Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4379 (Published 18 July 2014) Cite this as: BMJ 2014;349:g4379All rapid responses
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The outcome of the valuable meta-analysis by Keene et al (1) conformed with the prediction based on our knowledge of the biochemistry of HDLs (2) that increases in HDL cholesterol induced by drugs will not always reflect an increase in reverse cholesterol transport (RCT), and thereby lead to a reduction of atherosclerosis. Computer modelling has confirmed that, while on a population basis differences between subjects in RCT and HDL cholesterol will be positively correlated, within subjects an increase in HDL cholesterol in response to an intervention cannot be taken as a certain indication that the process has been enhanced (3). The HDL hypothesis (4) did not propose otherwise, only that there is an inverse relation of coronary heart disease (CHD) risk to HDL cholesterol in communities, which reflects the fact that subjects with low HDL particle concentrations on average have less efficient RCT than those with high concentrations.
There are several basic mechanisms by which a drug can raise HDL cholesterol: an increase in the uptake of cholesterol from tissues by HDLs; an increase in the transfer of cholesterol from other lipoproteins to HDLs; a reduction of the rate of transfer of cholesteryl esters from HDLs to the liver; and a reduction of cholesteryl ester transfer to other lipoproteins via the cholesteryl ester transfer protein (CETP) (2, 5). Of these modes of action only the first would be expected to enhance RCT. The others might have no effect, or even reduce it (3, 5). The effects on HDL metabolism of the three drug classes studied by Keene et al (CETP inhibitors, niacin and fibrates) are not fully understood, and there is no persuasive body of evidence that any one of them enhances RCT (5).
It is also important to note that the effects of the three classes are not limited to raising HDL cholesterol. Each also lowers LDL concentration in many subjects. Indeed both niacin and the fibrates were already being used for this purpose before publication of the HDL hypothesis. Therefore, it is not appropriate to describe them as “HDL targeted drug treatments”. What is striking about the results obtained by Keene et al is that none of the drugs achieved a further reduction of CHD risk in patients already taking statins in spite of their own LDL lowering activity. This is contrary to expectation, when another meta-analysis found that incremental reductions of LDL cholesterol by statins conferred increasing CHD benefit down to levels below 50 mg/dl (6). Given the observation by Leusink et al (7) that a CETP gene promoter allele that lowers plasma CETP concentration also blunts the efficacy of statins in preventing myocardial infarction, perhaps the explanation lies in the fact that like CETP inhibitors themselves, niacin and fibrates also lower CETP activity, in their case by suppressing CETP gene expression (8-10),
The HDL hypothesis can be tested only with drugs that are known to stimulate RCT. This is most likely to be achieved by increasing one or more of apo AI synthesis rate, the remodelling of alpha HDLs to generate small lipid-poor HDLs, and the activity of ABCA1 transporters in peripheral cells (2, 5). Studies in animals have universally supported a beneficial effect of such interventions (5). Recent clinical trials have supported earlier evidence (11, 12) that this may also be true in patients. Repeated infusions of recombinant apo AI/sphingomyelin particles (CER-001) were found to increase RCT and reduce carotid artery wall thickness in subjects with familial low HDL levels (13) and homozygotes for familial hypercholesterolaemia (14). RVX-208, a small molecule that stimulates apo AI synthesis in liver, had a favourable effect on coronary lesion progression in subjects with plasma C-reactive protein concentrations exceeding 2 mg/l (15). When the data from this study and another trial of RVX-208 of similar design were combined, a 55% (P=0.02) relative risk reduction of major adverse cardiac events (77% in diabetics, P=0.01) during six months was observed (16). In these studies the patients were already receiving standard care, including statins.
Thus, while the disappointing outcomes of some clinical trials of drugs whose effects on lipoproteins include a rise in HDL cholesterol have an important message for current clinical practice, they should not impact negatively on the search for other HDL raising therapies based on a comprehensive understanding of mechanisms of action.
References
1. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients. BMJ 2014; 349: g4379 doi: 10.1136/bmj.g4379 (18 July 2014)
2. Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res 1995; 36: 211–28.
3. Lu J, Hubner K, Nanjee MN, Brinton EA, Mazer NA. An in-silico model of lipoprotein metabolism and kinetics for the evaluation of targets and biomarkers in the reverse cholesterol transport pathway. PLOS Comput Biol 2014; 10(3) e1003509. doi:10.1371/journal.pcbi.1003509.
4. Miller GJ, Miller NE. Plasma high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet 1975;1:16–19.
5. Kingwell B, Chapman J, Kontush A, Miller NE. HDL-targeted therapies: progress, failures and future. Nature Rev Drug Discov 2014; 13: 445–64.
6. Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014; 64: 486-94.
7. Leusink M, Onland-Moret NC, Asselbergs FW, Ding B, Kotti S, van Zuydam NR, et al. Cholesteryl ester transfer protein polymorphisms, statin use and their impact on cholesterol levels and cardiovascular events. Clin Pharmacol Ther. 2014; 95: 314–20.
8. Van der Hoogt CC, De Haan W, Westerterp M, Hoekstra M, Dallinga-Thie GM, Romijn JA, et al. Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression. J Lipid Res 2007; 48: 1763–71.
9. Hernandez M, Wright SD, Cai TQ, Havekes LM, Rensen PCN. Critical role of cholesterol ester transfer protein in nicotinic acid-mediated HDL elevation in mice. Biochem Biophys Res Commun 2007; 355: 1075–80.
10. Van der Hoorn JWA, De Haan W, Berbée JFP, Havekes LM, Jukema JW, Rensen PCN, Princen HMG. Niacin increases HDL by reducing hepatic expression and plasma levels of cholesteryl ester transfer protein in APOE*3Leiden.CETP mice. Arterioscler Thromb Vasc Biol. 2008; 28: 2016–22.
11. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290: 2292-300.
12. Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007; 297: 1675-82.
13. Kootte RS, Smits LP, van der Valk FM, Dasseux JL, Keyserling C, Barbaras R, et al. (CER-001) promotes reverse cholesterol transport and reduces carotid wall thickness in patients with genetically determined low HDL. Atherosclerosis 2014; 235: e14 (abstract).
14. Hovingh GK, Stroes ES, Gaudet D, Stefanutti C, Sorand H, Kwok S, et al. Effects of CER-001 on carotid atherosclerosis by 3TMRI in homozygous familial hypercholesterolemia (HoFH): the Modifying Orphan Disease Evaluation (MODE) Study. Atherosclerosis 2014; 235: e13–e14 (abstract).
15. Puri R, Kataoka Y, Wolski K, Gordon A, Johansson J, Wong N, et al. Effects of an apolipoprotein A-I inducer on progression of coronary atherosclerosis and cardiovascular events in patients with elevated inflammatory markers. J Am Coll Cardiol 2014; 63 (12): A1451 (abstract).
16. Johansson JANO, Gordon AF, Halliday C, Wong NC. Effects of RVX-208 on major adverse cardiac events (MACE), apolipoprotein A-I and high-density-lipoproteins; a post-hoc analysis from the pooled SUSTAIN and ASSURE clinical trials. 2014. www.congress365.escardio.org. (abstract 4155).
Competing interests: No competing interests
I congratulate the authors of this article for highlighting the effects of different lipid modifying/lowering agents on HDL and their impact on all cause mortality. It has been observed that higher levels of LDL, TC and TGs are risk factors for cardiovascular diseases (CVDs) while higher level of HDL is cardio-protective.
It is true that Niacin, Fibrates and CETP inhibitors increase the HDL level and also decrease the cardiovascular events but they did not alter the all cause mortality rate in dyslipidemic patients.
Statins have pleiotropic effects (viz. lipid modifying actions, anti-inflammatory, antioxidant and anti-atherosclerotic actions), thus resulting in improving the dyslipidemia as well as prevent the cardiovascular events. But Statins did not showed much decrease in triglyceride level in hypertriglyceridaemic patients.
Studies have observed that Fibrates are useful in patients who have hypertriglyceridaemia, because they not only decrease TGs (more as compared to TC and LDL levels), but also increase HDL level. Whereas in hypertriglyceridaemia cases, statin monotherapy is unable to lower the raised TGs level to a greater extent, therefore mostly combination therapy of Statins with Fibrate is prescribed. Hypertriglyceridaemia is a common condition found in most of diabetic patients, therefore, combination therapy of Statin with Fibrate to be a better option in these cases.
A few studies have also shown that statins may increase the chance of hyperglycaemia (type 2 diabetes), which is a cause of concern. Therefore, Statins should be used carefully in type 2 diabetic patients who have dyslipidemia.
Henceforth, it is better to find out the exact role as well as impact on all cause mortality of both (fibrate and statin) /and other lipid modifying agents in dyslipidemic patients. Therefore, double blind RCT or prospective study should be conducted to find out the exact role of these agents on cardiovascular events and all cause mortality.
References:
1. Shah RV, Goldfine AB. “Statins and Risk of New-Onset Diabetes Mellitus”. Circulation. 2012;126:e282-e284.
2. Henriksbo BD, Lau TC, Cavallari JF et al. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes. 2014 June. DB_131398.Available online http://diabetes.diabetesjournals.org/content/early/2014/06/10/db13-1398.... assessed on 31-july 2014 at 5:45 am.
3. U.S. Food and Drug Administartion. FDA Expands Advice on Statin Risks http://www.fda.gov/forconsumers/consumerupdates/ucm293330.htm#3
4. Kumar Raj , Kohli Kamlesh, Kajal HL. A STUDY OF DRUG PRESCRIBING PATTERN AND COST ANALYSIS AMONG DIABETIC PATIENTS IN A TERTIARY CARE TEACHING INSTITUTE IN NORTH INDIA. Journal of Drug Delivery & Therapeutics; 2013, 3(2), 56-61. Available online at http://jddtonline.info/index.php/jddt/article/view/431/246 assessed on 31 July 2014 at 6:08 am.
5. Kumar Raj, Rai Jaswant, Goel Ashok Kumar. ‘A COMPARATIVE STUDY OF ROSUVASTATIN AND FENOFIBRATE AS MONOTHERAPY IN DYSLIPIDEMIA AND NCEP ATP III GOALS’. Journal of Drug Delivery & Therapeutics; 2013, 3(4), 108-113. Available online http://jddtonline.info/index.php/jddt/article/view/583/329 assessed on 31 July 2014 at 6:08 am.
Competing interests: No competing interests
It is no surprise that drugs to raise HDL are of no benefit but useful to see it confirmed in this paper. There is an association between low HDL and cardiovascular disease because they have a common cause, not because one causes the other. That cause is a diet high in sugar and carbohydrate [1]. Over a period of 2.5 million years prehistoric man became genetically adapted to eating 5% carbohydrate, 75% fat and 20% protein [2]. Since the start of agriculture 8,000 years ago we have increased carbohydrate consumption and this has been further increased by the misguided advice in the last 40 years to eat less fat. We now eat 60% carbohydrate, 20% fat and 20% protein. Our genetic makeup is unchanged so we are not adapted to the new diet. The increased carbohydrate consumption is a major factor in causing modern diseases of civilisation.
Lowering carbohydrate intake very effectively raises HDL and lowers triglyceride. I increased my HDL from 0.9 to 2.3mmol/L. The reason more people do not do this is the erroneous fear of cholesterol. A low carbohydrate diet can increase the total cholesterol level. Mine went up from 3.5 to 6.7mmol/L. This fear is irrational. There is no relationship between cholesterol level and heart disease. People with high cholesterol levels live longer [3] and have less cognitive decline in old age [2].
There are two points which are used to wrongly support the idea that raised cholesterol is dangerous. Firstly there is a weak association with heart disease in men under 65. This is because stress causes both heart attacks and raised cholesterol, not because raised cholesterol causes heart attacks [4]. Secondly statins reduce the incidence of heart attacks. This is because of their anti-inflammatory and anticoagulant effects, not due to cholesterol lowering. Because of an increase in other causes of death such as suicide and violence, when used in primary prevention, statins have no effect on average lifespan. They will change the diagnosis on a death certificate but not the date [5].
People also fear that eating fat will cause weight gain. This is not true. A Swedish expert committee, having looked at all the evidence, recommended that a low carbohydrate high fat diet is best for weight loss and will improve health markers, for example it will result in “a greater increase in HDL cholesterol without having any adverse effects on LDL cholesterol”[6].
Cereal, toast and orange juice for breakfast result in low HDL with more deaths. Bacon, eggs, lard and tea result in high HDL with fewer deaths [7].
A paper about the Norwegian HUNT 2 study [3] asks the question “Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid?” The answer is, “No, the use of cholesterol in mortality risk algorithms in clinical guidelines is not valid”. However, HDL and triglyceride are highly predictive of mortality.
References:
1. The Art and Science of Low Carbohydrate Living by Jeff S Volek and Stephen D Phinney
2. Grain Brain by David Perlmutter
3. Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from, Journal of Evaluation in Clinical Practice Volume 18, Issue 1, Article first published online: 25 SEP 2011, http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2753.2011.01767.x/pdf
4. Ignore the Awkward! How the Cholesterol Myths are Kept Alive by Uffe Ravnskov
5. Statin Nation, video produced by Justin Smith
6. Dietary Treatment for Obesity, A Systematic Review of the Literature, Swedish Council on Health Technology Assessment (SBU), http://www.dietdoctor.com/swedish-expert-committee-low-carb-diet-effecti...
7. Cholesterol Clarity by Jimmy Moore
Competing interests: No competing interests
HDL has been , once touted to be good cholesterol, under scanner since long.Most of the leading journals have published reviews on role of HDL. Is it a good cholesterol or surrogate molecule, the dilemma has never been solved. The trials raising HDL cholesterol miserably failed always. The current article perhaps deals a blow to the " good cholesterol" hypothesis.
Competing interests: No competing interests
against atherogenesis. The unfolding of multiple functions of HDL and its dynamic metabolism pose a challenge to such unilateral conclusion. Even today many still rely on plasma cholesterol level to assess cardiac risk in such patients in spite of numerous studies indicating that triglycerides are another important risk factor to be considered.1
A few studies that emphasized a fall in plasma cholesterol level which associated with a reduction of coronary artery disease did not take the triglyceride effect into consideration. This led to overestimation of cholesterol reduction as the major concern in patients with coronary artery disease and resulted in giving more importance to hypocholesterolemic agents.2,3 However, the focus is now shifted to other therapeutic methods such as raising HDL cholesterol levels through administration of CETP inhibitors. But the findings of studies related to CETP inhibitors seem to suggest that it is more important to restore HDL cholesterol functionality than merely increasing HDL cholesterol levels4, prompting more studies to evaluate the dynamics of lipoprotein metabolism in health and disease in general.
Particularly, there is a real need for revaluation and serious reconsideration to study the triglyceride effect on the dynamics of lipoprotein cholesterol and triglyceride in the pathophysiology of atherogenesis
1.Dhastagir Sultan Sheriff, Elshaari Faraj Ali, and Manopriya T. Priya ‘Triglyceride effect’ on the dynamics of plasma lipoproteins and its possible link to atherogenesis. Libyan J Med. 2012; 7: 10.3402/ljm.v7i0.18909.
2. Trobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov.2003;2:517–26. [PubMed]
3.Law M. Dietary fat and adult diseases and the implications for childhood nutrition: an epidemiologic approach.Am J Clin Nutr. 2000;72:1291S–6S. [PubMed]
4.Davidson MH, McKenny JM, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels. J Am Coll Cardiol. 2006;48:1774–81
Competing interests: No competing interests
How to Control Residual Risk During Statin era?
Keene D, et al’s paper reported that neither niacin, fibrates, nor CETP inhibitors, three highly effective agents for increasing high density lipoprotein levels, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. Although observational studies might suggest a simplistic hypothesis for high density lipoprotein cholesterol, that increasing the levels pharmacologically would generally reduce cardiovascular events, in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.1
Lowering low-density lipoprotein–cholesterol (LDL–C) is the primary target in the management of dyslipidemia in patients at high risk of cardiovascular disease. However, patients who have achieved LDL–C levels below the currently recommended targets may still experience cardiovascular events. This may result, in part, from elevated triglyceride (Tg) levels and low levels of high-density lipoprotein–cholesterol (HDL–C). Low HDL–C and high Tg levels are common and are recognized as independent risk factors for cardiovascular morbidity and mortality. Furthermore, atherogenic dyslipidemia, characterized by low levels of HDL–C, high Tg, and small, dense LDL particles, is a typical phenotype of dyslipidemia in subjects with insulin resistance and metabolic syndrome. Therefore, to reduce further the risk of coronary heart disease (CHD), raising HDL–C and lowering Tg may be the secondary therapeutic target for patients who achieve LDL–C levels below the currently recommended targets but are still at risk of CHD (fig 1). However, whether increasing HDL–C levels alone reduces CHD has not yet been confirmed in large randomized clinical trials, and whether functional HDL is more important than HDL–C in reducing CHD remains controversial.2
On the other hand, raised Tg concentrations are strongly associated with low concentrations of HDL-C, and the past 15 years have been dominated by HDL research, with less focus on Tg. However, the understanding from genetic studies and randomised trials that low HDL-C might not be a cause of cardiovascular disease as originally thought, has generated renewed interest in raised Tg.3 Indeed, a study investigated the causal role of HDL-C and Tg in CHD using multiple instrumental variables for Mendelian randomization and reported the genetic findings supported a causal effect of Tg on CHD risk, but a causal role for HDL-C, though possible, remains less certain.4
.
In contrast to statins, fenofibrate modifies the quality of the lipoprotein particles by promoting a shift from small, dense LDL particles toward larger, more buoyant particles with increased binding affinity for the LDL receptor. The combination of fenofibrate with low to moderate doses of atorvastatin resulted in better overall lipid control than statin monotherapy in patients with mixed dyslipidemia (fig. 2).5 Other additive beneficial effects of fenofibrate combined with statins are to improve vasomotor function and inflammatory markers, and further, to increase adiponectin levels and insulin sensitivity because statins dose-dependently increase the risk of type 2 diabetes mellitus.6,7 Combined statin and fenofibrate treatment reduced the 10-year probability for myocardial infarction to 4.2% compared with statin therapy alone (21.6%) in patients with type 2 diabetes mellitus and no preexisting CHD.8
It is obvious that statins are the first-line drug for the treatment of dyslipidemia, and their utility in preventing CHD events has been established in many studies. However, the CHD risk persists for many subjects, even after effective LDL–C reduction is achieved with statin therapy. A strategy to increase HDL–C, reduce high Tg, and modify the small, dense LDL particles is required. In this regard, optimal doses of statins combined with fibrates, peroxisome proliferator-activated receptor agonists are recommended. Besides improving the overall lipid control, these agonists to achieve the same target LDL-C level might allow for the beneficial cardiovascular effects of lowering LDL-C while minimizing adverse outcomes from high-dose statin treatment when taking for a life-long period. This approach is based on distinct and interrelated mechanisms. Randomized clinical trials to identify the efficacy of these approaches on reducing the risk of CHD and developing diabetes mellitus are needed urgently. The cost effectiveness of these combinations should also be evaluated.
Funding: None, Disclosures: None
REFERENCES
1. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ 2014;349:g4379.
2. Lim S, Park YM, Sakuma I, Koh KK. How to control residual cardiovascular risk despite statin treatment: Focusing on HDL-cholesterol. Int J Cardiol 2013;166:8-14.
3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease.
Lancet 2014;384:626-35.
4. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2014 Jan 27. [Epub ahead of print]
5. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 2005;45:1649-53.
6. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol 2010;55:1209-16.
7. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167:1696-702.
8. Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002;25:1198-202.
Competing interests: No competing interests