Int J Atheroscler 2007;2(1):48-54

Dyslipidemia secondary to pharmacologic agents

Martinez TLR, Fernandes SC

Abstract The side effects of a series of drugs introduced for a great number of diseases include the emergence of dyslipidemias. In this review the different drug classes causing dyslipidemia and related disorders as well as the mechanism of this action in this respect are discussed: antipsychotic drugs, antiviral agents, beta-blockers, diuretics, hormones, immunosuppressants, retinoids. Key words: Secondary dispyslipidemia; Antipsychotic drugs; Antiviral agents; Beta-blockers; Hormones; Immunosuppresants; Retinoids

Introduction It is well known that dyslipidemias play as an important role in the risk for cardiovascular diseases1-3. We also know that serum lipoprotein levels are determined by an interaction between genetic and environmental factors. In the last century there was a great increase in the prevalence not only of dyslipidemias, but also of obesity, diabetes mellitus and arterial hypertension, that began in developed countries and is now also present in developing countries, characterizing a global epidemic of these diseases. This is due mainly to changes in lifestyle, with the great majority of the world population becoming each day more and more sedentary and adopting the western diet, rich in fat and sugars and poor in vegetables. Parallel to these changes in environment, the last decades also witnessed the discovery of new drugs for the treatment of old (arterial hypertension), new (acquired immunodeficiency syndrome) and newly recognized (metabolic syndrome) diseases. If these newcomer drugs represented the control or even the cure for many diseases, they also involved a multitude of adverse and side effects, some of them related to the metabolism of lipoproteins. These observations are even more important because pharmaceutical products widely used for the treatment of cardiovascular diseases such as arterial hypertension and heart failure are among the drugs that can cause dyslipidemias.
Heart Institute (InCor) - University of So Paulo, Brazil.

The drugs causing dyslipidemias, the importance of this effect and the molecular mechanisms related to it will be discussed in the following sections of this review.

Drugs causing dyslipidemias I. Antipsychotic drugs The novel antipsychotic drugs clozipine, olanzipine, quetiapine, risperidone, and zoprasidone have been increasingly used over the last years due to their efficacy and lack of extrapyramidal effects when compared with the old drugs. However, some reports have shown that at least two of these drugs, namely olanzepine and clozepine, have adverse metabolic effects predisposing to obesity, insulin resistance and dyslipidemia. Most of these reports are retrospective studies conducted on series ranging from 9 to 117 patients4-7. These studies measured lipid levels before and during treatment with these medications and compared these levels to those detected with the use of haloperidol or another old drug, and all of them showed a significant increase in triglyceride levels with the use of clozapine or olanzapine. In two prospective studies, Dursun et al. and Osser et al., studying 8 and 25 patients taking clozapine and olanzepine for 16 months and 12 weeks, respectively, also showed a significant increase in plasma triglyceride levels

Correspondence: Rua Comandante Ismael Guilherme 358, 04031-120, So Paulo, SP, Brazil. Received 12/20/2006 Revision accepted 01.15.2007

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with these drugs8,9. The increases in triglyceride levels observed in the above mentioned studies ranged from 11% to more than 50%. Wirshing et al. reviewed the data of 590 patients taking clozapine, olanzapine, risperidone, quetiapine, haloperidol and fluphenazine, 215 of whom had complete laboratory data and were included in the study. Patients receiving clozapine and olanzapine had a >30% increase in triglyceride levels, patients taking risperidone had a 19% increase while patients taking haloperidol and fluphenazine had decreased triglyceride levels. In addition, all the novel antipsychotic drugs caused a significant elevation in triglyceride levels when compared with the old agents10. These increases in triglycerides observed in patients taking these novel antipsychotic medications could not be separated from the weight gain that these patients also presented. These novel agents affect many central neurotransmitter systems that may alter the satiety and feeding behavior; and they block dopamine D2 and adrenergic 1-receptors that are stimulated by amphetamines and other sympathomimetic drugs that promote weight loss. These drugs also affect neurotransmission through serotonin (5HT) and histamine H1 receptors, and in this way may stimulate food intake. The effect on weight gain may also be responsible for the abnormalities in glucose metabolism observed with the use of these medications11. II. Antiviral agents In the year 2004 there were an estimated 42 million people living with HIV infection worldwide, most of them in poor countries. In the same year the number of antiretroviral drugs in use was about 20, distributed into 4 classes. One of these classes, the protease inhibitors (PI), was introduced in the mid-1990s, and soon incorporated into triple-agent, highly active antiretroviral therapy (HAART). This therapeutic scheme soon led to a marked decrease in HIV-related morbidity and mortality. However, these benefits have a great metabolic cost because a syndrome of lipodystrophy, insulin resistance and dyslipidemia has been reported to be associated with the use of the protease inhibitors12,13. In analyses of some clinical studies the mean changes in total cholesterol, triglycerides and low density lipoprotein cholesterol (LDL-C), were +40%, +148% and +19% after 64 months of treatment and +66%, +80% and +37% after 48 months of treatment, respectively14. The prevalence of this condition is about 50% among patients receiving PI12. Following these metabolic changes, the cardiovascular risk also increased, and the incidence of myocardial infarcSecondary dyslipidemias

tion in men receiving PI for more than 29 months is approximately 3 times that of a the general male population15. To better understand the molecular mechanisms by which PI lead to this syndrome of insulin resistance and dyslipidemia, it is important to keep in mind the physiology of the nuclear receptors. These belong to a superfamily of receptors, named steroid receptors, located in the cell nucleus, expressed mainly in the liver, adipose tissue, muscles, and intestines, and have an important role in the control of lipid, carbohydrate, energetic, biliary salt, and xenoand endobiotic metabolism. (Some) Some of this familys members are the peroxisome proliferator-activated receptors (PPAR), liver X receptor, pregnyl X receptor, farnesyl X receptor, and thyroid hormone receptor. All of these receptors share a common feature: when forming heterodimers with the retinoid X receptor (RXR), they function as transcription factors, and in this way they can modify the expression of a multitude of genes responsible for the control of the above mentioned conditions. For example, PPAR agonists have been used to treat disorders like diabetes mellitus and dyslipidemia. The pathophysiological mechanism of this PI-induced syndrome is complex and comprises interactions of the drugs with the cytoplasmic retinoid-acid binding protein-1 (CRABP-1), low-density lipoprotein receptor-related protein (LRP), and cytochrome P 450 3A isoforms16. HIV-1 PI have high affinity for the catalytic site of HIV1 protease. CRABP-1 and LRP have 58% and 63% homology, respectively, with this catalytic site and therefore may also be inhibited by the PI. CRABP-1 is a protein that binds all intracellular retinoic acid, presenting it to the cytochrome P 450 3A isoforms, which catalyze the transformation of retinoic acid into cis-9-retinoic acid, the single RXR ligand17. With the inhibition of CRABP-1 and without the cis-9-retinoic acid there is no activation of the RXR, no heterodimer formation with the other nuclear receptors, and loss of function of these as transcription factors, with the stage therefore being set for the appearance of important metabolic derangements. Inhibition and consequently dysfunction of the LRP leads to impairment of hepatic uptake of chylomicron remnants resulting in hyperlipidemia. The PIs, in particular ritonavir, are potent inhibitors of CYP 3A isoforms18, and this action also contributes to the synthesis of 9-cis-retinoic acid, with further dysfunction of the nuclear receptors. Among the members of the PI class, atazanavir, to date, has not been shown to be associated with dyslipidemia, and the lipids of patients with hypercholesterolemia or hypertriglyceridemia using the other PIs (ritonavir, indinavir, nelfinavir, and sequinavir) return to pre-

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treatment levels when the medication is shifted to atazanavir. III. Beta-blockers Chronic administration of beta-blockers, especially the non-selective beta-blockers, can lead to a small increase in triglyceride levels19,20 and a decrease in high-density lipoprotein cholesterol (HDL-C)20. The selective beta-1 receptor antagonists and the beta-blockers with intrinsic sympathomimetic activity (ISA) have a smaller effect on these lipids. Serum levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) are not affected by these drugs. At least 2 mechanisms may be responsible for these changes: unopposed -adrenergic stimulation, as a result of suppression of -adrenergic activity, causes increased inhibition of lipoprotein lipase activity. The reduction of lipoprotein lipase activity causes reduced catabolism of VLDL and triglycerides21. The action of the cholesteryl ester transfer protein, exchanging triglycerides from verylow-density lipoprotein (VLDL) to cholesterol esters from HDL, leads to triglyceride enrichment of HDL, with increased catabolism of HDL-C. This also could explain why non-selective beta-blockers, and the beta-blockers with ISA, with a reduced peripheral beta receptor antagonism have a smaller effect on lipids. The second mechanism is related to the small increase in insulin resistance caused by these drugs that can lead to hypertriglyceridemia and decreased levels of HDL-C. IV. Diuretics Thiazide diuretics adversely affect plasma lipids in shortterm use by increasing triglycerides, LDL-C and VLDL-C, and not significantly changing HDL-C levels22. In the Treatment of Mild Hypertension Study (TOMHS)23 an increase in plasma cholesterol was observed after 1 year of treatment, but this alteration did not persist after 2 years. Although there is some concern that these hyperlipidemic effects of diuretics might offset the benefits of treating hypertension with these agents, some studies24,25 show that this is not the case, and diuretic treatment is as effective as other drugs for this purpose. Moreover, these alterations are dose-related and of little clinical importance with the low doses now used for treating hypertension. We should also keep in mind that diuretics, like beta blockers, have adverse effects on glucose metabolism, leading to impaired glucose tolerance, insulin resistance, worsening of diabetes control and even precipitation of overt diabetes, although these effects are also dose-related. With the combination of diuretics and beta blockers, mainly the non-selective ones, there is a great risk of de50

veloping dyslipidemia and insulin resistance26, and this is of particular importance when treating hypertensive patients with increased risk for these diseases, for example patients with metabolic syndrome or obesity. The mechanisms underlying diuretic-induced dyslipidemia are not fully known, but one hypothesis is that, due to the decreased insulin sensitivity, there is an increased hepatic production of cholesterol27. Furosemide has the same effects on serum lipids as the thiazide diuretics with short-term use, whereas spironolactone has not shown these adverse effects. V. Hormones Among the hormones that can be used in medicine for treatment purposes, some can change the plasma levels of lipoproteins. These hormones and their action on lipoprotein metabolism are shown below. V.1. Estrogens and progestins These hormones are mainly used as contraceptives or hormone replacement therapy for postmenopausal women. In general, estrogens taken by the oral route cause a slight elevation in serum triglycerides and serum HDL-C, and a slight decrease in total cholesterol, LDL-C and Lp[a]28,29. These effects are also seen with synthetic estrogen analogs like clomiphene, that have been used since 1960 to aid fertility in women with some anovulatory disorders30. The increase in HDL-C levels occurs by an increase in apoA-1 production and not by a decrease in apoA-1 catabolism28. Administration of estrogens reduces adipose tissue lipoprotein lipase, and this effect can increase triglyceride levels31. When used in patients with underlying lipid disorders these compounds can induce severe hypertriglyceridemia leading to pancreatitis32. When used via transdermal patches, the level of the drug entering the liver by the portal circulation is low, with minimal hepatic effects and a consequent reduction of the alterations in lipid profile33,34. Estrogens may augment cholesterol concentration in the bile, increasing the risk of gallstone formation. Progestins, particularly those 19-nortestosterone-derived, have opposite effects, increasing LDL-C and decreasing HDL-C and triglycerides. Newer non-androgenic progestins have a somewhat lower effect, decreasing less HDL-C and triglycerides and increasing less LDL-C and total cholesterol. The concomitant use of progestins reduces estrogen-induced hypertriglyceridemia35. V.1-1. Hormonal contraceptives Since the introduction of combined oral contraceptives in the 1960s, their use has been associated with an inSecondary dyslipidemias

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creased incidence of arterial hypertension, myocardial infarction, stroke and venous thromboembolism. Because the plasma levels of lipoproteins are associated with some of these diseases, the biochemical profile of women taking various formulations of oral contraceptives began to be investigated. Nevertheless, the results obtained are often conflicting due to varying relative proportions of estrogen and progestins used in the different preparations. In general, the net effect is that HDL-C, LDL-C and total cholesterol levels are not changed while triglyceride levels are slightly increased. However, the contribution of these lipid changes to the incidence of cardiovascular diseases in women taking combined contraceptives is uncertain, and probably the prothrombotic condition associated with their use is more important in the pathophysiology of these diseases. V.1-2. Hormone replacement therapy (HRT) Although estrogens may favorably affect the lipid profile, increasing HDL-C and decreasing LDL-C, even though they may increase triglycerides, two large randomized controlled studies36,37. have not found HRT to reduce coronary events in postmenopausal women. Since then, HRT is no longer indicated for the prevention of cardiovascular events. V.2. Androgens Androgen preparations have been available for many years, but in general physicians are not as familiar with them as they are with the female hormones. Besides the treatment of male hypogonadism, other potential uses of androgens are been explored, and we have seen abuse by athletes and body builders. It is therefore important that physicians be aware of their side effects. Androgen administration increases hepatic lipase (HL) mRNA and plasma HL activity. This may the basis for the increase in LDL-C, mainly in the small and dense fraction, and for the decrease in the HDL-C3 subfraction that are observed with androgen use31,38,39. Androgen administration also suppresses adiponectin levels40 and can lead to a decrease in insulin sensitivity, contributing to an increase in LDL-C and triglycerides and to a decrease in HDL-C. V.3. Glucocorticoids Glucocorticoids have a wide range of actions but are mainly used for their potent anti-inflammatory and immunosuppressor effects which are due to the inhibition of the release of some cytokines. However, they also have important metabolic effects, decreasing insulin sensitivity, with increased gluconeogenesis and decreased peripherSecondary dyslipidemias

al glucose utilization, increased glycogen deposition, lipolysis and protein breakdown, and decreased body calcium stores. They may facilitate the actions of other endogenous substances (growth hormone, for example), and affect the function of kidneys, cardiovascular system, central nervous system and skeletal muscle. Regarding lipid metabolism, the body fat redistribution that occurs with endogenous or exogenous hypercorticism is well known; peripheral and truncal adipocytes have different sensitivities to insulin and to glucocorticoidfacilitated lipolytic effects. Truncal adipocytes predominantly respond to the elevated levels of insulin resulting from glucocorticoid-induced hyperglycemia, and the peripheral adipocytes are less sensitive to insulin and respond to the glucocorticoid-facilitated effects of other lipolytic hormones. Due to their permissive role, facilitating the lipolytic action of growth hormone and beta adrenergic receptor agonists, glucocorticoids cause an increase in free fatty acids leading to an increase in both HDL-C and LDL-C and also in triglycerides40. VI. Immunosuppressants Immunosuppressants are a class of drugs used to treat diseases considered to have an autoimmune etiology, and also in organ and tissue transplantation. Although great advances have been made in the treatment of these conditions, the dyslipidemia associated with the use of immunosuppressants is an important cause of the morbidity occurring in the follow-up of these patients. Besides these agents, other factors contributing to the development of dyslipidemia include genetic factors, age, sex, body weight, renal failure, and use of other drugs, such as beta blockers and diuretics41,42. There are four classes of immunosuppressants currently in use: (1) glucocorticoids, (2) calcineurin inhibitors, (3) antiproliferative/antimetabolic agents, and (4) antibodies. Hyperlipidemia is mainly seen with the use of cyclosporine, sirolimus, and glucocorticoids, and the lipid profile differs with the use of the individual agents. The effects of glucocorticoids on lipids are described above in section V-3. Calcineurin inhibitors: cyclosporine and tacrolimus are currently the cornerstones of immunosuppression, and the great majority of modern-day treatment regimens use one of these two agents. Some studies show a marked dyslipidemia associated with cyclosporine therapy43-46. The increase in total cholesterol reaches 30%, the increase in triglycerides reaches 69%, and the increase in LDL-C reaches 57%, while HDL-C may remain unchanged or increases up to 61%. Kuster et al.47 found that increas51

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ing blood cyclosporine levels were associated with increased total cholesterol (TC), LDL-C, and TC:HDL-C ratio, but not triglycerides. Moreover, cyclosporine levels were inversely associated with HDL-C, HDL3-C, and apo A. Although tacrolimus has also the potential to cause an adverse lipid profile, its effect is smaller than that observed with cyclosporine48-50. In general, cyclosporine treatment leads to more cases of hypercholesterolemia , with higher total cholesterol and LDL-C than tacrolimus treatment. Calcineurin inhibitors may cause dyslipidemia through several mechanisms: impairment of hepatic cholesterol 7-hydroxylase, with a consequent reduction of bile acid synthesis from cholesterol, altered hepatic LDL receptor activity, increased activity of hepatic lipase (HL), inhibition of lipoprotein lipase (LPL), and increased activity of lecithin-cholesterol-acyl-transferase (LCAT)51-53. Cyclosporine also causes a greater increase in apolipoprotein (apo) B than tacrolimus (21% and 11%, respectively)54 and also leads to up-regulation of apo CIII55. Besides causing increased lipoprotein levels, cyclosporine induced greater LDL-C oxidation at three and six months when compared with baseline levels and tacrolimus56. This can increase the atherosclerosis risk associated with cyclosporine. Antiproliferative agents: regarding the three drugs of this class in use today, there are no data indicating that the use of mycophenolate mofetil or azathioprine is associated with dyslipidemia. In contrast, sirolimus can produce an early and profound increase in total cholesterol (up to 77%) and triglycerides (up to 97%)52,54,57. Sirolimus increases apo B-100, apo C-II, apo C-III, and hepatic verylow-density lipoprotein cholesterol (VLDL-C) production and decreases heparin-induced LPL activity, leading to a greater increase in total cholesterol and triglycerides than that seen with cyclosporine or tacrolimus55,58,59. Sirolimus increases the production of triglyceride-rich lipoproteins and prevents their breakdown. Due to the additive effects of these drugs on lipid profiles, the association of cyclosporine and sirolimus should be used with great caution or should not be used at all. It should be pointed out that the association of calcineurin inhibitors, particularly tacrolimus (but also cyclosporine), with glucocorticoids is diabetogenic due to a negative effect of tacrolimus on pancreatic beta cells. Especially at risk are obese, Afro-American and Hispanic patients. VII. Retinoid therapy Retinoids are vitamin A-derived compounds responsible for the regulation of a wide variety of metabolic and
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developmental processes, and are used therapeutically for the treatment of dermatologic disorders, vitamin A deficiency diseases and therapy or chemoprophylaxis for certain types of cancer. Dyslipidemia is a common side effect of the treatment with these compounds and is characterized by increased triglycerides, total cholesterol and LDLC and decreased HDL-C levels60,61. Whereas elevation of cholesterol is observed in patients who had dyslipidemia before the treatment, triglyceride elevation is unpredictable and appears in nearly 20% of patients treated with retinoids. Retinoids are ligands for specific receptors that belong to the superfamily of nuclear receptors and, upon their activation, the complexes formed by the ligand and the receptor act as transcription factors that control specific target genes. Two classes of retinoid receptors have been identified: RAR and RXR. When activated, RAR form heterodimers with RXR, and RXR may form homodimers or heterodimers not only with RAR, but also with some other nuclear receptors, such as PPAR, FXR, or LXR, all of them very important in the control of metabolism. These homo- or heterodimeric complexes bind to and modulate transcription from specific response elements located in the regulatory regions of the genes. In this way, retinoids influence key genes that control triglycerides and HDL-C metabolism. Two genes are of particular importance in the control of triglyceride metabolism: the lipoprotein lipase and the apo CIII genes. Lipoprotein lipase (LPL) is an enzyme that hydrolyses triglycerides present in chylomicrons and VLDL-releasing fatty acids, and also plays a role in lipoprotein remnant clearance from plasma, acting as a bridge linking lipoproteins to their specific receptors. Deficiency in this enzyme leads to a severe fasting hypertriglyceridemia. In both humans and rodents, retinoid treatment leads to hypertriglyceridemia but, whereas in rodents isotretinoin decreases LPL activity in adipose tissue and skeletal muscle, this does not occur in humans62. Apo CIII is an antagonist of triglyceride metabolism and its overexpression causes hypertriglyceridemia. Apo CIII inhibits the binding of triglyceride-rich lipoproteins to the endothelial surface, thus preventing the action of LPL. In addition, it also interferes with the apo E-mediated receptor clearance of lipoproteins from plasma. The increase in triglyceride levels observed with the use of retinoids in humans is also accompanied by the increase in apo CIII levels, and it was demonstrated that retinoids induce the expression of the apo CIII gene in liver, and that RXR-specific agonists induce apo CIII expression in human hepatocytes and human hepatoma HepG2 cells63. Administration of retinoids results in a decrease in
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HDL-C concentration, although the apo AI and apo AII concentrations are not affected62. Retinoids also increase the expression of the cholesteryl ester transfer protein (CETP), ABCG1 and ABCG 2 (these last 2 promote a unidirectional efflux of cholesterol and phospholipids from cells to HDL). Thus, the effect of retinoids on HDL metabolism is complex and needs further studies to be clarified. When using retinoids, it is very important to weigh their beneficial actions against their metabolic side effects that can increase the cardiovascular risk of the patient.

17. 18. 19. 20. 21.

22. 23.

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