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Management of atherogenic dyslipidemia of the metabolic syndrome: evolving rationale for combined drug therapy Gloria Lena Vega, PhDa,b,* a
Department of Clinical Nutrition, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052, USA b Nutrition and Lipid Metabolism Research Laboratory, Metabolic Unit, Veterans Administration Medical Center, 4500 South Lancaster Road, Mail Code 151, Dallas, TX 75216, USA
The metabolic syndrome is frequently associated with atherogenic dyslipidemia, which is characterized by increased plasma levels of triglyceride and total cholesterol and by reduced high-density lipoprotein (HDL) cholesterol [1]. The elevations in triglyceride and cholesterol are in apolipoprotein B (apo B)–containing lipoproteins. The latter include metabolic precursors of low-density lipoprotein (LDL)—that is, very low density lipoproteins (VLDL) and intermediate density lipoprotein (IDL)—as well as small LDL particles. Collectively, these apo B–containing lipoproteins make up the fraction known as non-HDL. These lipoproteins have one molecule of hepatic apo B per lipoprotein particle. In atherogenic dyslipidemia, there is usually an increase in the number of apo B–containing lipoproteins, even when LDL cholesterol levels are not elevated. Small apo B–containing lipoproteins that reside in the LDL fraction add to higher apo B levels. Several lines of evidence suggest that all non-HDL lipoproteins are atherogenic and that cholesterol-enriched VLDL and IDL are as proatherogenic as are LDL. For this reason it seems appropriate to therapeutically reduce not only the number of LDL particles but also their precursors. The purpose of this article is to summarize the evolving rationale supporting coadministration of hypolipidemic agents targeted to non-HDL reduction. Atherogenic dyslipidemia is more prevalent than isolated high LDL cholesterol. The clinical concomitants of acquisitions with the former include central obesity, hypertension, impaired glucose tolerance, and * Department of Clinical Nutrition, Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9052. E-mail address:
[email protected] 0889-8529/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2004.03.013
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hyperuricemia. This form of dyslipidemia often precedes the full clinical manifestation of the metabolic syndrome. It is therefore of interest to examine safety and efficacy information regarding drug combinations that are used to treat atherogenic dyslipidemia.
The metabolic basis of atherogenic dyslipidemia The metabolic basis of atherogenic dyslipidemia provides a rationale for drug therapy. Normal levels of plasma LDL cholesterol generally result from a balanced metabolism of non-HDL lipoproteins. This process is mediated by a number of enzymes, cofactors, and lipoprotein receptors. The key enzymes include lipoprotein lipase (LPL), hepatic lipase (HL), and lecithin-cholesteryl acyl transferase (LCAT); the cofactors are cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP); and the receptors include the LDL receptor. Normally VLDL is acted upon by LPL, CETP, and PLTP. These proteins also are important in the formation of IDL. In turn, HL appears to be a key enzyme in the conversion of IDL to LDL (Fig. 1) as well as in metabolism of HDL. In the presence of normal LDL receptor activity, a fraction of partially catabolized non-HDL lipoproteins is effectively removed from circulation. VLDL serves as a vehicle for export of triglyceride from the liver to the peripheral tissues, and it returns cholesteryl esters to the liver carried by LDL. Although it is still unclear how hepatic secretion of lipoproteins is regulated, hormones like insulin seemingly play a role in VLDL secretion and in the levels of
Fig. 1. Metabolic basis of atherogenic dyslipidemia. Schematic representation of the pathway for interconversion of VLDL to LDL in healthy subjects and in subjects with atherogenic dyslipidemia. Normal-sized VLDL, IDL, and LDL are produced as a result of the action of LPL, HL, and CETP and PLTR in the presence of normal LDL receptor activity. Small lipoproteins result from the imbalance in the action of enzymes and cofactors. Small lipoproteins are prevalent in atherogenic dyslipidemia. A high number of small lipoproteins can be the result of hepatic hypersecretion of VLDL particles or decreased clearance by hepatic lipoprotein receptors.
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enzymes such as LPL. Steroid hormones such as estrogen and testosterone in contrast have a greater effect on HDL metabolism. Atherogenic dyslipidemia commonly is associated with decreased LPL and increased CETP and HL activities [2–4]. A decreased LPL activity raises VLDL levels. CETP enhances exchange of triglyceride for cholesteryl esters between VLDL and HDL. Increased apo C-III can also impair the action of LPL and slow the removal of VLDL and IDL by inhibiting LDL-receptor activity. Through CETP action, cholesteryl esters in VLDL and IDL are increased, as is the triglyceride content of HDL. The action of HL on triglyceride-rich HDL reduces HDL levels and increases apo A-I removal from circulation. The abnormal lipoproteins of atherogenic dyslipidemia include high levels of small VLDL, IDL, and LDL (see Fig. 1). When these lipoproteins enter the arterial wall, they are taken up by scavenger receptors or pass through other pathways present on the surface of macrophages; their uptake by macrophages contributes to formation of foam cells. Atherogenic lipoproteins have been implicated in endothelial dysfunction as well as vascular wall inflammation. Arteriosclerosis begins with a lipid accumulation phase; this is followed by proliferation of the smooth muscle in the intima. Atherosclerotic plaques eventually become unstable, threatening plaque rupture and acute coronary syndromes. Abnormal or high levels of non-HDL contribute to the lipid accumulation phase; they likely play an important role in the destabilization of plaques in lipid-rich areas of lesions. Another important component of atherogenic dyslipidemia is reduced HDL cholesterol. At least two subspecies of HDL are large, buoyant HDL (HDL2) and small, denser HDL (HDL3). A reduction in HDL cholesterol is usually associated with a reduction in the ratio of large to small HDL. Large HDL predicts a reduced risk for coronary heart disease (CHD), whereas smaller HDL imparts a significantly greater risk. Several functions have been ascribed to the HDL subfractions. One is transport of cholesterol from peripheral tissues to the liver. Mediators of this process include the ATPbinding cassette protein 1 transporter, LCAT, CETP, and the HDL receptor (scavenger receptor class B type I) [5]. HDL further may be antiinflammatory and antioxidant [6,7].
Role of abnormal lipoproteins in atherogenesis All classes of small lipoproteins (VLDL, IDL, LDL, and HDL) must be considered to be proinflammatory agents [8]; this is appropriate when atherosclerosis is viewed as an inflammatory disease [9]. One view holds that monocytes infiltrate the endothelium in response to signals released by lipoprotein modification (eg, lipid oxidation or breakdown product). The macrophages in turn take up the modified lipoproteins. This process transforms macrophages into foam cells. When macrophages are activated
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by lipid uptake, they begin to secrete growth factors that induce cell proliferation and matrix damage. Various mechanisms have been postulated to explain the sequence of atherogenesis. For example, oxidized LDL and its precursors activate endothelial cells to produce monocyte chemotactic protein 1 (MCP-1). This protein attracts monocytes from the vessel lumen into the subendothelial space and promotes their differentiation into macrophages. In turn, macrophages release tumor necrosis factor a and interleukin 1. These cytokines activate endothelial cells to produce adhesion molecules that bind more monocytes and they accumulate in the subendothelial space through the action of MCP-1 [10]. Whether or not this sequence will hold up under future investigations remains to be seen. Multiple mechanisms have been suggested whereby HDL may be antiatherogenic. One theory suggests that HDL can inhibit the oxidation of small LDL and its precursors [11]. For example, HDL transports paraoxanase, which inhibits oxidation of small LDL [7]. Moreoever, the cytokine-induced production of adhesion molecules is inhibited by the phospholipid components of HDL [12,13]. Therefore, small HDL may not be as anti-atherogenic as large HDL acting through anti-inflammatory and antioxidative mechanisms, because its phospholipid surface is limited. Based on these in vitro observations, it has been suggested that therapies that reduce small lipoproteins or increase large HDL may reduce the inflammatory atherogenic process.
Quantitation of lipoproteins in atherogenic dyslipidemia A simple way to quantify the degree of atherogenic dyslipidemia is to determine non-HDL cholesterol levels [1]. Non-HDL contains all the cholesterol in VLDL, IDL, and LDL. Its value is calculated by taking the difference between total plasma cholesterol and HDL cholesterol. Additionally, non-HDL cholesterol correlates highly with total plasma apo B [14]. High throughput methods have been introduced recently to quantify the cholesterol in each lipoprotein subspecies. These include the Vertical Auto Profile cholesterol test [15], nuclear magnetic resonance [16], and nondenaturing polyacrylamide gel electrophoresis [17]. Each method provides information about the microheterogeneity of lipoprotein species. Reference (desirable) levels of cholesterol in each lipoprotein fraction are shown in Table 1. VLDL and HDL have at least two major subfractions, and LDL consists of three distinct fractions. All three of the latter are thought to be atherogenic. The availability of the current technology to quantify lipoprotein subspecies will make it possible to include these measurements in clinical trials that examine safety and efficacy of hypolipidemic agents in patients who have atherogenic dyslipidemia. These methods provide the opportunity to examine changes in size distribution of non-HDL
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G.L. Vega / Endocrinol Metab Clin N Am 33 (2004) 525–544 Table 1 Levels of lipoprotein cholesterol and recommended goals of treatment
Lipoprotein VLDL cholesterol LDL cholesterol
Reference levels (mg/dL of Lipoprotein cholesterol) subfraction \30 \130
Non-HDL cholesterol \160 HDL cholesterol 40 a
Large VLDL cholesterol Small VLDL cholesterol IDL cholesterol LDL cholesterol Lp(a) cholesterol Non-HDL cholesterol Large HDL cholesterol Small HDL cholesterol
Goal of treatment Reference suggested by levels ATP III (mg/dL of (mg/dL cholesterol) of cholesterol) \20 \10 \10 \110 \10 \160 >10 >30
\30a \100a
\130a >40
Goals of treatment for individuals in secondary prevention [1].
lipoproteins. Subfraction analysis, however, is generally not employed in routine medical practice.
Prevalence of atherogenic dyslipidemia Atherogenic dyslipidemia occurs in several different metabolic and lipoprotein disorders—for example, combined hyperlipidemia (high cholesterol and triglycerides), various mixed hyperlipidemias, and diabetic dyslipidemia and the metabolic syndrome (Table 2). More specifically, it occurs in familial conditions including dysbetalipoproteinemia [18], familial combined hyperlipidemia [19], and familial ‘‘mixed’’ hyperlipidemia [20]. Many of the patients with these disorders have features of the metabolic syndrome (Table 2). Differences in risk among these different conditions relate not only to the lipoprotein abnormality but to concomitant lipid and nonlipid risk factors. Dysbetalipoproteinemia is characterized by premature CHD, xanthomata, and atherogenic dyslipidemia [18]. Patients are frequently obese and have diabetes mellitus, hypertension, hyperuricemia, and hypothyroidism. The patients have very abnormal non-HDL consisting of b-VLDL, small dense LDL, and reduced HDL. With dysbetalipoproteinemia, plasma triglycerides typically range between 400 mg/dL and 800 mg/dL; plasma total cholesterol usually ranges between 300 and 600 mg/dL. The E2 allele of the apo E gene is characteristic of this disorder. The E2 allele accounts for the b-VLDL but is only one factor determining the severity of the dyslipidemia [18]. Other abnormalities of lipoprotein metabolism must be present as well. The clinical manifestations of dysbetalipoproteinemia typically appear at puberty or thereafter. This form of dyslipidemia occurs in 1 of 5000 individuals.
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Table 2 Variable presentations of atherogenic dyslipidemia: clinical concomitants Dyslipidemia phenotype
Central obesity
Hypertension
Dysbetalipoproteinemia Combined hyperlipidemia Mixed hyperlipidemia Type 2 diabetes
þ þ þ þ
þ/ þ/ þ/ þ/
Hyperuricemia
Impaired fasting glucose
b-Cell dysfunction
þ/ þ/ þ/ þ/
þ/ þ/ þ/ þ
þ/ þ/ þ/ þ
Data are gleaned from multiple references in the literature.
Combined hyperlipidemia can be arbitrarily defined as a high LDL cholesterol (>160 mg/dL) and elevated plasma triglycerides (>150 mg/dL) [19]. Familial forms of combined hyperlipidemia include a variable lipoprotein phenotype among different members of affected families [21]. In other words, some affected family members will not show increases in both triglycerides and LDL cholesterol, some will have high triglycerides only, and some will have high LDL only. Dyslipidemia is usually detected first in adulthood. Patients are often hypertensive, obese, or overweight and may also have diabetes or gout. In other words, they commonly have the metabolic syndrome, which is an underlying condition that brings the dyslipidemia to light. When activity of the LDL receptor is reduced, levels of LDL cholesterol are elevated. Thus, to have combined hyperlipidemia, most people will have a defect in both triglyceride metabolism and reduced activity of LDL receptors. High triglycerides with combined hyperlipidemia appears to be due to increased hepatic secretion of VLDL [21]. This hypersecretion of VLDL may be driven in part by obesity or insulin resistance. The latter conditions likely bring the hyperlipidemia to light in an individual who carries latent lipoprotein defects. Mixed hyperlipidemia is a term that can be used for patients who have increased VLDL triglyceride without elevated LDL cholesterol (\160 mg/ dL) [22]. The term mixed is used because total cholesterol levels may be increased (>240 mg/dL), although LDL cholesterol is not. The distinction between combined and mixed dyslipidemia thus is arbitrary and is determined by the LDL cholesterol level. Some affected persons with relatives having combined hyperlipidemia will have mixed hyperlipidemia. Patients with mixed hyperlipidemia also present with excess body fat, hypertension, impaired fasting glucose, or diabetes mellitus type 2 and hyperuricemia. The metabolic syndrome is common in patients with mixed hyperlipidemia. Various secondary causes of hyperlipidemia including chronic renal failure can cause mixed hyperlipidemia. With renal failure, the lipoprotein phenotype may be associated with impaired metabolism of LDL precursors [22]. In the United States, the prevalence of the different components of atherogenic dyslipidemia varies among persons who manifest the metabolic
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syndrome [1]. For example, the prevalence of high plasma triglycerides (>150 mg/dL) is reported to be approximately 35% in men and 25% in women. Low HDL occurs in 35% of men and 39% of women [23].
Mechanisms of action of hypolipidemic agents Many hypolipidemic agents are currently employed to manage dyslipidemia. Their mechanism of action and relative efficacy is summarized in Table 3. The most potent LDL-lowering drugs are the statins (see Table 3). Fibrates and nicotinic acid lower VLDL effectively and also raise HDL cholesterol to varying degrees. Fibrates also increase LPL, reduce apo C-III and increase apo A-I [24]. Nicotinic acid is more effective in raising HDL cholesterol than any other lipid-lowering agent currently available (see Table 3); it has multiple effects on lipoprotein metabolism and fatty acid metabolism as detailed later. Many multicenter trials have been conducted with statins, fibrates, and nicotinic acid to test efficacy, safety, and impact on risk reduction. Because these agents differ in their mechanism of action and the relative efficacy on lipoprotein cholesterol levels (see Table 3), it seems reasonable to consider their potential use in combination to treat multiple lipoprotein alterations. For example, the treatment of atherogenic dyslipidemia clearly requires optimal reduction of non-HDL cholesterol, normalization of the size of the lipoprotein particles, and increase in large HDL. Optimal reduction of nonHDL will likely be achieved with combinations of drugs targeted to reduce both LDL and its precursors. Some candidate drugs for combination Table 3 Targets of current lipid-lowering agents and efficacy patterns
Drugs/supplements
Site of action
Statins Fibrates Nicotinic acid
HMG-CoA reductase PPAR-a PUMA-G and HM74 receptorsb Niemann-Pick C1 like 1 protein Enterohepatic circulation of bile acids Bile acid micelles PPAR-a PPAR-c
Ezitimibe Bile acid sequestrants Stanol esters Fish oils Thiazolidinedionec
LDL cholesterol reduction
HDL cholesterol increase
Triglyceride reduction
20%–60% 10%–20%a 10%–25%
5%–15% 10%–15% 15%–35%
10%–30% 20%–50% 20%–50%
14%–18%
4%
8%
15%–30%
3%–5%
5%–25%
10%–15% Neutral 18%
Neutral Neutral 3%
Data are gleaned from multiple studies from the literature. Fenofibrate only. b Putative receptor: not determined with certainty. c Pioglitazone in patients who have diabetes mellitus (one study only). a
Neutral 25%–35% 15%
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therapy are listed in Table 3. In this section, an overview of the relative safety and efficacy of combination of statins and fibrates is discussed. Statins Statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. Statins block cholesterol biosynthesis in a dosedependent manner. They safely reduce LDL cholesterol when used in moderate doses. In so doing, they reduce risk of morbidity and mortality from CHD (see Table 3). Statins lower levels of VLDL cholesterol by the same percentage that they lower LDL cholesterol, and HDL cholesterol is raised to a small extent (see Table 3). Statins have various putative pleitropic effects [25]. Some investigators believe that multiple actions of statins account for their anti-atherogenic actions. Statins are used widely as the first choice of drugs to reduce LDL cholesterol. Standard doses of statins reduce LDL cholesterol by approximately 30% to 40%. In some cases, they are titrated to higher doses to reach recommended goals of treatment, particularly in high risk patients. However, the relative efficacy of statins for LDL lowering is diminished with increasing doses. For this reason, it may be necessary to use a statin in combination with a bile acid sequestrant, ezitimibe, or stanol esters to achieve optimum LDL lowering (see Table 3). Seven major multicenter trials have been conducted with statins in primary and secondary prevention (Table 4). The first trial was the
Table 4 Risk reduction in major statin and fibrate monotherapy trials Statin trials
Trial Air Force/Texas Coronary Atherosclerosis Prevention Study [30] Cholesterol and Recurrent Events Study [27]
Fibrate trials Risk reduction (%) Trial
Risk reduction (%)
37
24
Scandinavian Simvastatin 34 Survival Study (20 mg, 40 mg) [26] Long-Term Intervention 25 with Pravastatin in Ischaemic Disease [28] West of Scotland 31 Pravastatin Study [29] Heart Protection Study [31] 24
Veterans Affairs 22, High Density Lipoprotein P = .006 Intervention Trial (Gemfibrozil) [33]
Diabetes Atherosclerosis Intervention Study (Fenofibrate) [34] Helsinki Heart Study (Gemfibrozil) [35]
40% less progression 34, P \ .02
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Scandinavian Simvastatin Survival Study [26]. This study showed a decreased cardiac morbidity and mortality in patients who had CHD and high LDL cholesterol levels. The Cholesterol and Recurrent Events Study [27] showed significant reduction in the incidence of subsequent myocardial infarction, death from coronary heart disease, stroke, and need for revascularization procedures in patients who had recent myocardial infarction and who had normal levels of total cholesterol at baseline. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study [28] demonstrated a reduction in overall mortality and incidence of myocardial infarction and stroke in patients who had CHD; patients had a broad range of cholesterol levels at baseline. There were also two primary prevention trials that have become very influential, the West of Scotland Pravastatin Study (WOSCOPS) [29] and the Air Force/Texas Coronary Atherosclerosis Prevention Study [30]. The former study was conducted in hypercholesterolemic subjects who had no clinical evidence of CHD; it showed decreased coronary morbidity and mortality. The latter study found significant reduction in the incidence of first acute major coronary events in patients who did not have CHD but who had normal to mildly elevated total and LDL cholesterol levels and low HDL cholesterol levels. The Heart Protection Study (HPS) successfully demonstrated in a very large number of patients that statin therapy reduced the risk of heart attacks, revascularization procedures, and stroke in patients who had high cardiovascular risk [31]. This type of evidence makes a compelling case for treatment of LDL cholesterol to reduce CHD mortality and morbidity in higher-risk patients. Statins have a relatively good record of safety [32]. In multicenter trials, less than 2% of patients discontinued the studies because of side effects. In long-term studies, patients that were taking statins experienced similar side effects as those that were taking placebo. A low percentage of patients taking statins in clinical trials showed increased levels of transaminases without other signs of hepatic toxicity. Elevated liver enzymes usually returned to normal levels when treatment with statins was discontinued. Statin should be used with great caution when there are conditions that increase the likelihood of severe myopathy (eg, severe infection, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders). Fibrates This class of drugs includes gemfibrozil, fenofibrate, and bezafibrate. Two fibrates, gemfibrozil and fenofibrate, have been approved by the US Food and Drug Administration to lower levels of plasma triglycerides. The fibrates activate peroxisome proliferator-activated receptors (PPARs) a located in the liver and other tissues. Fibrate activation of PPAR-a increases catabolism of VLDL and reduces hepatic secretion of VLDL. It also promotes increases in HDL and promotes b oxidation of fatty acids [24]. Fibrates may have favorable effects on the arterial wall, such as improving
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endothelial function [24] and favorably affecting macrophage responses. It is possible that these systemic effects of fibrates may contribute to reduction in risk for CHD independently of their effect on lipoprotein metabolism. Two major clinical trials and one angiographic trial of note have been conducted with fibrates (see Table 4). A recent secondary prevention trial demonstrated a 24% reduction in major coronary events [33]. In addition, an angiographic trial showed reduced progression of atherosclerosis in patients who have diabetes [34]. The Helsinki Heart Study (HHS) was a primary prevention trial that included 135 patients who had diabetes mellitus; in this small subset, CHD risk was reduced by 68% [35]. Fibrates lower levels of VLDL and increase HDL cholesterol (Table 3). They are generally well tolerated. Side effects are relatively rare. One significant risk is that of developing cholesterol gallstones. In addition, some patients are not able to tolerate the drugs because of dyspepsia, diarrhea, fatigue, nausea, vomiting, abdominal pain, eczema, rash, vertigo, and myalgias. Combination of statins and fibrates Because statins lower primarily LDL cholesterol and fibrates lower VLDL and raise HDL, it seems reasonable to combine these drugs to treat atherogenic dyslipidemia. The efficacy of this condition in treatment of atherogenic dyslipidemia is summarized in Table 5. The patient populations included in these reports were subjects with combined hyperlipidemia, ‘‘mixed’’ hyperlipidemia [36–53] or type 2 diabetes mellitus [54,55]. Most subjects studied ranged in age from 28 years to 78 years, and they were generally overweight and had other risk factors for CHD. Some patients were inadequate responders to monotherapy with lipid-lowering agents; therefore, the combination of statins and fibrates was tested for efficacy and safety [45]. The statins employed in these trials included various doses of lovastatin, pravastatin, fluvastatin, atorvastatin, and simvastatin; most of the trials employed gemfibrozil, and a few included ciprofibrate or fenofibrate. The study designs were either crossover or parallel. The results from most of the trials are summarized in Table 5, and they suggest that the combination of a statin plus a fibrate produce a lipoprotein profile that is better than the profile during monotherapy. Most of the trials showed that LDL reduction was superior with the statin compared with the fibrate. With combined therapy, reduction of non-HDL paralleled LDL reduction and HDL increases. The range of responses reflects not only differences in doses of drugs used in the various trials but also interindividual variation. The changes in LDL associated with combination therapy also produced favorable changes in the distribution of large and small LDL. Several reports have shown that combination of fibrates, particularly gemfibrozil, with a statin can lead to myopathies and to rhabdomyolysis
Table 5 List of studies reporting effects of co-administration of statins and fibrates on lipoprotein cholesterol in subjects who have atherogenic dyslipidemia Percent changes in levels from baseline Study medications
Total cholesterol
Triglyceride
LDL cholesterol
HDL cholesterol
Non-HDL cholesterol
Dyslipidemia
Reference
Combined hyperlipidemia
[39] [40] [43] [50] [52]
14 20 20 7 40
PþG SþF LþG FþG SþB
30 28 20 28 23
27 53 18 49 24
35 24 27 29 26
20 23 0 8 5
35 36 24 29 26
Familial combined hyperlipidemia
[36] [37]
[41] [44] [45]
20 17 135 130 124 26 30 10
SþC LþG PþG SþG SþC PþG LþG LþB
26 28.8 31 35 38 31 32 19
51 56 48 59 57 47 51 21
26 28 35 35 42 35 34 23
14 26 14 25 17 20 19 NA
31 36 37 43 45 35 34 23
Mixed hyperlipidemia
[47] [48] [49] [51]
148 13 26 149
SþG LþG PþG FþB
18 36 25 23
41 62 53 46
24 22 14 14
20 36 20 6
24 35 14 14
Type 2 diabetes mellitus
[50] [51] [53]
16 44 13 10
LþG AþG CþF BþF
25 25 32 21
63 24 53 46
30 27 36 26
23 5 19 19
48 34 39 27
[38]
Patients who have CHD
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Number of subjects
Abbreviations: A, atorvastatin; B, bezafibrate; C, ciprofibrate; F, fluvastatin; G, gemfibrozil; L, lovastatin; NA, not available; P, pravastatin; S, simvastatin. 535
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[32]. Data of various types suggest that a statin in combination with fenofibrate is less likely to cause CKP elevations and myalgias than is a statin combined with gemfibrozil. Some statins, such as simvastatin, have US Food and Drug Administration approval to use with fenofibrate when the simvastatin is used at low doses (10 mg/d). The mechanisms of myalgias and CPK elevations that could lead to renal failure are not understood. Regardless, caution is always warranted when these drug combinations are used, and it may be more appropriate to institute combined drug therapy under the management of lipid clinics.
Coadministration of statins and nicotinic acid Nicotinic acid has been used extensively to lower levels of plasma nonHDL lipoproteins and to raise HDL cholesterol in a number of trials [56]. The drug has multiple effects on lipoprotein metabolism [57]. For example, the reduction in plasma triglyceride levels is secondary to reduced hepatic secretion of VLDL, whereas the rise in HDL has been associated with increased production of apo A-I and reduced clearance of HDL. Two clinical trials that are frequently cited noted reduction in total mortality in secondary prevention. First, the Coronary Drug Project was a study conducted over an 8-year period in patients with a history of myocardial infarction [58]. Patients were treated with nicotinic acid for 5 years; they had a 27% reduction in nonfatal myocardial infarction, and a 21% reduction in strokes. Another major trial, the Stockholm Ischemic Heart Disease Study [59], showed that the combination of nicotinic acid and clofibrate reduced mortality from CHD by 36% after 5 years of treatment and total mortality by 26%. Other large trials have employed combination of nicotinic acid with bile acid sequestrants to determine the effect of treatment on atherosclerosis regression (Table 6) [60–63]. These trials lasted
Table 6 Changes in lipoproteins during drug trials using niacin in combination with LDL-lowering drugs % Change from baseline Trial
Reference
LDL cholesterol
HDL cholesterol
Risk reduction (%)
CLAS I
[60]
43
þ37
52% Reduction in progression; 18% regression
CLAS II FATS UCSF-SCOR HATS
[60] [61] [62] [71]
32 39 43
þ43 NA þ29
39% Regression 33% Regression 90% RRR of events
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2 to 4 years and employed coronary angiography for primary end points. The studies showed that the drug combination promote regression of coronary atherosclerotic lesions (Table 6). Because statins are used widely to lower LDL cholesterol, many trials using coadministration of a statin plus nicotinic acid have been conducted (Table 7) [56,64–72]. These trials were performed in patients with combined hyperlipidemia. The relative efficacy of LDL cholesterol lowering and HDL cholesterol raising in these trials is summarized in Fig. 2. The results were obtained in a total of 249 patients treated from 4 to 88 weeks. The ranges in responses for LDL-lowering were 25% to 57% and for HDL-raising were 13% to 36% (see Fig. 2A). As shown in one study [72], most of the LDL lowering is achieved with the statin (see Fig. 2B). Adding nicotinic acid improves the lipoprotein profile through its effect on HDL (see Fig. 2B). Still, nicotinic acid probably affects LDL metabolism as well because it reduces hepatic secretion of VLDL, the precursor of LDL. Nicotinic acid has a number of side effects that require monitoring and sometimes discontinuation of therapy. It is common for the drug to produce flushing and itching, and it can raise fasting blood glucose in a dosedependant manner. Because pharmacologic doses of nicotinic acid are needed to treat atherogenic dyslipidemia, it appears that doses greater than 2 g/d may be associated with more frequent incidences of elevated glucose and some worsening of glycemic control in patients with type 2 diabetes mellitus [73]. One clinical trial [74] that employed low doses of nicotinic acid (2 g/d) has reported a low frequency of glucose increases or little worsening of glycemic control in type 2 diabetic patients.
Table 7 Efficacy of coadministration of nicotinic acid plus a statin in the treatment of atherogenic dyslipidemia
Reference
Number of subjects
Drug combination
[56] [65] [66] [67] [68] [69] [70] [71] [63] [72]
269 158 74 33 25 21 16 14 40 814
NþL NþP NþL NþP NþL NþP NþP NþP NþP NþL
% Change from baseline LDL cholesterol
HDL cholesterol
32 49 40 36 35 25 33 35 40 47
þ26 þ16 þ30 þ34 þ5 þ29 þ16 þ13 þ20 þ41
Abbreviations: L, lovastatin; N, nicotinic acid; P, pravastatin.
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Fig. 2. Effect of coadministration of statin and nicotinic acid on levels of plasma LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). (A) Findings reported in nine trials [56,64–71] conducted mostly in subjects who had combined hyperlipidemia. Most of these trials involved the use of pravastatin in combination with niacin. The average LDL cholesterol reduction from baseline in these trials was 36%, whereas HDL cholesterol increased by 21%. The boxes show median responses and 95th percentile confidence intervals. (B) Results from one clinical trial [72] showing the dose-response of LDL cholesterol lowering and HDL cholesterol raising using lovastatin 20 or 40 mg/d and 1 or 2 g of extended release nicotinic acid (Advicor). Changes are shown from baseline.
Drug combinations that target fatty acid metabolism An important component of atherogenic dyslipidemia is the dysregulation of the plasma levels of nonesterified fatty acids (NEFAs). Plasma NEFAs arise from a number of enzymatic reactions that involve hormonesensitive lipase (HSL) (in adipose tissue), LPL (on systemic endothelium), and HL (on hepatic endothelium) (Fig. 3). NEFAs enter a variety of tissues, particularly muscle and liver, where they can be channeled to either boxidation in the mitochondria or to triglyceride synthesis in the cytosol. It has been proposed that excessive influx of NEFAs into the liver leads to hypersecretion of hepatic VLDL and atherogenic dyslipidemia. If so, drug therapy should also be targeted to regulation of NEFA release from adipose tissue by modulating the action of HSL. It has been suggested that nicotinic acid modulates NEFA release from adipose tissue. Nicotinic acid may have an effect on HSL activity; however, there are no systematic studies that have examined the efficacy of nicotinic acid regulation of NEFA in the treatment of atherogenic dyslipidemia. Fibrates reduce plasma triglyceride principally by modulating hepatic secretion of VLDL and increasing LPL activity. A reduced secretion of VLDL may be secondary to increased b-oxidation in the liver. Support for this mechanism derives from studies conducted in animals and from an observation that fibrates reduce hepatic steatosis in humans. However, there are no systematic studies that have examined the effects of fibrates on NEFA metabolism. One study from our laboratory showed that in patients
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Fig. 3. Schematic representation of the role of NEFAs in the causation of atherogenic dyslipidemia. NEFAs are produced during the hydrolysis of triglycerides by HSL in the adipose tissue, LPL located on the surface of endothelial cells, and HL. NEFAs enter the liver or nonhepatic tissues. Many organs such as skeletal muscle, heart muscle, and the liver can take up NEFAs mediated by fattyacyl binding proteins, and the internalized fatty acid can undergo b oxidation or it can be incorporated into triglyceride. It has been proposed that excess fatty acids drive hepatic triglyceride synthesis and secretion of VLDL. It has also been suggested that NEFAs contribute to triglyceride accumulation in hepatocytes, muscle, and pancreatic b cells, leading to lipotoxicity. Three drugs currently approved by the US Food and Drug Administration may affect NEFA metabolism: fibrates, nicotinic acid, and thiazolidenediones.
who have atherogenic dyslipidemia of the metabolic syndrome, fenofibrate reduced plasma triglycerides, apparently without increasing LPL, reducing plasma apo C-III, or affecting levels and fluxes of NEFA [75]. The mechanisms whereby fibrates modify atherogenic dyslipidemia thus are not fully understood. Thiazolidinediones are PPAR-c agonists that improve insulin sensitivity and appear to have some effect on plasma triglycerides and NEFA. More work needs to be done with this class of compounds to determine the relative efficacy in the regulation of NEFA metabolism. Some studies also suggest that thiazolidinediones reduce hepatic steatosis. If so, this is another target of therapy that may improve atherogenic dyslipidemia.
Summary Atherogenic dyslipidemia is common in a variety of conditions associated with central obesity, hypertension, hyperurecemia, and impaired pancreatic b cell function, (ie, the metabolic syndrome). Most high-risk patients who have atherogenic dyslipidemia will require statin therapy; such therapy is encouraged on the basis of clinical trial evidence. Coadministration of drugs targeted for the reduction of LDL precursors (VLDL and IDL) are likely to improve the profile of atherogenic lipoproteins. In addition, coadministration will produce a significant rise in HDL cholesterol. Large clinical trials that show CHD risk reduction or improvement in CHD are needed with combined drug therapy. New drugs undoubtedly are needed to target fatty acid metabolism and inflammation. As we progress in the understanding of the metabolic origins of atherogenic dyslipidemia, new targets of therapy
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likely will be identified and new drug combinations will prove to be even more efficacious than those currently available for treatment of atherogenic dyslipidemia.
References [1] ATP. III Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [2] Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler Thromb 1993;13(8):1227–35. [3] Tato F, Vega GL, Tall AR, Grundy SM. Relation between cholesterol ester transfer protein activities and lipoprotein cholesterol in patients with hypercholesterolemia and combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1995;15(1):112–20. [4] Tato F, Vega GL, Grundy SM. Determinants of plasma HDL-cholesterol in hypertriglyceridemic patients. Role of cholesterol-ester transfer protein and lecithin cholesteryl acyl transferase. Arterioscler Thromb Vasc Biol 1997;17(1):56–63. [5] Kawashiri MA, Maugeais C, Rader DJ. High-density lipoprotein metabolism: molecular targets for new therapies for atherosclerosis. Curr Atheroscler Rep 2000;2(5):363–72. [6] Barter PJ, Baker PW, Rye KA. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipidol 2002;13(3):285–8. [7] Mackness MI, Arrol S, Abbott CA, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 1993;104:129–35. [8] Aviram M. Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins. Antioxid Redox Signal 1999;1(4):585–94. [9] Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340(2):115–26. [10] Nathan CF. Secretory products of macrophages. J Clin Invest 1987;79(2):319–26. [11] Mackness MI, Abbott C, Arrol S, Durrington PN. The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J 1993;294(Pt 3):829–34. [12] Xia P, Vadas MA, Rye KA, Barter PJ, Gamble JR. High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL. J Biol Chem 1999;274(46):33143–7. [13] Baker PW, Rye KA, Gamble JR, Vadas MA, Barter PJ. Ability of reconstituted high density lipoproteins to inhibit cytokine-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells. J Lipid Res 1999;40(2):345–53. [14] Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C. ACCESS Study Group. Atorvastatin Comparative Cholesterol Efficacy and Safety Study. Correlation of non-highdensity lipoprotein cholesterol with apolipoprotein B: effect of 5 hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88(3):265–9. [15] Kulkarni KR, Garber DW, Marcovina SM, Segrest JP. Quantification of cholesterol in all lipoprotein classes by the VAP-II method. J Lipid Res 1994;35(1):159–68. [16] Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM. Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement. Clin Chem 1992; 38:1632–8.
G.L. Vega / Endocrinol Metab Clin N Am 33 (2004) 525–544
541
[17] Muniz N. Measurement of plasma lipoproteins by electrophoresis on polyacrylamide gel. Clin Chem 1977;23(10):1826–33. [18] Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res 1999;40(11): 1933–49. [19] Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973; 52(7):1544–68. [20] McNeely MJ, Edwards KL, Marcovina SM, Brunzell JD, Motulsky AG, Austin MA. Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20year prospective study. Atherosclerosis 2001;159(2):471–81. [21] Kissebah AH, Alfarsi S, Evans DJ. Low density lipoprotein metabolism in familial combined hyperlipidemia. Mechanism of the multiple lipoprotein phenotypic expression. Arteriosclerosis 1984;4(6):614–24. [22] Vega GL, Grundy SM. Influence of lovastatin therapy on metabolism of low density lipoproteins in mixed hyperlipidaemia. J Intern Med 1991;230(4):341–50. [23] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287(3):356–9. [24] Fruchart JC, Staels B, Duriez P. PPARS, metabolic disease and atherosclerosis. Pharmacol Res 2001;44(5):345–52. [25] Davignon J. The cardioprotective effects of statins. Curr Atheroscler Rep 2004;6(1):27–35. [26] Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9. [27] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. [28] The long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339: 1349–57. [29] Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–7. [30] Downs M Jr, Clearfield S, Weis E, Whitney DR, Shapiro PA, Beere A, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615–22. [31] Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. [32] Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40(3):567–72. [33] Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410–8. [34] Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357:905–10.
542
G.L. Vega / Endocrinol Metab Clin N Am 33 (2004) 525–544
[35] Koskinen P, Ma¨ntta¨ri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care 1992;15:820–5. [36] Kontopoulos AG, Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Mayroudi MC, Boudoulas H. Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease. Coron Artery Dis 1996;7:843–50. [37] East C, Bilheimer DW, Grundy SM. Combination drug therapy for familial combined hyperlipidemia. Ann Intern Med 1988;109:25–32. [38] Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, Didangelos TP, Carina MV, Kranitsas DF, et al. Safety and efficacy of long-term statin-fibrate combination in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997;80:608–13. [39] Napoli C, Lepore S, Chiariello P, Condorelli M, Chiariello M. Long-term treatment with pravastatin alone and in combination with gemfibrozil in familial type IIB hyperlipoproteinemia or combined hyperlipidemia. J Cardiovasc Pharmacol Ther 1997; 2(1):17–26. [40] Vega GL, Vega GL, Ma PT, Cater NB, Filipchuk N, Meguro S, et al. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol 2003;91(8):956–60. [41] Athyros VG, Papageorgiou AA, Hagikonstantinou HJ, Papadopoulos GV, Zamboulis CX, Kontopoulos AG. Combined treatment with pravastatin and gemfibrozil in patients with refractory familial combined hyperlipidemia: a clinical study. Drug Invest 1994;7(3): 134–42. [42] Glueck CJ, Oakes N, Speirs J, Tracy T, Lang J. Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. Am J Cardiol 1992;70:1–9. [43] Glueck CJ, Speirs J, Tracy T. Safety and efficacy of combined gemfibrozil-lovastatin therapy for primary dyslipoproteinemias. J Lab Clin Med 1990;115:603–9. [44] Zambon D, Ros E, Rodriguez-Villar C, Laguna JC, Vazquez M, Sanllehy C, et al. Randomized crossover study of gemfibrozil versus lovastatin in familial combined hyperlipidemia: additive effects of combination treatment on lipid regulation. Metabolism 1999;48(1):47–54. [45] Yeshurun D, Abukarshin R, Elias N, Lanir A, Naschitz JE. Treatment of severe, resistant familial combined hyperlipidemia with a bezafibrate-lovastatin combination. Clin Ther 1993;15:355–63. [46] Farnier M, Bonnefous F, Debbas N, Irvine A. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med 1994;154:441–9. [47] Murdock DK, Murdock AK, Murdock RW, Olson KJ, Frane AM, Kersten ME, et al. Long-term safety and efficacy of combination gemfibrozil and HMG-CoA reductase inhibitors for the treatment of mixed lipid disorders. Am Heart J 1999;138:151–5. [48] Vega GL, Grundy SM. Management of primary mixed hyperlipidemia with lovastatin. Arch Intern Med 1990;150(6):1313–9. [49] Iliadis EA, Rosenson RS. Long-term safety of pravastatin-gemfibrozil therapy in mixed hyperlipidemia. Clin Cardiol 1999;22(1):25–8. [50] Smit JW, De Bruin TW, Eekhoff EM, Glatz J, Erkelens DW. Combined hyperlipidemia is associated with increased exercise-induced muscle protein release which is improved by triglyceride-lowering intervention. Metabolism 1999;48(12):1518–23. [51] Spieker LE, Noll G, Hannak M, Luscher TF. Efficacy and tolerability of fluvastatin and bezafibrate in patients with hyperlipidemia and persistently high triglyceride levels. J Cardiovasc Pharm 2000;35:361–5. [52] Deslypere JP. Addition of fibrates to simvastatin therapy in hyperlipidemia patients. Atherosclerosis 1992;97:S67–71.
G.L. Vega / Endocrinol Metab Clin N Am 33 (2004) 525–544
543
[53] Papadakis JA, Ganotakis ES, Jagroop IA, Winder AF, Mikhailidis DP. Atatin þ fibrate combination therapy fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease. Int J Cardiol 1999;69:237–44. [54] Garg A, Grundy SM. Gemfibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM. Diabetes 1989;38(3):364–72. [55] Wagner AM, Wagner AM, Jorba O, Bonet R, Ordonez-Llanos J, Perez A. Efficacy of atorvastatin and gemfibrozil, alone and in low dose combination, in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab 2003;88(7):3212–7. [56] Guyton JR. Effect of niacin on atherosclerotic cardiovascular disease. Am J Cardiol 1998; 82(12A):18U–23U [discussion: 39U–41U]. [57] Kamanna VS, Kashyap ML. Mechanism of action of niacin on lipoprotein metabolism. Curr Atheroscler Rep 2000;2(1):36–46. [58] Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245–55. [59] Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223(5):405–18. [60] Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013–7. [61] Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990;323(19):1289–98. [62] Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264(23):3007–12. [63] Brown BG, Bardsley J, Poulin D, Hillger LA, Dowdy A, Maher VM, et al. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol \100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol 1997;80(2):111–5. [64] Davignon J, Roederer G, Montigny M, Hayden MR, Tan MH, Connelly PW, et al. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Am J Cardiol 1994;73(5):339–45. [65] Jacobson TA, Chin MM, Fromell GJ, Jokubaitis LA, Amorosa LF. Fluvastatin with and without niacin for hypercholesterolemia. Am J Cardiol 1994;74(2):149–54. [66] Tsalamandris C, Panagiotopoulos S, Sinha A, Cooper ME, Jerums G. Complementary effects of pravastatin and nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients. J Cardiovasc Risk 1994;1(3):231–9. [67] Vacek JL, Dittmeier G, Chiarelli T, White J, Bell HH. Comparison of lovastatin (20 mg) and nicotinic acid (1.2 g) with either drug alone for type II hyperlipoproteinemia. Am J Cardiol 1995;76(3):182–4. [68] O’Keefe JH Jr, Harris WS, Nelson J, Windsor SL. Effects of pravastatin with niacin or magnesium on lipid levels and postprandial lipemia. Am J Cardiol 1995;76(7): 480–4. [69] Gardner SF, Schneider EF, Granberry MC, Carter IR. Combination therapy with lowdose lovastatin and niacin is as effective as higher-dose lovastatin. Pharmacotherapy 1996; 16(3):419–23. [70] Gardner SF, Gardner SF, Marx MA, White LM, Granberry MC, Skelton DR, et al. Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control. Ann Pharmacother 1997;31(6):677–82. [71] Pasternak RC, Brown LE, Stone PH, Silverman DI, Gibson CM, Sacks FM. Effect of combination therapy with lipid-reducing drugs in patients with coronary heart disease and
544
[72]
[73] [74]
[75]
G.L. Vega / Endocrinol Metab Clin N Am 33 (2004) 525–544 ‘‘normal’’ cholesterol levels. A randomized, placebo-controlled trial. Harvard Atherosclerosis Reversibility Project (HARP) Study Group. Ann Intern Med 1996;125(7):529–40. Kashyap ML, McGovern ME, Berra K, Guyton JR, Kwiterovich PO, Harper WL, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002;89:672–8. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA 1990;264(6):723–6. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, et al. Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 2002;162(14):1568–76. Vega GL, Cater NB, Hadizadeh DR 3rd, Meguro S, Grundy SM. Free fatty acid metabolism during fenofibrate treatment of the metabolic syndrome. Clin Pharmacol Ther 2003;74(3):236–44.