Pharmacology of Hyperlipidemia Lecture Notes PDF
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Wayne State University
Lawrence H. Lash, Ph.D.
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Summary
These lecture notes provide a detailed overview of the pharmacology of hyperlipidemia, covering learning objectives, lecture outlines, various aspects of atherosclerosis, statins, and other cholesterol-lowering drugs. They aim to explain the causal role of LDL-C in cardiovascular disease and the mechanisms of treatment.
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Lecture 58: Pharmacology of Hyperlipidemia Pharmacology of Hyperlipidemia Lawrence H. Lash, Ph.D. Professor, Department of Pharmacology Office: 7312 Scott Hall T: 1-313-577-0475; E-mail: [email protected] Learning Objectives: 1. Describe the causal role played by LDL-C in cardiovascular dis...
Lecture 58: Pharmacology of Hyperlipidemia Pharmacology of Hyperlipidemia Lawrence H. Lash, Ph.D. Professor, Department of Pharmacology Office: 7312 Scott Hall T: 1-313-577-0475; E-mail: [email protected] Learning Objectives: 1. Describe the causal role played by LDL-C in cardiovascular disease (CVD). 2. Describe the physiological mechanisms that control serum cholesterol levels and identify potential pharmacological targets for modulating serum cholesterol levels. 3. Describe how the science of familial hypercholesterolemia informs CVD treatment. 4. Describe the mechanisms by which statins reduce CVD risk. 5. Describe the adverse reactions and drug interactions associated with statin treatment. 6. Describe the mechanisms and actions of other classes of cholesterol-lowering medications. 1 Lecture 58: Pharmacology of Hyperlipidemia Lecture Outline Pharmacology of Hyperlipidemia I. Atherosclerosis and cardiovascular disease: Background pathophysiology A. Lipid hypothesis. B. Importance of LDL-C and HDL-C in CVD. II. Control of serum cholesterol levels: Role of dietary uptake, biosynthesis, LDL-R, and bile acids. A. Regulation of cholesterol biosynthesis. B. Familial hypercholesterolemia and LDL-R. C. PCSK9 discovery. III. Statins. A. Mechanisms. 1. Direct impact on reducing cholesterol biosynthesis. 2. Indirect impact: Upregulation of LDL-R. B. Clinical use: Lower LDL-C and risk of CV events. 1. CVD risk factors. 2. Statin use for secondary and primary prevention. 3. Effects on lipid profile. C. Adverse reactions. D. Drug interactions. IV. Other classes of cholesterol-lowering drugs. A. PCSK9 inhibitors. B. Ezetimibe. C. Bile acid sequestrants. D. Niacin. E. Fibrates. V. Statin combination therapies. 2 Lecture 58: Pharmacology of Hyperlipidemia Pharmacology of Hyperlipidemia I. Atherosclerosis and cardiovascular disease: Background pathophysiology. A. Lipid hypothesis. Plasma lipids are transported in complexes called lipoproteins. Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemia or hyperlipidemia. Hyperlipemia specifically denotes increased levels of triglycerides. Lipid Hypothesis: High serum cholesterol levels lead to plaque buildup. This realization led to two treatment strategies: 1) Limiting dietary fat, particularly cholesterol; and 2) Development of cholesterol-lowering drugs (e.g., statins). Major clinical consequences of hyperlipidemia: Acute pancreatitis Atherosclerosis Atherosclerosis: Leading cause of death for both genders in the USA and other Western countries; Lipoproteins containing apolipoprotein (apo) B-100 convey lipids into the artery wall; These are low-density (LDL), Intermediate-density (IDL), very-low-density (VLDL), and lipoprotein(a) (Lp[a]); Remnant lipoproteins that 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 atherosclerotic plaques (atheromas) include foam cells (i.e., transformed macrophages) and smooth muscle cells filled with cholesteryl esters; Lipoproteins become modified by free radicals and undergo endocytosis and bind to scavenger receptors; 3 Lecture 58: Pharmacology of Hyperlipidemia The atheroma grows with the accumulation of foam cells, collagen, fibrin, and frequently calcium; Besides slowly occluding blood vessels, these lesions or atherosclerotic plaques can rupture, leading to activation of platelets and formation of occlusive thrombi. B. Importance of LDL-C and HDL-C in CVD. Definitions of types of circulating lipids: Chylomicrons: synthesized from fatty acids of dietary triglycerides and cholesterol absorbed by small-intestinal epithelial cells; are the largest and lowest-density plasma lipoproteins. Chylomicron remnants: After removal of much of the dietary triglycerides by lipoprotein lipase (LPL) at the capillary luminal surface, the chylomicron remnants (which contain all the dietary cholesterol) detach from the capillary surface and are removed from the circulation by the liver. Very low-density lipoproteins (VLDL): VLDLs are produced in the liver when triglyceride production is stimulated by an increased flux of free fatty acids or by increased de novo synthesis of fatty acids by the liver. VLDLs are catabolized in capillary beds by LPL, similar to the process for chylomicrons. Low-density lipoproteins (LDL): Virtually all the LDL particles in the circulation are derived from VLDL. Plasma clearance of LDL is mediated primarily by LDL receptors (LDL-R). Because the liver expresses a large complement of LDL-Rs and removes about 75% of all LDL from the plasma, manipulation of hepatic LDL-R gene expression is a very effective way to modulate plasma LDL-cholesterol (LDL-C) levels. Note: The most effective dietary alteration (decreased consumption of saturated fat and cholesterol) and pharmacological treatment (statins) for hypercholesterolemia act by increasing hepatic LDL-R expression. High-density lipoproteins (HDL): HDLs are protective lipoproteins so are said to exert antiatherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL are an independent risk factor for atherosclerotic disease and thus are a potential target for intervention. A schematic summary of liver metabolism of lipoproteins is shown in Figure 1. A schematic summary of pathways involved in chylomicron metabolism is shown in Figure 2. 4 Lecture 58: Pharmacology of Hyperlipidemia Figure 1. Metabolism of lipoproteins of Figure 2. The major pathways involved hepatic origin. in the metabolism of chylomicrons The heavy arrows show the primary synthesized by the intestine and VLDL pathways. Nascent VLDL are secreted synthesized by the liver. via the Golgi apparatus. They acquire additional apo C lipoproteins and apo E Chylomicrons are converted to from HDL. Very-low-density lipoproteins chylomicron remnants by the hydrolysis (VLDL) are converted to VLDL remnants of their triglycerides by LPL. (IDL) by lipolysis via lipoprotein lipase in Chylomicron remnants are rapidly the vessels of peripheral tissues. In the cleared from the plasma by the liver. process, C apolipoproteins and a portion “Remnant receptors” include the LRP, of the apo E are given back to high- LDL receptors, and perhaps other density lipoproteins (HDL). Some of the receptors. FFA released by LPL is used VLDL remnants are converted to LDL by by muscle tissue as an energy source or further loss of triglycerides and loss of taken up and stored by adipose tissue. apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B- 100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum. (Adapted with permission from Rosenberg RN, Prusiner S, DiMauro S, et al: The Molecular and Genetic Basis of Neurological Disease, 2nd ed. Philadelphia, PA: Butterworth- Heinemann; 1997.) 5 Lecture 58: Pharmacology of Hyperlipidemia II. Control of serum cholesterol levels: Role of dietary uptake, biosynthesis, LDL-R, and bile acids. A. Regulation of cholesterol biosynthesis. Figure 3. Lovastatin and the HMG-CoA reductase reaction. HMG-CoA reductase: rate-limiting step in de novo synthesis of cholesterol. There are 4 components to the regulation of cholesterol levels: 1) Dietary intake. 2) New synthesis: Typically, the body makes about 10-fold more cholesterol per day than is ingested in the diet; the liver is the major synthesis site. 3) Cellular uptake of LDL particles from serum: Mediated by LDL-R. 4) Excretion: Cholesterol is only removed from the body through the low-level excretion of bile acids, which are detergent-like molecules derived from cholesterol. Most of the secreted bile acids are recycled back from the intestine to the liver. Potential pharmacological targets to regulate serum cholesterol levels are illustrated in Figure 4. 6 Lecture 58: Pharmacology of Hyperlipidemia Figure 4. Sites of action of HMG-CoA reductase inhibitors, PCSK9 MAb, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. PCSK9 MAb decreases destruction of LDL receptors by PCSK9. VLDL, very- low-density lipoproteins; R, LDL receptor; L, lysosome. B. Familial hypercholesterolemia and LDL-R. Autosomal dominant trait. Usual genetic causes are mutation in gene for LDL-R, producing either nonfunctional or kinetically impaired LDL-Rs. In most heterozygotes, serum cholesterol levels range from 260 to 400 mg/dL but triglycerides are normal. CHD tends to occur prematurely. In homozygous familial hypercholesteremia, CHD can occur in childhood and levels of cholesterol can range from 500 to > 1000 mg/dL. In heterozygous patients, LDL can be normalized with either HMG-CoA reductase inhibitors or combined drug regimens (see Figure 4). Homozygotes and those who retain even minimal LDL-R function may partially respond to combination of niacin, ezetimibe, and HMG-CoA reductase inhibitors. C. PCSK9 discovery. PCSK9 protein was discovered by analysis of additional familial hypercholesteremia cases, which identified dominant, up-regulating mutations that map to a unique gene (i.e., distinct from the LDL-R gene) called PCSK9. 7 Lecture 58: Pharmacology of Hyperlipidemia The PCSK9 gene encodes a serum protease that is a proprotein convertase that has major effects on LDL-R. PCSK9 protein binds to LDL-R, inducing its endocytosis and lysosomal degradation in an LDL binding-independent manner. Thus, individuals with abnormally high levels of PCSK9 protein have reduced LDL-R levels and thus, high levels of serum LDL-C and high heart attack risk. Conversely, analysis of the genomes of some individuals with low LDL-C identified inactivating PCSK9 mutations. III. Statins. A. Mechanisms. The statins are competitive inhibitors of HMG-CoA reductase because they are structural analogues of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A). The example of lovastatin is shown in Figure 5. Major statins include: Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Rosuvastatin Direct effect of statins: competitive inhibition of HMG-CoA reductase; occurs by formation of a mevalonic acid- like moiety. Liver: Major site of cholesterol storage and synthesis so also the major site of statin action. Besides directly inhibiting the rate- limiting step in cholesterol biosynthesis to lower LDL-C, statins also have an Figure 5. Inhibition of HMG-CoA indirect effect involving transcriptional reductase. up-regulation of LDL-R. Top: The HMG-CoA intermediate that is the immediate precursor of mevalonate, Statin-induced decreases in intracellular a critical compound in the synthesis of cholesterol levels lead to up-regulation cholesterol. Bottom: The structure of of LDL-R transcription, enabling lovastatin and its active form, showing increased LDL endocytosis and thus, the similarity to the normal HMG-CoA decreased serum LDL-C levels. intermediate (shaded areas). 8 Lecture 58: Pharmacology of Hyperlipidemia B. Clinical use: Lower LDL-C and risk of CV events. 1. CVD risk factors. Table 1. Risk factors for atherosclerotic cardiovascular disease. Risk factor category Comments Age Male > 45 years of age or female > 55 years of age Family history of premature A first-degree relative (male < 55 years of age or CHD* female < 65 years of age when the first CHD clinical event occurred) Current cigarette smoking Defined as smoking within the preceding 30 days Hypertension Systolic bp ≥ 140, diastolic bp ≥ 90 or use of antihypertensive medication irrespective of bp; risks increase progressively with bp > 115/75 Low HDL-C < 40 mg/dL (males); < 50 mg/dL (females) High LDL-C > 130 mg/dL Obesity BMI > 25 kg/m2 and waist circumference > 40 inches (males) or > 35 inches (females) Type 2 diabetes mellitus Insulin resistance, hyperinsulinemia, and elevated blood glucose associated with increased CVD risk * CHD (Coronary Heart Disease): defined as myocardial infarction, coronary death, or a coronary revascularization procedure. Summary and Recommendations for Treatment of Elevated LDL-C: https://www.uptodate.com/contents/management-of-elevated-low-density-lipoprotein- cholesterol-ldl-c-in-primary-prevention-of-cardiovascular-disease Counsel patients to exercise, eat a prudent diet, and lose weight as appropriate. Calculate a baseline risk for CVD events in all adult patients. For patients with LDL-C > 100 mg/dL (2.59 mmol/L) and > 10% risk of a CVD event within 10 years, recommend statin therapy. For such patients with a 10-year risk of 5-10%, discuss the potential benefits and costs/risks to patients for statin therapy. In primary prevention, when decision is made to treat, suggest a moderate dose of a statin (e.g., 20 mg of atorvastatin or 5-10 mg of rosuvastatin) rather than starting at a higher dose. 9 Lecture 58: Pharmacology of Hyperlipidemia Measure LDL-C response at 6 weeks after initiating therapy and every 12 months thereafter. For patients without established disease but with a very high risk for a CVD event, high-intensity statin therapy is recommended. For most primary prevention patients who do not tolerate statins, recommendation is not to use a non-statin lipid-lowering drug; rather, potential interventions include lifestyle modifications and, in higher-risk patients, antiplatelet therapy. However, in patients with very high LDL-C levels and high CVD risk, it is reasonable to consider a non-statin drug. Summary and Recommendations for Treatment of Low Levels of HDL-C: https://www.uptodate.com/contents/hdl-cholesterol-clinical-aspects-of-abnormal-values Low levels of HDL-C are associated with increased risk of CVD events and high levels with a decreased risk. No firm evidence of benefit from drug therapy to target low HDL-C, so drug therapy not recommended. Exercise, weight loss (in overweight subjects), smoking cessation, and substitution of monounsaturated for saturated fatty acids raise HDL-C. 2. Statin use for secondary and primary prevention. Rather than treating ongoing symptoms, statins are mostly used as risk reduction drugs – lowers the risk of CV events, i.e., heart attacks and strokes. Cardiovascular disease is a “silent killer,” with the patient typically being asymptomatic until a precipitating event (e.g., heart attack). Treatment is primarily about assessing risk and then reducing risk. ADME: Properties vary with the different statins. Statins are orally administered either once or twice daily in pill form. Intestinal absorption varies from 30% to 85%. 10 Lecture 58: Pharmacology of Hyperlipidemia All statins, except simvastatin and lovastatin, administered in the beta-hydroxy form, which is the form that inhibits HMG-CoA reductase. Simvastatin and lovastatin are administered as inactive lactones that are converted in the liver to their respective beta-hydroxy acids. Extensive first-pass hepatic uptake of all statins, mediated primarily by the organic anion transporter OATP1B1. Time of administration: Because hepatic cholesterol synthesis is maximal between midnight and 2 AM, statins with short half-lives ≤ 4 hours (all except atorvastatin and rosuvastatin) are administered in the evening. Atorvastatin and rosuvastatin have longer half-lives and may be taken at other times of the day to optimize adherence. Differences among statins in plasma protein binding and liver metabolism contribute to differences in bioavailability. 3. Effects on lipid profile. Table 2. Classification of plasma lipid levels (in mg/dL). Non-HDL-C < 130 Desirable 130 – 159 Above desirable 160 – 189 Borderline high 190 – 219 High ≥ 220 Very high HDL-C < 40 (males); < 50 (females) Low > 60 High; desirable because of negative risk LDL-C < 70 Optimal for very high risk < 100 Desirable 100 – 129 Above desirable 130 – 159 Borderline high 160 – 189 High ≥ 190 Very high Triglycerides < 150 Normal 150 – 199 Borderline high 200 – 499 High ≥ 500 Very high Most prominent effect is on LDL-C levels, which can be reduced by 25 to 55%, depending on the statin and dose used. 11 Lecture 58: Pharmacology of Hyperlipidemia HDL-C levels: Impact of statins is modest, with some studies finding 10 – 20% elevations at most and other studies finding no significant changes. Triglycerides: High TG levels (e.g., > 250 mg/dL) are substantially lowered by statins, often by 30 – 50%. C. Adverse reactions. As cholesterol is an essential membrane component, one might worry that drug-induced manipulation of cholesterol levels might lead to profound toxicities. However, a broad portion of the population has been taking statins for decades and it is quite clear that they have a mild side effect profile. Side effects do occur but are relatively rare and are generally mild. Myopathy: muscle weakness and/or flu-like muscle pain; most frequent statin side effect, occurring in 5–10% of patients. Dose-dependent side effect; Generally reversed by reducing dosage or switching to a different statin; Hypothesis that myopathy is due to coenzyme Q10 deficiency; o CoQ10 is an essential mitochondrial respiratory chain cofactor o CoQ10 is a product of the sterol biosynthetic pathway; thus, its synthesis would also be inhibited by statins; o Although CoQ10 is often found to be reduced when myopathy presents, no clear benefit on myopathy incidence is seen with CoQ10 supplementation. Rhabdomyolysis: o Rare, but very serious and potentially fatal statin toxicity; o Rapidly induced muscle breakdown o Likely involves an autoimmune component; o Breakdown products damage and may shut down kidneys. Type 2 Diabetes Risk: Increased blood glucose levels (increased HbA1C and fasting glucose levels) in some patients taking statins; Large-scale patient studies indicate a 9% increased risk of developing type 2 diabetes mellitus with long-term statin therapy; 12 Lecture 58: Pharmacology of Hyperlipidemia Nonetheless, cardiovascular benefits of statin therapy still judged to far outweigh the increased diabetes risk. Cognitive Problems: Anecdotal patient reports of memory problems that resolve with discontinuation of statin therapy; Placebo-controlled studies have shown no obvious cognitive effects. D. Drug interactions. Myopathy is often due to interacting drugs that increase blood levels of statins; Simvastatin, lovastatin, and atorvastatin are metabolized by CYP3A4: o Drugs that inhibit CYP3A4 can dramatically increase circulating levels of statins; o Examples of common CYP3A4 inhibitors include macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., itraconazole), many HIV protease inhibitors, and grapefruit juice; o Drugs such as phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the plasma concentrations of statins metabolized by CYP3A4. Inhibitors of CYP2C9, such as ketoconazole and its congeners metronidazole, sulfinpyrazone, amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Gemfibrizol: o Taken for high triglycerides (see below); o Doubles plasma levels of statins, increasing risk of myopathy and rhabdomyolysis; o Gemfibrizol blocks liver uptake and glucuronidation of many statins, thus inhibiting statin metabolism and turnover; o The alternative fibrate, fenobibrate, does not have these effects and is thus preferred for statin combination therapy. Conclusion: Statins have hugely impacted cardiovascular health, preventing millions of heart attacks and strokes over the past few decades. Each new clinical study finds lower mortality with increased statin dosing. This improvement is seen for individuals both at the high and low ends of the risk spectrum. Even for patients with LDL-C levels within the normal range, further lowering of LDL-C levels with statins substantially reduces CHD/stroke risk. 13 Lecture 58: Pharmacology of Hyperlipidemia IV. Other classes of cholesterol-lowering drugs. A. PCSK9 inhibitors. Recently approved class of drugs; monoclonal antibodies that raise LDL-R levels, leading to decreased LDL-C levels. Examples: Alirocumab, evolucumab; Humanized monoclonal antibodies bind and remove PCSK9 from the blood: o Increase in surface LDL-R o Decrease in blood LDL-C Highly effective – up to 70% reduction in LDL-C levels; may be used to augment statin therapy; Target patients: those whose LDL-C levels are insufficiently lowered by statins and potentially patients who are unable to take statins due to side effects; Administered by injection, 2x per month; Appears to be safe and effective and not likely to have the myopathy side effects of the statins; Unfortunately, very high cost due to limited insurance coverage: As of mid-2016, mean required cost-sharing for a 30-day supply was $336 for alirocumab and $321 for evolocumab. This contrasts with cost-sharing for atorvastatin, which averaged $4. B. Ezetimibe. Inhibits the intestinal cholesterol transporter, blocking absorption of cholesterol from the diet; Limited use as monotherapy because only a minority of the body’s cholesterol is typically absorbed from the diet; Figure 6. Structure of ezetimibe. Typically used in combination with statins: Vytorin (= simvastatin + ezetimibe) can reduce LDL-C levels by 60%. 14 Lecture 58: Pharmacology of Hyperlipidemia C. Bile acid sequestrants. Bile acids, a collection of detergent-like chemicals derived from cholesterol that are secreted by the liver (gall bladder) into the intestine to solubilize and absorb dietary fats; ~ 50% of the cholesterol synthesized daily is used for bile acid synthesis; Bile acids are typically recycled – secreted and then reabsorbed; Bile acid-binding resins: o Examples: cholestyramine, colestipol; o Were the main cholesterol-lowering medications prior to the introduction of statins; o Insoluble, gel-like substances – are ingested, reside in the intestine, and tightly bind to bile acids and are eventually eliminated in the feces; o Causes more cholesterol to be diverted to bile acid synthesis, reduces liver cholesterol levels thereby inducing more LDL-R-mediated scavenging of serum LDL-C; o When used as monotherapy, the depletion of liver cholesterol is often compensated by up-regulation of the biosynthetic pathway; o However, when used in combination with statins, the cholesterol biosynthetic pathway is blocked, increasing the benefit of these drugs. D. Niacin. Favorable effects on all lipids; Lowers LDL-C, raises HDL-C, and lowers triglycerides; High doses required for LDL-C lowering (2-3 g/day); Figure 7. Structures of niacin (nicotinic Side effects: flushing, GI, pruritis, acid) and nicotinamide. blurred vision, etc. Benefits not clearly demonstrated. Mechanism: Niacin inhibits VLDL secretion, in turn decreasing production of LDL and reducing triglycerides. 15 Lecture 58: Pharmacology of Hyperlipidemia E. Fibrates. Mostly used for lowering triglycerides; effects on LDL-C and HDL-C are variable; When used with statins (e.g., in patients with high LDL-C + high triglycerides) get substantial increase in risk of myopathy and rhabdomyolysis; Mechanism: Primarily as ligands for the nuclear transcription Figure 8. Structures of gemfibrozil and receptor PPAR-alpha; fibrates fenofibrate. transcriptionally up-regulate certain proteins and down- regulate other proteins, resulting in increased lipolysis and hepatic and muscle fatty acid oxidation. V. Statin combination therapies. For patients for whom LDL-C lowering is insufficient with statins alone or for patients who are unable to take higher doses of statins due to side effects (e.g., myopathy), a statin can be combined according to the following guidelines: 1. Statin + PCSK9 inhibitor: Increased LDL-R transcription (statin) + reduced receptor turnover (PCSK9 inhibitor) à 70% LDL-C reductions with proportionate reductions in mortality and morbidity. 2. Statin + ezetimibe: Blocks new synthesis (statin) + dietary uptake (ezetimibe) à Decreases LDL-C by up to 60% with proportionately augmented mortality and morbidity benefit. 3. Statin + bile acid binding resin (e.g., cholestyramine or colestipol): Induced excretion of bile acids (cholesterol biosynthesis pathway) à reduced liver cholesterol levels and up-regulation of LDL-R; 20-30% more LDL-C reductions than statins alone. 4. Statin + niacin: Niacin typically improves all aspects of the lipid profile and is often prescribed to patients with low HDL-C levels. No added mortality/morbidity benefit over statins alone, yet increased myopathy risk. 16 Lecture 58: Pharmacology of Hyperlipidemia 5. Statin + fibrates: For patients with high triglycerides + high LDL-C à Substantially increased myopathy risk. Statin – Gemfibrizol combination should be avoided. References: Basic & Clinical Pharmacology, 16th Edition by Vanderah, T.W., McGraw Hill, New York, 2024. Chapter 35: Agents Used in Dyslipidemia. https://accessmedicine.mhmedical.com/book.aspx?bookid=3382 Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th Edition, Brunton, Chabner & Knollman, McGraw Hill, New York, 2023. Chapter 37: Drug Therapy for Dyslipidemias. https://accesspharmacy.mhmedical.com/book.aspx?bookid=3191 17