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Tg y tto coc 2012

  1. 1. REVIEW CURRENT OPINION Triglycerides: a case for treatment? Anthony S. Wierzbicki a, Rosemary E. Clarke a, Adie Viljoen b, and Dimitri P. Mikhailidis c Purpose of review To discuss the relevance of triglycerides to cardiovascular disease (CVD) risk. Recent findings Triglycerides are a commonly measured component of lipid profiles. Raised triglycerides are a component of the metabolic syndrome and are strongly associated with future risk of diabetes as well as cardiovascular disease. Triglyceride-rich particles form a component of cardiovascular risk above that delineated by low density lipoprotein (LDL) cholesterol. Elevated triglycerides are a marker of atherogenic small dense LDL, excess baseline and residual CVD risk even after statin therapy. Additional methods to lower triglycerides include niacin, fibrates and omega-3 fatty acids. Trials in monotherapy with both niacin and fibrates suggest some benefit in reducing CVD events based on evidence mostly derived from older studies. However, endpoint trials of adding either niacin or fenofibrate to statins have not shown any benefit, except possibly in patients with an increased atherogenic index (triglyceride : HDL-C ratio), or have been underpowered. Trials of omega-3 fatty acids have been performed at doses insufficient to affect lipid profiles in populations with inadequate control of LDL-C but did reduce CVD events. Summary Further trials of lipid-lowering agents beyond statins will be required in patients with LDL-C adequately controlled on statin therapy. Keywords cardiovascular disease, fibrate, insulin resistance, lipid-lowering drug, metabolic syndrome, niacin, omega-3 fatty acid, statin, triglyceride INTRODUCTION particles is the difference between TC and HDL-C The routine lipid profile measured clinically and levels, that is, non-HDL-C. used in most epidemiological studies consists of total cholesterol (TC), triglycerides, and high EPIDEMIOLOGY density lipoprotein cholesterol (HDL-C). Though low density lipoprotein cholesterol (LDL-C) is rou- Epidemiological studies show little association of tinely cited in most studies, the value quoted triglyceride levels with cardiovascular disease && is derived by mathematical calculation using the (CVD) risk [4,5 ] that is not confounded by Friedewald equation [1] and thus dependent on the antithetic association of triglycerides with the samples being fasting, not from patients with HDL-C, and thus most CVD risk calculators only uncontrolled diabetes, and derived from patients with low triglyceride levels. This assumption is a Guy’s and St Thomas’ Hospitals, London, Lambeth, bLister Hospital, reasonable in many cases, but high triglycerides Hertfordshire, Stevenage and cRoyal Free Hospital Campus, University (>5 mmol/l) occur in 1.7% of the population and College London Medical School, University College London, London, UK are becoming more frequent [2], with levels more Correspondence to Anthony S. Wierzbicki, Consultant Chemical Path- than 1.6 mmol/l in up to 47–57% of dyslipidaemic ologist, St Thomas’ Hospital, Lambeth Palace Road, Lambeth, London patients [3]. Occasionally apolipoproteins associ- SE1 7EH, UK. Tel: +44 207 188 1256; fax: +44 207 188 7325; e-mail: ated with HDL (apolipoprotein A-1) or with particles containing apolipoprotein B are measured. Curr Opin Cardiol 2012, 27:398–404 A simpler measure of apolipoprotein B containing DOI:10.1097/HCO.0b013e328353adc1 Volume 27 Number 4 July 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  2. 2. Triglyceride lowering and drugs Wierzbicki et al. chylomicron driven disease is not associated with KEY POINTS a substantial increase in the rate of CVD [14]. Triglycerides are an additional risk marker The limitations of using LDL-C are best seen in for atherosclerosis. patients with diabetes. In these patients using cal- culated LDL-C can grossly underestimate real LDL-C Fibrates, niacin and omega-3 fatty acids as well as due to the delayed catabolism of triglyceride-rich statins can be used to reduce triglycerides. lipoproteins that is a feature of insulin resistance. Recent trials have not been able to answer which is the Even using direct LDL-C, as for instance was optimal drug to combine with a statin for treating measured in the Heart Protection Study, does not high-risk patients with hypertriglyceridaemia. fully account for the increased CVD risk even if the assays do measure what they are claimed to measure [15]. Thus, additional CVD risk is present in theseuse the TC : HDL ratio to derive the lipoprotein- patients and part of this residual excess risk may berelated component of CVD risk. Earlier studies due to triglyceride-rich lipoproteins [16]. Triglycer-did show an association but were also confounded ide-rich lipoprotein metabolism is intimately linked[6]. Though LDL-C is used as a treatment target, to insulin resistance and to low HDL-C through theTC : HDL ratio is a better predictor than the LDL- combined effects of increased activity of cholesterolC : HDL-C ratio [7]. However, this is an oversimpli- ester transfer protein, apoC-3 and hepatic lipase andfication, as stronger associations of lipids with CVD decreased activity of lipoprotein lipase and LDL-are seen when using either the apoB : apoA-1 ratio or receptor activity. The action of these transfer factorswith the non-HDL-C : HDL-C ratio [8]. Whether and enzymes leads to the production of small denseswitching to the use of non-HDL or apolipoproteins particles including LDL subfractions [17,18]. Thewould improve CVD risk prediction and goal setting association with insulin resistance is so clear thatin guidelines is controversial, as, though these high triglyceride : HDL-C ratio forms part of themeasures have superior predictive efficiency, it is definition of the metabolic syndrome [19], whosenot so great as to render the use of TC : HDL ratio or presence shows a far greater association with futurecalculated LDL-C ineffective. It is, therefore, useful incidence of type 2 diabetes than CVD [20] butto consider where the additional risk is derived from. nevertheless remains a significant risk factor forThe additional lipid particle fractions identified CVD if not corrected for its component lipid using non-HDL-C or apoB concentration of There is controversy as to whether nonfasting,LDL particle number comprise the triglyceride-rich that is, postprandial triglyceride measurement addsparticles – very low density lipoprotein (VLDL) and to risk determination above fasting levels [21,22]. Inintermediate density lipoprotein (IDL) – as well as most studies the concordance between the twochylomicrons and their remnants. In most patients measures is good, especially 4 h after a meal [23],the cholesterol content of these particles is about but fasting triglycerides are preferred due to their10% of that found in LDL-C. The significance of this greater potential for standardization between visitsfraction for CVD risk increases as its proportion and their utility in enabling calculation of LDL-Cincreases [9]. This is confirmed by meta-analyses from the other principal components of the lipidof epidemiological studies that find increased profile [21].CVD risk associated with triglycerides, either con-trolling for both HDL-C levels [10] or after control-ling for LDL : HDL ratio such that triglyceride more TREATMENT OF TRIGLYCERIDESthan 2.3 mmol/l is associated with a clear increase in Given the intimate link of triglycerides with theCVD risk with LDL : HDL ratio greater than 5 [11]. metabolic syndrome, the optimal therapy for trigly-The relationship strengthens in the rarer sub-groups cerides is to reduce insulin resistance. This is bestwith higher triglyceride levels, such that by trigly- achieved through reductions in weight and alcoholceride more than 9 mmol/l risk is increased three- intake (both for lipid effects and calorie intake pur-fold to eight-fold [12,13]. This relationship is also poses) and increased physical activity. A 1 kg loss ofseen in patients with a genetic predisposition to weight in epidemiological studies is associated withremnant hyperlipidaemia and associated panvascu- a 2% decrease in triglycerides and a 1% increase inlar atherosclerosis who have the apoE2/E2 genotype HDL-C [24]. This relationship has been seen in trials[13]. with weight loss drugs [25,26] and to a small extent A small subset of patients with highly elevated in case series from bariatric surgery, and also seemstriglycerides (10 mmol/l) are at increased risk to occur in patients receiving treatment with gluca-of pancreatitis and secondary diabetes due to gon-like peptide (GLP-1) agonists or other drugs forpancreatic beta-cell failure/destruction, but their diabetes [27].0268-4705 ß 2012 Wolters Kluwer Health | Lippincott Williams Wilkins 399Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  3. 3. Lipids and heart disease STATINS greatest for HDL-C and less on triglycerides, and Statins reduce LDL-C and are the mainstay of CVD with some reduction in both LDL-C and lipoprotein event reduction strategies. Some compounds claim (a) [42]. Fibrates have their principal action on additional efficacy in raising HDL-C, but only one triglycerides, with smaller effects in increasing statin trial has recruited patients with prespecified HDL-C, and some (but not gemfibrozil) reduce low HDL-C – the Air Force/Texas coronary athero- LDL-C [43,44]. Although many studies have shown sclerosis prevention study (AFCAPS/TexCAPS) that fibrates and niacin reduce triglyceride levels by [28,29]. In no study apart from the Scandinavian 20–50% and also raise HDL-C (niacin more than Simvastatin Survival Study (4S) did HDL-C contrib- fibrates), no endpoint trial has specifically recruited ute to the efficacy of the statin [30], and there is no patients with high triglycerides. Most early trials general relationship for statin efficacy and change in recruited patients with hypercholesterolaemia and HDL-C or triglycerides [31]. The actual action of the outcome trials show that niacin in the Coronary statins is to increase LDL-receptor (LDLR) expression Drug Project (CDP) reduced CVD events by 22% on hepatocytes. The LDL receptor has two ligands – [45], as did gemfibrozil in the Helsinki Heart Study apoB and to a lesser extent apoE [32,33]. However, (HHS) (32%) [46]. Subsequent post-hoc analyses of triglyceride-rich particles have many apoE mol- the CDP trial suggested greater benefits in sub- ecules and only one apoB. Thus, statins acting groups with lower HDL-C and the metabolic syn- through LDLR expression reduce triglycerides in drome [47]. Clofibrate showed no benefit and direct proportion to their activity on LDL-C and indeed excess adverse effects in the large WHO trial the baseline triglyceride concentration [34,35]. in hypercholesterolaemia [48]. Later studies con- This relationship has been validated in clinical firmed that gemfibrozil reduced events in patients trials up to triglyceride levels of 8 mmol/l [36]. with low HDL-C (but mostly normal triglyceride Therefore, statin treatment will benefit most levels) in the Veterans Administration HDL Inter- patients with elevated triglycerides provided that vention Study [49]. Bezafibrate showed little effect the extent of the triglyceride elevation does not in a hypercholesterolaemic secondary prevention exceed the efficacy of the statin. The practical population in the Bezafibrate Infarct Prevention limit of triglyceride reduction achieved with Study [50] but a post-hoc analysis suggested some statins seems to be in the range of 20–30%. If benefit for patients with high triglycerides. All these triglyceride levels exceed 2.3 mmol/l then signifi- studies showed that CVD event rates were greater in cant quantities of small dense atherogenic LDL and patients with higher baseline triglyceride and lower nonfunctional small dense HDL are present and HDL-C levels [51]. Analysis of the HHS showed no LDLR function is reduced such that reduction in association of benefit with changes in triglyceride or non-HDL or apoB achieved with statin therapy HDL-C, but in Veterans Affairs HDL Intervention tends to be less than at lower triglyceride levels, (VA-HIT) efficacy was proportional to change in wherein their efficacy on apoB and LDL-C is HDL-C [52]. More recently studies have been con- approximately equivalent [37]. Patients with ducted with fenofibrate. In the fenofibrate Interven- hypertriglyceridaemia have an excess risk depend- tion in Endpoint Lowering in Diabetes study ent on residual triglyceride levels even in combi- fenofibrate reduced CVD events (a secondary end- nation fibrate–statin therapy [38]. point) by 11% but the similar effect on coronary heart disease rates (the primary endpoint) was not significant [53]. Meta-analysis of the fibrate studies Nonstatin methods of reducing triglycerides is always complicated by the WHO trial but their Ezetimibe has little effect on triglyceride levels [39], lipid efficacy seems to be related to changes in whereas bile acid sequestrants raise triglycerides triglycerides. Fibrates deliver a 22% reduction in despite their effects in improving insulin resistance nonfatal CHD events with no benefits on fatal [40,41]. events or total mortality [54,55]. Fenofibrate shows additional benefits on microvascular disease end- points (renal disease – proteinuria, retinopathy) and Fibrates and niacin on rates of amputation for peripheral arterial disease One of the major problems of assessing the efficacy [56]. As few endpoint trials existed with niacin it of lipid-lowering drugs that have significant effects has generally been added to fibrates in a general on triglyceride levels is that the evidence base for meta-analysis of the efficacy of all lipid-lowering these compounds in monotherapy often comes drugs to raise HDL-C [57]. This analysis showed a from trials which preceded the systematic measure- small benefit to raising HDL-C. No specific meta- ment of complete lipid profiles. Niacin has pleio- analysis has been conducted for their efficacy on tropic actions on lipid profiles, with its effects being baseline triglyceride. 400 Volume 27 Number 4 July 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  4. 4. Triglyceride lowering and drugs Wierzbicki et al.FIBRATES AND NIACIN ADDED TO The study is far larger, comprising 30 000 patientsSTATINS but no prior lipid qualification criteria. It includesThe monotherapy studies had suggested that both 6000 patients with diabetes.niacin and some fibrates had a limited effect inreducing CVD events. However, these studies weredated and preceded statin therapy becoming the TRIGLYCERIDE REDUCTION ANDuniversal first choice for CVD event prevention. THIAZOLIDINEDIONESStatins do have effects in reducing triglycerides Triglycerides can be reduced by hypoglycaemicand a modest effect in raising HDL-C. The recent drugs. The best illustration of the differential lipidtrials have addressed adding fenofibrate to statin effects of hypoglycaemic therapies is seen in trials oftherapy in type 2 diabetes in the Action to Control the thiazolidinediones (glitazones). RosiglitazoneCardiovascular Risk in Diabetes (ACCORD) study had lesser lipid effects and its use often resulted in[58] and niacin to baseline statin in dyslipidaemic an increase in LDL-C as a consequence of its action(low HDL-C) patients with cardiovascular disease in to reduce insulin resistance [64]. In contrast, piogli-the Atherothrombosis Intervention in Metabolic tazone reduced triglycerides, raised HDL-C and hadsyndrome with low HDL/high triglycerides: Impact minimal effect on LDL-C [64]. Rosiglitazone showedon Global Health outcomes (AIM-HIGH) trial [59]. an increase in CHD events in meta-analyses, thoughThe ACCORD trial recruited 5518 patients with type not in the Rosiglitazone Evaluated for Cardiac Out-2 diabetes already on underlying statin therapy and comes and Regulation of Glycaemia in Diabetes trialadded fenofibrate or placebo in a 2 Â 2 design with [65], and has since been withdrawn. In contrast,aggressive or standard glycaemic control [60]. Tri- in the PROspective pioglitAzone Clinical Trialglycerides were reduced by 14%, HDL-C increased In macroVascular Events (PROACTIVE) study inby 2% and LDL-C was unaffected by fibrate therapy 5238 patients with type 2 diabetes pioglitazone non-but reduced by 19% (0.49 mmol/l) in both groups. significantly reduced total CVD events from 21.7 toCreatinine increased by 19% with fibrate therapy. 19.4% [relative risk (RR) 0.9; P ¼ 0.09] and reducedThe primary endpoint of cardiovascular events was the secondary endpoint of fatal and nonfatalsimilar in both groups [2.2 vs. 2.4%/year; odds ratio coronary events and strokes from 13.6 to 11.5%(OR) 0.92; 95% confidence interval (CI), 0.79–1.08; [RR ¼ 0.86; P ¼ 0.03; number needed (NNT) toP ¼ 0.32]. There were no differences with respect to treat/year of therapy ¼ 137] [66]. Part of the differ-any secondary outcome, including nonfatal myo- ence between these two drugs may arise from theircardial infarction (MI) [1.32 vs. 1.44%/year; OR 0.91 differential effects on lipid profiles.(0.74–1.12); P ¼ 0.39]. Total mortality was similar(1.5 vs. 1.6%; OR 0.91 (0.75–1.10); P ¼ 0.33). Asuggestion of benefit was seen in the 941 patients OMEGA-3 FATTY ACIDSin the study with high baseline triglyceride Most human triglycerides are composed of a mix-(2.3 mmol/l) and low HDL-C (0.88 mmol/l) ture of saturated fatty acids (SFAs) and monounsa-(12 vs. 17%; P ¼ 0.06) [58]. turated fatty acids (MUFAs). There seems to be little The AIM-HIGH trial recruited 3414 patients difference in epidemiological studies in CVD riskwith a HDL-C of 0.90 mmol/l, an atherogenic associated with different diets differing in this com-index (triglyceride : HDL-C ratio) of 2 and LDL-C ponent of triglycerides. Intervention studies have 1.84 mmol/l [61 ]. The study was powered for a been underpowered to investigate the effects of 25% difference in CVD events [62 ] based on the MUFA as opposed to SFA on CVD events, thoughoutcomes of the VA-HIT trial using gemfibrozil – a lower concentrations of SFAs are associated withfibrate [43]. It was abandoned as futile after 3 years as improvements in the lipid profile [67,68]. Omega-there was no added benefit of niacin treatment. The 3 fatty acids are trace components of triglycerides indesign of AIM-HIGH tried to isolate the effects of man. The relationship between omega-3 fatty acidsHDL-C from LDL-C by allowing postrandomization and dietary intake is complex. The interventionoptimization of LDL-C to less than 2 mmol/l. Pre- trials with dietary omega-3 components have beendictably, this occurred more commonly in the controversial, with conflicting results [69,70]. Meta-placebo arm wherein there was greater usage of analyses suggest that any intake of omega-3 fattyezetimibe. An excess of withdrawals was seen in acids is beneficial compared with no intake [71].the active treatment group. However, overall the Interventional pharmacological studies havebiggest problem with this study was that it was used purified preparations with varying contentsunderpowered. The Heart Protection-2 Treatment of docosahexaenoic acid (DHA) and eicosapenta-of HDL to Reduce the Incidence of Vascular Events enoic acid (EPA) – the principal omega-3 fatty acids.(HPS2-THRIVE) trial may give a different result [63]. Omega-3 fatty acids reduce triglycerides in a dose0268-4705 ß 2012 Wolters Kluwer Health | Lippincott Williams Wilkins 401Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
  5. 5. Lipids and heart disease proportional manner. This has been validated (GISSI-HF) study [75] showed, in contrast to in a hypertriglyceridaemic population recently in previous statin trials and to its second portion com- the Multicenter, plAcebo-controlled, Randomized, prising a comparison of rosuvastatin 20 mg with double-blINd, 12-week study with an open-label placebo [76], that 1 g DHA-EPA reduced heart failure Extension trial using EPA and showing up to 45% admissions by 9%, again independent of any lipid reduction in triglycerides with little effect on HDL- effects. C or LDL-C [72]. Clinical trials of omega-3 fatty acids have used lower doses which in themselves are insufficient to significantly affect lipid levels. CONCLUSION The Grupo Italiano per lo Studio della Sopravvi- Triglycerides are a weak risk factor for CVD, becom- venza nell’Infarcto miocardio – prevenzione ing significant only at the increased levels present in (GISSI-P) study [73] recruited 11 324 patients with fewer than 5% of the population. They are a marker recent myocardial infarcts (3 months) who were of underlying changes in lipoprotein particle randomized to 1 g (V-3) fatty acids (50% EPA; 50% dynamics, such as the presence of small dense DHA) or 300 mg vitamin E in a 2 Â 2 open label LDL, and a marker of many other causes of dyslipi- design and followed up for 42 months. The supple- daemia often related to liver function. Statin ment had no effect on lipid profiles in a study therapy is the basis of CVD prevention, and statins with baseline LDL-C of 3.55 mmol/l and HDL-C do reduce triglycerides, so part of their action will be 1.08 mmol/l. A predictable increase occurred in mediated through this component of the lipid pro- statin treatment, with rates of prescribing rising file, though it is difficult to separate this statistically from 4.7% at baseline to 28.6% at 6 months and from their prime action in reducing LDL-C [77,78]. 45.5% at 42 months, paralleled by slight reductions Though evidence exists in monotherapy for both (3–7%) in aspirin, beta-blocker and angiotensin niacin and fibrates, trials to date have shown no converting enzyme inhibitor therapy. A two-way benefit of adding these agents to background statin analysis showed no effect of vitamin E and a 10 in the vast majority of patients with CVD. Similarly (1–18)% reduction in the primary endpoint from the omega-3 trials have been done at doses insuffi- 13.9 to 12.6% (P ¼ 0.048), giving a number to treat cient to affect triglycerides. Rates of CVD are falling of 263 patients/year. For cardiovascular death and with the increasing use of aggressive statin therapy nonfatal events the reduction was from 10.8 to in the UK. During the period 1995–2010 acute CHD 9.7%, giving a reduction of 11% (P ¼ 0.053) and admissions have been reduced in patients with and a NNT of 322/year. Better results were seen in without diabetes by 5%/year [79,80]. However, ear- the four-way analysis, with a 15% reduction in lier data suggested no effect on long-term CHD the primary endpoint (14.6! 12.3%; P ¼ 0.02; events [79] and the rate of events in patients with NNT ¼ 157/year) and 20% for the secondary end- diabetes remains three-fold to five-fold higher than point (11.4! 9.2%; P ¼ 0.008; NNT ¼ 159/year), in normoglycaemic patients [80]. It is acknowledged though as the study had one-third fewer events that the evidence base for triglyceride-reducing than predicted it may be underpowered for this drugs is inadequate. The large HPS-2 THRIVE trial original endpoint. Most of the benefit was seen in will clarify the effects of niacin added to statin. The the first 6 months of the study. US Food and Drug Administration has formally The Japan EPA Lipid Intervention Study [74] requested that a trial of fibrate therapy is performed investigated the effect of 1.8 g EPA added to new in a high triglyceride: low HDL population to clarify background 10–20 mg pravastatin or 5–10 mg sim- the utility of these agents [81]. By definition this is vastatin in 18 645 patients at least 6 months post-MI likely to include large numbers of patients with with total cholesterol more than 6.5 (LDL-C diabetes and the metabolic syndrome. In addition, 4.4 mmol/l). The primary endpoint was cardiovas- there is a need for a trial of high-dose omega-3 added cular death, fatal and nonfatal MI and stroke, and to adequate underlying statin therapy to determine percutaneous coronary intervention. Statin therapy the efficacy of these agents at doses sufficient to was effective in reducing LDL-C by 25% in both affect triglycerides. Again a trial in type 2 diabetes is groups to 3.25 mmol/l. The overall results showed most likely to deliver the required data. a 19 (5–31)% reduction in events (3.5! 2.8%; P ¼ 0.01; NNT ¼ 658/year). At 4.6 years there was a Acknowledgements nonsignificant 18% reduction in the primary pre- None. vention group (1.7! 1.4%; P ¼ 0.11; NNT ¼ 1538/ year), whereas events were reduced by 19% in the secondary prevention group (10.7! 8.7%; Conflicts of interest P ¼ 0.048; NNT ¼ 375/year). GISSI-Heart Failure There are no conflicts of interest. 402 Volume 27 Number 4 July 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.
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TheHEART. patients with type 2 diabetes mellitus: a prospective, randomized crossover org. 2011. [Accessed 10 January study. Diabetes Metab Res Rev 2007; 23:392–399. 2012] 404 Volume 27 Number 4 July 2012Copyright © Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.