation and readily passes the placenta plasma half-life is 1.5 hours 70% is eliminated through the kidneys, mostly unmodified The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives.  FENOFIBRATE Most commonly used and given once a day An isopropyl ester that hydrolyzed completely in the intestine. Plasma half-life is 20 hours 60% is excreted in the urine as glucuronide and about 25% in feces. B. MECHANISM OF ACTION Fibrates function primarily as ligands for the nuclear transcription receptor PPAR-α. transcriptionally upregulate LPL, apo A-I, and apo A-II, and they downregulate apo C-III, an inhibitor of lipolysis. major effect is an increase in oxidation of fatty acids in liver and striated muscle increase lipolysis of lipoprotein triglyceride via LPL Only modest reductions of LDL occur in most patients. those with combined hyperlipidemia, LDL often increases as triglycerides are reduced. “So you to target both LDL and triglycerides” HDL cholesterol increases moderately. Part of this apparent increase is a consequence of lower triglyceride in plasma ► resulting in reduction in the exchange of triglycerides into HDL in place of cholesteryl esters. C. THERAPEUTIC USES AND DOSAGE Fibrates are useful hypertriglyceridemia in which VLDL predominate and in dysbetalipoproteinemia. may be of benefit in treating the hypertriglyceridemia that results from treatment with antiviral protease inhibitors. Gemfibrozil is 600 mg orally once or twice daily 9 | Page Rare adverse effects of fibrates include: ✓ rashes, ✓ gastrointestinal symptoms, ✓ myopathy, arrhythmias, ✓ hypokalemia, and ✓ high blood levels of aminotransferases or alkaline phosphatase. - Mas common sa statins ang muscle problems than the fibrates decreases in white blood count or hematocrit. Both agents may potentiate the action of anticoagulants, and doses of these agents should be adjusted. FIBRATES ✓ Risk of myopathy increases when fibrates are given with reductase inhibitors ✓ Fenofibrate is the fibrate of choice for use in combination with a statin. ✓ should be avoided in patients with hepatic or renal dysfunction. ✓ should be used with caution in patients with biliary tract disease or in those at higher risk such as women, obese patients, and Native Americans. NIACIN (NICOTINIC ACID) Niacin but not niacinamide decreases triglycerides and LDL levels, and Lp(a) in most patients. Often increases HDL level significantly A. CHEMISTRY AND PHARMACOKINETICS In its role as a vitamin, niacin (vitamin B3) is converted in the body to the amide, which is incorporated into niacinamide adenine dinucleotide (NAD) which in turn has a critical role in energy metabolism. effects on lipid metabolism that are poorly understood B. MECHANISM OF ACTION Niacin inhibits VLDL secretion, in turn decreasing production of LDL Increased clearance of VLDL via the LPL pathway contributes to reduction of triglycerides Inhibits the intracellular lipase of adipose tissue via receptor-mediated signaling, possibly reducing VLDL production by decreasing the flux of free fatty acids to the liver C. THERAPEUTIC USES AND DOSAGE Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 In combination with a resin or reductase inhibitor, niacin normalizes LDL in most patients with heterozygous familial hypercholesterolemia and other forms of hypercholesterolemia. In severe mixed lipemia that is incompletely responsive to diet, niacin often produces marked reduction of triglycerides, an effect enhanced by marine omega-3 fatty acids. useful in patients with combined hyperlipidemia and in those with dysbetalipoproteinemia. Niacin is clearly the most effective agent for increasing HDL and reduces Lp(a) in most patients. hypercholesterolemia, 2–6 g of niacin daily is usually required; more than this should not be given. other types of hypercholesterolemia and for hypertriglyceridemia, 1.5–3.5 g daily is often sufficient. Crystalline niacin should be given in divided doses with meals, starting with 100 mg two or three times daily and increasing gradually. D. TOXICITY Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose when niacin is started or the dose increased. Taking 81–325 mg of aspirin 30 minutes beforehand blunts this prostaglandin-mediated effect. Naproxen, 220 mg once daily, also mitigates the flush Tachyphylaxis to flushing usually occurs within a few days at doses above 1.5–3 g daily. Most side common side effect, this causes the discontinuation of Niacin Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans have been reported. Nausea and abdominal discomfort Should be avoided in patients with significant peptic disease. Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. liver function should be monitored at baseline and at appropriate intervals. association of severe hepatic dysfunction, including acute necrosis, with the use of over- the counter sustained-release preparations of niacin has been reported. This effect has not been noted to date with an extended-release preparation, Niaspan, given at bedtime in doses of 2 g or less. Hyperuricemia occurs in some patients and occasionally precipitates gout. Significant platelet deficiency can occur rarely and is reversible on cessation of treatment. 10 | Page PHARMACOLOGY CHECKPOINT: 210 1. Diet should be initiated as a first line therapy for patients who have hyperlipidemia? T/F 2. HMG-CoA reductase mediates the first committed step in sterol biosynthesis? T/F 3. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than two times the upper limit of normal. T/F 4. This may occur with monotherapy of statins? 5. This drug has toxic effect of tachyphylaxis to flushing? T/T/F/Myopathy/Niacin BILE ACID- BINDING RESINS  COLESTIPOL, CHOLESTYRAMINE & COLESEVELAN are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins. A. CHEMISTRY & PHARMACOKINETICS The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed. B. MECHANISM OF ACTION Bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7αhydroxylation, which is normally controlled by negative feedback by bile acids. C. THERAPEUTIC USES & DOSAGE used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. Supplement them with other medications to bring down the LDL further If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL, requiring the addition of a second agent such as a fibrate or niacin. are also used in combination with other drugs to achieve further hypocholesterolemic effect They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. They may be useful in digitalis toxicity Colestipol and cholestyramine are available as granular preparations. Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30–32 g/d may be needed for maximum effect. The usual dosage for a child is 10–20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colestipol is also available in 1-g tablets that must be swallowed whole, with a maximum dose of 16 g daily. Colesevelam is available in 625-mg tablets and as a suspension (1875-mg or 3750-mg packets). The maximum dose is six tablets or 3750 mg as suspension, daily. Resins should be taken in two or three doses with meals. D.TOXICITY Common: constipation and bloating, usually relieved by increasing dietary fiber. should be avoided in patients with diverticulitis. Heartburn and diarrhea are occasionally reported. patients who have preexisting bowel disease or cholestasis, steatorrhea may occur. Prothrombin time should be measured frequently in patients who are taking resins and anticoagulants. Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic acid, phenylbutazone, aspirin, and ascorbic acid, among others. In general, additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption INHIBITORS OF INTESTINAL STEROL ABSORPTION  EZETIMIBE Most famous sterol inhibitor inhibits intestinal absorption of phytosterols and cholesterol - yung raw form niya Added to statin therapy, it provides an additional effect, decreasing LDL levels and further reducing the dimensions of atherosclerotic plaques A. CHEMISTRY & PHARMACOKINETICS Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours. undergoes enterohepatic circulation, and its halflife is 22 hours Approximately 80% of the drug is excreted in feces 11 | Page PHARMACOLOGY 210 Plasma concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine B. MECHANISM OF ACTION selectively inhibits intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, is the target of the drug (which transports the lipoprotein) effective in the absence of dietary cholesterol because it also inhibits reabsorption of cholesterol excreted in the bile. C. THERAPEUTIC USES & DOSAGE effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5–20 mg/d. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone. D TOXICITY Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Not competitive inhibitor Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor Myositis has been reported rarely. INHIBITION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN Microsomal triglyceride transfer protein (MTP) plays an essential role in the addition of triglycerides to nascent VLDL in liver, and to chylomicrons in the intestine. Its inhibition decreases VLDL secretion and consequently the accumulation of LDL in plasma.  LOMITAPIDE Is available but is currently restricted to patients with homozygous familial hypercholesterolemia. is given orally in gradually increasing doses of 5 to 60-mg capsules once daily 2 hours after the evening meal. Causes accumulation of triglycerides in the liver in some individuals. Elevations in transaminases can occur. Patients must maintain a low-fat diet to avoid steatorrhea and should take steps to minimize deficiency of essential fat-soluble nutrients. Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 ANTISENSE INHIBITION OF APO B-100 SYNTHESIS PHARMACOLOGY   MIPOMERSEN an antisense oligonucleotide that targets apo B100, mainly in the liver. Subcutaneous injections of mipomersen reduce levels of LDL and Lp(a). Mild to moderate injection site reactions and flulike symptoms can occur drug is available only for use in homozygous INHIBITION OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN familial hypercholesterolemia restricted (REMS) program.  They found out that those patients who were, yung functional mutations on this gene usually results in low LDL and the absence of morbidities – so hindi sila nagkakaroon ng early CADs -> they developed drugs that inhibit the PCSK9 -> they came up with these evolocumab, alirocumab AGENTS UNDER DEVELOPMENT 12 | Page AMP KINASE ACTIVATION AMP-activated protein kinase acts as a sensor of energy status in cells. When increased ATP availability is required, AMP kinase increases fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Although the trials to date have been directed at decreasing LDL-C levels, AMP kinase activation may have merit for management of the metabolic syndrome and diabetes. An agent combining AMP kinase activation and ATP citrate lyase inhibition is in clinical trials. Development of inhibitors of convertase subtilisin/ kexin type 9 (PCSK9) followed on the observation that loss of function mutations results in very low levels of LDL and no apparent morbidity. Therapeutic agents currently available in this class are humanized antibodies to PCSK9 (EVOLOCUMAB, ALIROCUMAB). LDL reductions of up to 70% at the highest doses have been achieved with these agents when administered subcutaneously every two weeks. Triglycerides and apo B-100 are reduced, and Lp(a) levels decrease by about 25%. Rarely, hypersensitivity reactions have occurred Local reactions at the injection site, upper respiratory and flu-like symptoms have been observed more frequently. Use of these agents is restricted to patients who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. given with diet and maximal tolerated statin and/or ezetimibe. These agents are very expensive and not readily available 210 Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from mature, large diameter HDL particles to triglyceride rich lipoproteins that ultimately deliver the esters to liver whence both cholesterol and bile acids can be eliminated into the intestine. Inhibition of CETP leads to accumulation of mature HDL particles and diminution of the transport of cholesteryl esters to liver. The accumulation of large HDL particles does not have the cardioprotective effect anticipated on the basis of epidemiologic studies. Some reduction of LDL-C can be achieved and cholesterol efflux capacity enhanced. Thus far no drug (e.g., torcetrapib, anacetrapib) in this class has been approved. Ito yung mga susunod na medications or targets for the management na malalim yung treatment strategy PCSK9 INHIBITION CETP INHIBITION  CYCLODEXTRINS These are circular sugar polymers that can solubilize hydrophobic drugs for delivery and are approved for this purpose. They can also solubilize cholesterol from tissue sites such as arteriosclerotic plaque. Early-stage animal studies on this potential therapeutic activity are in progress TREATMENT WITH DRUG COMBINATION Combined Drug Therapy 1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin 2) when LDL and VLDL levels are both elevated initially 3) when LDL or VLDL levels are not normalized with a single agent 4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias The lowest effective doses should be used in combination therapy and the patient should be Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 monitored more closely for evidence of toxicity. In combinations that include resins, the other agent (with the exception of niacin) should be separated temporally to ensure absorption.   HMG-CoA REDUCTASE INHIBITORS & BILDE ACID-BINDING RESINS This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. NIACIN & REDUCTASE INHIBITORS If the maximum tolerated statin dose fails to achieve the LDL cholesterol goal in a patient with hypercholesterolemia, niacin may be helpful. This combination may be useful in the treatment of familial combined hyperlipoproteinemia.     COMBINATIONS OF RESINS, EZETIMIBE, NIACIN & REDUCTASE INHIBITORS These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. effects are sustained, and little compound toxicity has been observed. COMBINATIONS OF PCSK9 WITH STATIN AND EZETIMIBE ANTIBODY These agents can be used together to achieve maximal reduction of LDL. Because of the need for parenteral administration of PCSK9 antibody and its expense, this therapy is reserved for patients with familial hypercholesterolemia or atherosclerotic vascular disease who do not respond adequately to other regimens. NIACIN & BILE ACID-BINDING RESINS This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1–3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia.  210 Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. FIBRIC ACID DERIVATIVE & BILE ACIDBINDING RESINS This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis.  PHARMACOLOGY CHECKPOINT: 1) This class of drugs are used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. 2) This drug is currently restricted to patients with homozygous familial hypercholesterolemia. 3) T/F: For the drugs that inhibit microsomal triglyceride transfer protein, Patients must maintain a low-fat diet to avoid steatorrhea and should take steps to minimize deficiency of essential fat-soluble nutrients? 4) These drugs are given with diet and maximal tolerated statin and/or ezetimibe. 5) T/F: Combined drug therapy is used when LDL and VLDL levels are both decreased initially? Bile Acid-Binding resins/Lomitapide/T/PCSK9 inhibitor/F REDUCTASE INHIBITORS & EZETIMIBE This combination is synergistic in treating primary hypercholesterolemia and may be of use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function. REDUCTASE INHIBITORS & FENOFIBRATE Fenofibrate appears to be complementary with most statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin appears to be especially well tolerated. 13 | Page Apple/ Camille/Charitie/Klemson/Jenna PINES CITY COLLEGES DOCTOR OF MEDICINE 2025 Agents Used in Dyslipidemia Lecturer: Dr. Desi James Ojascastro Date: JANUARY 17, 2023 APPENDIX 14 | Page PHARMACOLOGY 210 Apple/ Camille/Charitie/Klemson/Jenna