Central Journal of Family Medicine & Community Health

Research Article *Corresponding author Seema Jain, Department of Family Medicine, Queens University, Kingston, Ontario, Canada, Email: seema. HDL and its Role in [email protected] Submitted: 22 January 2015 Cardiovascular Disease: A Accepted: 24 March 2015 Published: 08 June 2015 Copyright Primary Care Perspective © 2015 Jain S et al. Seema Jain1* and Michael A. Ward1,2 OPEN ACCESS 1Department of Family Medicine, Queens University, Canada 2Department of Family and Community Medicine, University of Toronto, Canada Keywords • High density lipoprotein • Cardiovascular disease Abstract • Niacin Lipid profiles are a part of the routine blood work ordered by many family • Fibrates physicians. For decades, manipulation of lipid levels has been a central theme in the • Cholesteryl ester transfer protein inhibitors effort to decrease the impact of cardiovascular disease. In particular, the high density lipoprotein (HDL) fraction has been the subject of much research and controversy. In the 1960’s, strong epidemiological evidence demonstrated an inverse relationship between HDL and the risk of cardiovascular disease. This paper sought to examine the risk reduction of such events by therapeutically targeting HDL with niacin, fibrates or the cholesteryl ester transfer protein (CETP) inhibitors. A literature search yielded 5 relevant articles which were then critically analyzed. Results demonstrated no benefit of increasing HDL with niacin, gemfibrozil, bezafibrate or fenofibratein those patients already treated with statins. However, patients not on statins were found to have a decreased risk of non-fatal MI with niacin and fibrate use. Niacin also reduced the incidence of strokes. Despite disappointing phase three trials with the CETP inhibitors, torcetrapib and dalcetrapib, trials for anacetrapib and evacetrapib are ongoing.

INTRODUCTION Study, the Coronary Primary Prevention Trial and the Multiple Risk Factor Intervention Trial – Gordon et al. concluded that a The global impact of cardiovascular mortality and morbidity 0.03 mmol/L increase in HDL resulted in a 2-3% decrease in the remains daunting despite an intensive focus on the management risk of future coronary heart disease [7]. Since that time, HDL as of risk factors by health care providers worldwide. From 2000 a risk factor in primary cardiovascular disease has been largely to 2012, the world has seen an increase in the number of years- accepted [5,8-10]. However, in terms of secondary prevention and of-life lost (YLL) from non-communicable disease. Ischemic heart the statin treated population, the role of HDL remains contested [10,11]. Re-analysis of data from JUPITER, a primary prevention diagnoses driving this change– increasing 16% and 12% disease and stroke represent the first and third most common trial in which 8 900 patients were randomized to rosuvastatin respectively over the 12 year time frame. Globally, ischemic heart versus placebo, demonstrated no relationship between the disease accounts for over 4% of the total YLL in men and almost different quantiles of HDL concentration and coronary risk 8% in women [1]. In 2012, Canadian cardiovascular mortality either at baseline or on treatment [11]. In contrast, post-hoc ranked second in leading causes of death with rates of 112.2 per analysis done on the TNT study population found that the inverse 100,000 in men and 68.1 per 100,000 in women [2,3]. relationship between HDL and cardiovascular events persisted The role of high density lipoprotein cholesterol (HDL) is despite taking atorvastatin daily [12]. In 2012, Boekholdt et al. frequently cited in theories that have attempted to explain completed a meta-analysis including both the aforementioned residual cardiovascular risk. The inverse relationship between study populations and six others for a total of 62 154 patients. This group found the predictive value of cardiovascular events Gofman et al. in 1966 [4,5]. Soon after, as part of the Framingham by HDL level persisted despite the use of statins [13]. On the basis Study,HDL and decreased risk of ischemic HDL washeart associated disease was with first described each major by of this information, many attempts have been made to decrease manifestation of coronary heart disease. It was considered to be a more potent vascular risk factor than any other lipid type Recently, Voight et al used the technique of Mendelian cardiovascular risk by targeting HDL specifically. (including low density lipoprotein cholesterol (LDL))[6]. randomization to study the relationship between alterations in After analyzing four large studies- the Framingham Heart HDL and cardiovascular risk. The presence of a variant of the Study, the Lipid Research Clinics Prevalence Mortality Follow-up LIPG allele (Ans396Ser), which was carried by 2-6% of the study

Cite this article: Jain S, Ward MA (2015) HDL and its Role in Cardiovascular Disease: A Primary Care Perspective. J Family Med Community Health 2(3): 1037. Jain S et al. (2015) Email: Central

METHODS An electronic literature search of the OVID, PUBMED and Cochrane Library databases was conducted with the following search terms: high density lipoprotein, cardiovascular disease,

(CETP)niacin or inhibitors nicotinic or acid, anacetrapib fibrates or or dalcetrapib clofibrate or or bezafibratetorcetrapib or evacetrapib.fenofibrate orAdditionally, gemfibrozil, the cholesteryl references esterof meta-analyses transfer protein were manually reviewed. “The English language”, “humans” and “age older than 19” were set as limits in the search. No time criterion was applied to the search. Of the 765 results, 590 were eliminated with title review. Inclusion and exclusion criteria were used to narrow the remaining articles to the most relevant. Trials were included if they were either randomized control trials (RCTs) with strong internal validity or meta-analyses comparing niacin,

diseasea fibrate (as or opposeda CETP inhibitor to the increases to placebo. in HDLIf a study resultant was designedfrom the useto test of the that efficacy drug) andof a haddrug a in laboratory the prevention marker of ascardiovascular the primary

[17], HPS 2 THRIVE [18], a meta-analysis by Keene et al. [19], a outcome,meta-analysis it was done excluded. by Lee Theet al. five [20] final and studies Dal OUTCOMES were: AIM [21]. HIGH Niacin

is processed by the body into coenzymes used in lipid metabolism. ThisNiacin result is in one HDL of theincreases first medications between 30-35% used to treatas well low as HDL. other It [22]. Proposed mechanisms for anti-atherogenic effects of Figure 1 changesOne ofto the lipidearliest profile studies done on niacin in cardiovascular HDL. The pathways involved in decreasing cardiovascular risk disease was the Coronary Drug Project (CDP). Conducted from are hypothesized as including participation in reverse cholesterol 1966 to 1974, the CDP tested secondary prevention of coronary transportation, counter-acting LDL oxidation and restoring endothelial function. Images altered from 54-56. HDL: High-Density Lipoprotein; LDL: Low-Density Lipoprotein medication streams or placebo. Of these, three streams (two differentheart disease. estrogen 8 341 regimes men were and randomly dextrothyroxine allocated sodium) to one of were five stopped prior to the scheduled completion of the study due to population, was found to be associated with an increase in HDL safety concerns. However, the remaining two medications, niacin by 0.08 to 0.28 mmol/L per copy. There were no appreciable changes in other cardiovascular risk factors including LDL, triglycerides, body mass index and systolic blood pressure. They decreaseand clofibrate, total cholesterolwere continued. and triglyceride The primary levels endpoint and resultedin the CDP in analyzed over 116 320 patients but found no association between riskwas reductiontotal mortality. of non-fatal The use myocardial of niacin infarctions was seen to(MI) significantly [23]. A 15 LIPG Ans396Ser and the risk of myocardial infarctions (OR: 0.99; year follow-up demonstrated an 11% decrease in total mortality 95% CI: 0.88 to 1.11; p=0.85) despite epidemiological evidence (p=0.0004) hypothesizing risk reduction of 13%. Fourteen additional common genetic variants which exclusively affect HDL were [23]. [24]. However, significant adverse effects included an evaluated and none were found to be associated with a decrease increased incidence of a trial fibrillation and other arrhythmias in risk of myocardial infarction (OR: 0.93; 95% CI: 0.68 to 1.26; Following this, many studies assessing the effect of niacin p=0.63) [14]. on atherosclerosis were completed. These include CLAS I [25], FATS [26], CLAS II [27], HATS [28] and AFREGS [29]. Each of these Current Canadian and American Heart Association (AHA) demonstrated a reduction in progression and increased regression of atherosclerotic lesions with niacin use. Further, testing done increase in HDL with pharmacotherapy due to a lack of causal in the ARBITER 2 [30] and 6 [31] trials looked at the behavior lipid guidelines do not make specific suggestions for targeting an of atherosclerosis when niacin was used in combination with a both historical and contemporary evidence to help family physiciansevidence for develop its benefit an understanding [15,16]. This review of the serves HDL enigma. to explore We in atherosclerosis, ARBITER 6 demonstrated superiority of niacin tostatin. ezetimibe Unlike inARBITER reducing 2which mean showed carotid no intima-media significant difference thickness classes of pharmacotherapeutic agents that have been used to targetreview increases the potential in HDL benefits in the hopeand pitfalls of decreasing associated cardiovascular with three in LDL and triglycerides in addition to HDL, making these results mortality and morbidity. [30,31]. However, in [31]. ARBITER 6, there were significant changes

difficult to interpret J Family Med Community Health 2(3): 1037 (2015) 2/12 Jain S et al. (2015) Email: Central

Figure 2 as well as inhibiting CETP preventing conversion of HDL to LDL and VLDL. Fibrates act to increase HDL through various effects on the liver. CETP Summary of effects of targeting HDL with niacin, the fibrates or the CETP inhibitors. Niacin acts as the levels of the liver to increase HDL HDL: High-Density Lipoprotein; LDL: Low-Density Lipoprotein; VLDL: Very Low –Density Lipoprotein; MI: Myocardial Infarction; CETP: Cholesteryl Esterinhibitors Transfer act specifically Protein at CETP promoting an increase in HDL levels. Image altered from 55-57.

Perhaps the most relevant niacin trials are the recently randomized to placebo ended the trial taking higher doses of published AIM HIGH [17] and HPS2 THRIVE [18] studies. AIM simvastatin and requiring the additional ezetimibe. HIGH studied the incidence of cardiovascular events when After 2 years of follow up, niacin had increased HDL (25% patients were treated with niacin and a statin. 3,414 patients vs. 9.8% in placebo; p<0.001), decreased triglycerides (28.6% over the age of 45 participated in this double blinded randomized control trial (RCT). These patients had a history of either coronary vs. 5%). The trial was terminated 19 months early due to lack of heart, cerebrovascular, carotid or peripheral artery disease and vs. 8.1%) but did not significantly change LDL (12% decrease dyslipidemia including low levels of HDL, elevated triglycerides group and 16.7% in the placebo (HR: 1.02; 95% CI: 0.87 to 1.21; and an LDL less than 4.65 mmol/L. They were selected from over efficacy. The primary end point was seen in 16.4% of the niacin 92 clinical centers across North America. The large majority of ischemic strokes in the treatment group (HR: 1.61; 95% CI: 0.89 these patients were Caucasian, male, had hypertension and/or top=0.80). 2.90; p=0.11). There was This also increase a non-significant in strokes was trend not forseen increased in prior metabolic syndrome. Just over one third had diabetes. All patients studies or meta-analyses. Other adverse effects included liver were started on 40-80 mg of simvastatin with an additional abnormalities, muscle symptoms and rhabdomyolysis [17]. 10 mg of ezetimibe if necessary. They were then randomized to receive either 1500-2000 mg of extended release niacin or Most recently, HPS 2 THRIVE assessed whether there was placebo (which contained 50 mg of immediate release niacin to a decrease in major vascular events when patients already on help maintain blinding). The primary outcome was the composite effective statin therapy were started on niacin and laropiprant. This double blinded randomized trial involved 245 sites in the MI, ischemic stroke, hospitalization for acute coronary syndrome United States, Scandinavia and China. 25,673 patients between (ACS)of the orfirst symptom event of driven death coronaryfrom coronary or cerebral heart revascularization.disease, non-fatal the ages of 50 and 80, with a history of MI, cerebrovascular disease, peripheral artery disease or diabetes with symptomatic between the patients in the two arms of this study. An intention coronary disease participated. Most patients were European toBaseline treat protocol analysis was demonstrated used and endpoint no significant data was collected differences for men. Approximately one third had diabetes and one third had all patients except for 52. However, there were higher rates metabolic syndrome. Prior to randomization, patients had a mean of discontinuation of therapy in the treatment cohort (8.4%; LDL of 1.64 mmol/L and HDL of 1.14 mmol/L. Patients were then assigned either 2 g of niacin with 40 mg of laropiprant daily or p<0.001). Additionally, significantly higher numbers of patients J Family Med Community Health 2(3): 1037 (2015) 3/12 Jain S et al. (2015) Email: Central placebo and followed for an average of 3.6 years. Laropiprant is a prostaglandin antago and was used to maintain blinding. Adherence to the treatment didwith not niacin explain had thedifficulty methods with of blinding randomization due to theand predominance blinding they medication was poor;nist falling shown to 69.9%to decrease by the flushing end of fromthe second niacin of flushing as a side effect. Furthermore, some of the older trials year. More patients in the treatment group discontinued the medication (25.4% vs. 16.6% in the placebo group; p<0.001). studies.employed, Finally, making some validity trials assessment were designed difficult. to withhold High dropout more thanrates onewere intervention a significant from concern the placebo in many group of the [25,26,33].niacin and fibrateAll the events in the niacin group (p<0.001). The most prominent was a included studies were, however, homogenous. The majority of 55%There increase were significantly in disturbances more fatalof glucose and non-fatal control serious(11% vs. adverse 7.5%; the included participants were men approximately 41 to 73 years p<0.001). An increase in the diagnosis of diabetes (5.7% vs. old from several continents including Europe, Asia and North 4.3%; p<0.001), bleeding, cutaneous and peptic ulcerations, gout, America. Of the RCTs that reported ethnicities of participants, a myopathy and rashes were also seen. New side effects which were not previously seen with niacin and laropiprant were also portion of this analysis, 11 RCTs with 35,301 patients were noted. These included infections (8.0% vs. 6.6%; p<0.001) and included.large majority Follow were up rangedCaucasian. from Turning 6 to 60 months.specifically Niacin to the was niacin seen bleeding (including intracranial and gastrointestinal) (2.5% vs. to result in increases in HDL of 17-43%. In the 30,310 patients 1.9%; p<0.001) [18]. cause mortality (OR: 1.03; 95% CI: 0.92 to 1.15; p=0.59), coronary On average, treatment with niacin resulted in a decrease hearton statins, disease there mortality(OR: was no significant 0.93; 95% effect CI: of 0.76 adding to 1.12; niacin p=0.44), on all- of 0.25 mmol/L in LDL, a 0.16 mmol/L increase in HDL and a non-fatal MI(OR: 0.85; 95% CI: 0.72 to 1.01; p=0.07) or strokes (OR: 0.96; 95% CI: 0.75 to 1.22; p=0.72). However in patients not difference was seen in the incidence of major vascular events taking statins, niacin lowered the incidence of non-fatal MI (OR: (13.2%0.37 mmol/L in treatment decrease and in triglycerides. 13.7% in placebo; However, RR: 0.96;no significant 95% CI: 0.69; 95% CI: 0.56 to 0.85; p=0.0004) and stroke (OR: 0.78; 95% 0.90 to 1.03; p=0.29). The only individual component of the CI: 0.61 to 1.00; p=0.05) [19]. revascularization procedures (RR: 0.90; 95% CI: 0.82 to 0.99; Currently it appears that targeting low HDL with niacin p=0.03).primary outcomeThere was to no have effect a significant on stroke withresult treatment was a decrease (RR: 1.00; in in patients who are already on statin therapy has no added increase in the incidence of death from any cause in the treatment not be pursued. However, there is data that supports the use of group95% CI: (RR: 0.88 1.09; to 1.13;95% p=0.56).CI: 0.99 to There 1.21; p=0.08)was also [18]. a non-significant niacincardiovascular in patients benefit. who Thereare not is takingevidence currently of harm statins and this to strategy reduce both non-fatal MI and stroke. This trial data is summarized in Over the last decade, many attempts have been made to (Table 1). trial data and cardiovascular outcome. However, most of these Prior to the initiation of niacin, the American Heart meta-analysestry and understand have examined the somewhat the role conflicting of niacin results (as opposed of HDL Association (AHA) lipid guidelines suggest baseline measures of to increased HDL) in cardiovascular disease prevention. One hepatic transaminases, hemoglobin A1C and uric acid be obtained such study, done in 2013 by Lavigne and Karas [32], sought to and then repeated every six months during therapy. Additionally, understand the reduction of cardiovascular events with niacin use through analysis of 11 RCTs and 9,961 patients. They found niacin. This includes patients with elevated transaminases, a decrease in incidence of cardiovascular disease events which poorlygiven the controlled side effect hyperglycemia, profile, certain and patients acute gout, should abdominal not receive pain included cardiac death, non-fatal MI, hospitalization for ACS, with no apparent cause, gastrointestinal or cutaneous symptoms, stroke or a revascularization procedure with niacin treatment [15]. (OR: 0.66; 95% CI: 0.49 to 0.89; p=0.007). However, interestingly, weightFibrates loss or new onset a trial fibrillation no significant association was seen between the change in HDL agonists and therefore, regulate the synthesis, elimination and Lavigneand the and risk Karas of cardiovascular suggest that the events. decreased Thus, risk it may is difficult be due to Fibrates are α peroxisome proliferator receptor (PPAR-α) otherattribute properties these protective of niacin [32].findings to the increase in HDL. In fact, HDL [20,34]. oxidation of many different particles of the lipid profile, including As above, one arm of the Coronary Drug Project was cardiovascular risk reduction by increasing HDL was done by KeeneThe et only al meta-analysis found looking specifically at of coronary heart disease. Although it decreased cholesterol designed to investigate clofibrate in the secondary prevention was analyzed.[19]. Secondary The efficacy outcomes in decreasing included coronary all-cause mortality, mortality mortality. In fact, it was seen to increase the incidence of various non-fatalby using niacin,MI, stroke fibrates and andadverse CETP events. inhibitors Keene to ettarget al. conducted low HDL non-fataland triglyceride cardiovascular levels, it did events not lower including total or pulmonary all-cause specific emboli, an extensive computerized and manual search for published and unpublished RCTs. Although the authors state the selected and angina pectoris (81.3%vs. 75.8%) [23]. This increased harm studies needed to examine one of the HDL increasing medications thrombophlebitis,signal was also seen a trial by Geizerova fibrillation, et intermittent al. claudication

deaths from all causes and causes other When than ischemic clofibrate heart was validityand measure concerns one withof the some aforementioned of the included outcomes, RCTs. Manyno specific done diseasestudied inischemic with treatment heart (3%disease, vs. 2.4%there were in the significantly high cholesterol more exclusion criteria were listed. In addition, there were significant

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Table 1: Summary of all included Niacin studies.

Summary of Included Niacin Studies Study Follow Up Population Therapy Primary outcome Results Publication Year (months) Coronary Drug 8 341 men aged from 60 Conjugated estrogens 2.5 mg Total mortality, Project[25] 30-64 years old with daily (ended early) 2.58) mortality TC:Clofibrate: 6.5% decrease (significance z>2.58 or z<- 1975 than 3 months ago Conjugated estrogens 5 mg andcause nonfatal specific TG: 22.3% decrease evidence of ≥ 1 MIs more daily (ended early) cardiovascular Primary outcome: 0.9% decrease in all- outcomes cause mortality compared to placebo Dextrothyroxine sodium 6 mg (z=-0.60) daily (ended early) 1.6% decrease in cardiovascular mortality compared to placebo (z=-1.17) 5.5% increase in number of patients with nonfatal cardiovascular outcomes NiacinClofibrate 3 g daily1.8 g daily (z=3.61)

Placebo Niacin: TC: 9.9% decrease TG: 26.1% decrease Primary outcome: 1.2% increase in all- cause mortality compared to placebo (z=-0.19) 0.1% decrease in cardiovascular mortality compared to placebo (z=-0.12) 1.2% decrease in number of patients with nonfatal cardiovascular outcomes (z=-0.83) CLAS I[25] 162 men between 40 24 Niacin 3-12 g daily and Angiographic Niacin and colestipol: and 59 years old with colestipol 30 g daily coronary global HDL: 37% increase (p<0.001) 1987 previous coronary change score Primary outcome: 3.8% less patients had bypass surgery and Placebo progression in native arteries (p=0.001) angiographic evidence of 5.3% less patients had new lesions in atherosclerosis native arteries (p=0.23)

FATS[26] 30 Niacin 125mg BID -1.5g QID Average Niacin and colestipol: old with elevated apo- and colestipol 5-10g TID percentage change 1990 lipoprotein146 men ≤ 62 B and years family between two Primary outcome: decreased 0.9% history of CAD Lovastatin 20- 40 mg BID and angiographic comparedHDL: increased to placebo 15% (p>0.05)(p<0.005) All had evidence of colestipol studies for the coronary atherosclerosis worst lesion in Lovastatin and colestipol: on angiogram Placebo +/- colestipol nine proximal segments Primary outcome: decreased 0.7% comparedHDL: increased to placebo 43% (p<0.02)(p>0.05) CLAS II[27] 103 men (subgroup 24 Niacin 3-12 g daily and Angiographic Niacin and colestipol: from CLAS I who did not colestipol 30 g daily coronary global HDL: 37% increase (p<0.001) 1990 require further bypass change score Primary outcome: 29.9% less patients surgery) Placebo had progression in native arteries (p=0.001) 26.1% less patients had new lesions in native arteries (p=0.001)

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HATS[28] 160 patients with 24 Simvastatin 10-20 mg OD and Mean change Simvastatin and niacin coronary disease, low niacin 0.25g -1g BID per patient from HDL: increase 18% (p<0.001) 2001 HDL and normal LDL Primary outcome: decreased 0.4% Antioxidants (800 IU vitamin arteriogram in compared to placebo (p<0.001) E, 1000 mg of vitamin C, 25 percentinitial to stenosis final of mg of beta carotene and 100 most severe lesion Simvastatin, niacin and antioxidants µg of selenium) in 9 proximal HDL: increased 6% (p<0.001) Simvastatin, niacin and coronary segments Primary outcome: increased 0.7% antioxidants compared to placebo (p<0.005)

Placebo Antioxidants

Primary outcome: increased 1.8% HDL: decreased 3% (p>0.05) ARBITER 2[30] 167 patients with known 12 Niacin 0.5- 1g OD to Change in common Niacin: coronary heart disease background statin carotid intima HDL:compared increased to placebo 21% (p=0.002)(p>0.05) 2004 and low HDL thickness after 1 Primary outcome: 68% decrease Placebo year compared to placebo (p=0.08) AFREGS[29] 143 military retirees 30 Percentage younger than 76 years niacin 0.240g - 3g daily and change in global HDL: 36% increase (p<0.001) 2005 old with low HDL and cholestyramineGemfibrozil 600mg 2g-16 BID, g daily angiographic PrimaryGemfibrozil, outcome: niacin 1.91% and cholestyramine: decrease in angiographic coronary stenosis global stenosis compared to placebo disease Placebo (p=0.04) ARBITER 6[31] 363 patients with 14 Niacin 0.5-2 g daily Change in mean Niacin: coronary heart disease common carotid HDL: 18.4% increase (p< 0.001) 2009 or at risk for such Ezetimibe 10 mg daily intima-media Primary outcome: 1929% decrease receiving long term thickness compared to ezetimibe (p= 0.01) statin with low HDL and low to normal LDL AIM HIGH[17] 3,414 patients older than 36 niacin 1.5- 2 g daily and First event of Niacin: 45 yo with a history of Simvastatin 40-80 mg OD ± the composite HDL: 25% increase (p<0.001) 2011 either coronary heart, ezetimibe 10 mg daily of death from Primary outcome: 0.3% decrease cerebrovascular, carotid coronary heart compared to placebo (p=0.80) or peripheral artery placebo (50 mg of immediate disease, nfMI, disease and dyslipidemia release niacin) and ischemic stroke, Simvastatin 40-80 mg OD ± hospitalization for ezetimibe 10 mg daily acute coronary syndrome, symptom driven coronary or cerebral revascularization HPS 2 THRIVE[18] 25,673 patients 48 Niacin 1-2 g daily and First major Niacin: between 50-80 yo laropiprant 20-40 mg daily vascular event: HDL: 14% increase 2014 with a history of MI, added to simvastatin 40mg nfMI, death from Primary outcome: 0.5% decrease cerebrovascular disease, daily ± ezetimibe 10 mg daily coronary causes, compared to placebo (p= 0.29) peripheral artery stroke or arterial disease or diabetes with placebo added to simvastatin revascularization symptomatic coronary 40mg daily ± ezetimibe 10 disease mg daily TC = Total Cholesterol; TG = Triglycerides; HDL = High-Density Lipoprotein; LDL = Low-Density Lipoprotein RCT = Randomized Controlled Trial nfMI = non-fatal Myocardial Infarction; PE = Pulmonary Embolus; TIA = Transient Ischemic Attack; CAD = Coronary Artery Disease; IHD = Ischemic Heart Disease placebo patients). No single explanation for the increase in were also seen in the VA HIT study [39]. Here, in patients with a documented history of coronary heart disease, treatment mortality could be identified [35,36]. disease deaths (95% CI: -2 to 41%; p=0.07) and 23% decrease of with the publication of the Helsinki Heart Study (HHS) in 1987 non-fatalwith gemfibrozil MI (95% resulted CI: 4 to in38%; a 22% p=0.02) reduction of coronary heart [37,38].Almost Here a decade 5,081 later, men fibrates with no were history brought of back cardiovascular into favor reduce mortality, non-fatal MI or sudden[39]. death Bezafibrate, [40]. on the 34% reduction in cardiac death, fatal and non-fatal MI was seen other hand, in the Bezafibrate Infarction Prevention study did not (p<0.02).disease were This randomized was driven largelyto either by gemfibrozil a 37% reduction or placebo. in non- A Recently, a more contemporary trial, the FIELD study, fatal MI (p<0.05) investigated the prevention of cardiovascular disease in type 2

[38]. Results consistent with these findings J Family Med Community Health 2(3): 1037 (2015) 6/12 Jain S et al. (2015) Email: Central

Table 2:

Summary of all included fibrate studies. Summary of Included Fibrate Studies Follow Up Study Population Therapy Primary outcome Results (months) Coronary Drug 8 341 men aged from 60 Conjugated estrogens 2.5 Total mortality, cause Project25 30-64 years old with mg daily (ended early) nonfatal cardiovascular TC:Clofibrate: 6.5% decrease (significance 1975 more than 3 months ago Conjugated estrogens 5 mg outcomesspecific mortality and TG:z>2.58 22.3% or z<-2.58) decrease evidence of ≥ 1 MIs daily (ended early) Primary outcome: 0.9% decrease in all-cause Dextrothyroxine sodium 6 mortality compared to mg daily (ended early) placebo (z=-0.60) 1.6% decrease in cardiovascular mortality compared to placebo (z=- NiacinClofibrate 3 g daily1.8 g daily 1.17) 5.5% increase in number Placebo of patients with nonfatal cardiovascular outcomes (z=3.61)

Niacin: TC: 9.9% decrease TG: 26.1% decrease Primary outcome: 1.2% increase in all-cause mortality compared to placebo (z=-0.19) 0.1% decrease in cardiovascular mortality compared to placebo (z=- 0.12) 1.2% decrease in number of patients with nonfatal cardiovascular outcomes (z=-0.83)

Geizerova et al36 15 745 men between 60 Group I: men in the upper Fatal IHD, nfMI 30-59 years old third of serum cholesterol and acute coronary TC: 8.2-9.7% decrease 1978 FatalClofibrate: IHD: 0.1% increase 1.6 g daily cause mortality compared to Group II distribution on clofibrate insufficiency and all- Group II: men in upper compared to Group III third of serum cholesterol (p<0.01)(p>0.05) and 0.7% increase on placebo nfMI and acute coronary

Group III: men in lowest compared to Group II third of serum cholesterol (p<0.05)insufficiency: and 2.9%1.6% increasedecrease on placebo compared to Group III All-cause mortality: 1.1% increase compared to Group II (p<0.05) and 2% increase compared to Group III

HHS[38] 4 081 asymptomatic 60 Cardiac endpoints men aged between 40- (Fatal MI, nfMI and HDL: 9% increase (p<0.05) 1987 55 years old PlaceboGemfibrozil 600mg BID cardiac death) CardiacGemfibrozil: endpoint: 34% decrease compared to placebo (p<0.02)

VA HIT[39] 2 531 patients with 61 Combined nfMI and coronary heart disease coronary heart disease HDL: 6% increase (p<0.001) 1999 less than 74 years of age PlaceboGemfibrozil 1200 mg daily death PrimaryGemfibrozil: outcome: 4.4% decrease compared to placebo (p=0.006)

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BIP[40] 3 090 patients between 74 Fatal MI, nfMI and 45-74 years of age with colestipol sudden death HDL: 18% increase 2000 CAD Bezafibrate 400 mg daily ± PrimaryBezafibrate outcome: 9.4% Placebo ± colestipol reduction compared to the placebo (p=0.26) FIELD[41] 9 795 patients between 26 First occurrence of 50-75 years old with either nfMI or death 2005 type 2 diabetes PlaceboFenofibrate 200 mg daily from coronary heart PrimaryFenofibrate: outcome: 11% disease reductionHDL: 1.2% compared increase (p>0.05) to

ACCORD[42] 5 518 patients between 56 First occurrence of 409 years old with major cardiovascular HDL:placebo 8.4% (p>0.05) increase (p=0.01) 2010 type 2 diabetes and simvastatinFenofibrate 160 mg daily event PrimaryFenofibrate: outcome: 0.2% cardiovascular disease and modified doses of decrease (p=0.32)

doses of simvastatin Placebo and modified TC = Total Cholesterol; TG = Triglycerides; HDL = High-Density Lipoprotein; LDL = Low-Density Lipoprotein RCT = Randomized Controlled Trial nfMI = non-fatal Myocardial Infarction; PE = Pulmonary Embolus; TIA = Transient Ischemic Attack; CAD = Coronary Artery Disease; IHD = Ischemic Heart Disease placebo and followed for non-fatal MI or coronary death. There triglyceride status, both hypertriglyceridemia and reduced HDL wasdiabetes. a reduction 9,795 patients in non-fatal were randomized MI (RR: 0.76; to either 95% fenofibrate CI 0.62-0.94; or andno pre-specified patients without HDL atherogenicstatus, reduced dyslipidemia. HDL with noThose pre-specified with only increased triglycerides were found to have a 25% risk reduction heart disease mortality (RR: 1.19; 95% CI 0.90-1.57; p=0.22) and totalp=0.01). mortality However, (7.3% a non-significant vs. 6.6% in the increase placebo in group) both was coronary seen 0.65 to 0.86; p<0.001). Patients with low HDL had a 16% risk reductionof vascular (RR: events 0.84; when 95% treated CI: 0.77 with to fibrates 0.91; p<0.001) (RR: 0.75; and 95% those CI: with both high triglycerides and low HDL had a 29% reduction with allocation to fenofibrate. These non-significant increases [41].may reflect a more widespread usage of statins amongst the decrease in risk in patients with no dyslipidemia (RR: 0.96; 95% placebo group than in the fibrate group (17% vs. 8 %; p<0.0001) CI:(RR: 0.85 0.71; to 95%1.09; CI: p<0.53). 0.62 to However, 0.82; p<0.001). there Therewere problems was no significant with the Next, the ACCORD trial investigated whether simvastatin and validity of this study which may call some of these results into question. Although homogeneity was found when each group 2 diabetic patients. Unlike the FIELD study, no difference was fenofibrate therapy decreased cardiovascular risk in 5,518 type was individually analyzed, there was heterogeneity between the groups themselves. Also, the division of patients in the four study stroke or cardiovascular death (HR: 0.92; 95% CI: 0.79 to 1.08; groups was done through post-hoc analysis. Further, there was p=0.32)found in [42]. the timeThis todifference the first suggestscardiovascular that concurrent event: non-fatal statin useMI, a lack of small studies with neutral or unexpected harm results summarized in (Table 2). some publication bias suggested by the funnel plots; specifically decreases the benefit of fenofibrate therapy. Fibrate trial data is in the hypertriglyceridemia and combined hypertriglyceridemia Akin to niacin, multiple meta-analyses assessing the and low HDL groups [20]. Keene et al. [19] included 20 RCTs and 46,099 patients when One such analysis by Lee and colleagues, examined 6 RCTs with they examined cardio-protection through increasing HDL with 25,409cardiovascular patients protection [20]. The aimoffered was by to fibrates analyze have the treatmentbeen conducted. effect of statins- ACCORD and FIELD (42; 41; 19; 23). This analysis foundfibrates. no Only difference two of the in all-cause20 trials mortalityallowed the (OR: simultaneous 0.98; 95% use CI: forof fibratesat least 6 in months. patients In addition, with atherogenic participants dyslipidemia. and the number To beof 0.89 to 1.08; p=0.66), coronary heart disease death (OR: 0.92; monitoredincluded, articles events hadhad to be reporteda RCT comparing separately. a fibrate Patients to alsoplacebo had 95% CI: 0.81 to 1.04; p=0.19), non-fatal MI (OR: 0.83; 95% CI: to have a triglyceride level over 200 mg/dl and/or an HDL of less 0.69 to 1.01; p=0.07) or stroke (OR: 1.01; 95% CI: 0.90 to 1.13; than 40 mg/dl. Studies were excluded if a cohort had less than p=0.84). However, when patients were not concomitantly on 100 patients and the difference between treatment and control statin therapy, a reduction of non-fatal MI was seen (OR: 0.78; consisted of more than 1 intervention. The only restrictions 95% CI: 0.71 to 0.86; p<0.001) [19]. used in the search were “human beings” and it covered a period spanning1966 to April 2010 [20]. Of the 6 trials found, 3 focused should not be combined with statins to target low HDL as they [40]. Follow up was between 2.7 to 6.3 years. Eighty- In summary, gemfibrozil, bezafibrate and fenofibrate on gemfibrozil [38,39,43], 2 on fenofibrate [41,42] and 1 on heartbezafibrate disease and/or diabetes and/or atherogenic dyslipidemia. provide no added benefit. However, without concurrent statin Forfive thispercent analysis, of the patients included were patients subdivided had a into history groups of coronarybased on associatedtherapy, these with three increased fibrates risk can of decrease mortality. the If starting risk of non-fatal therapy, theMI. AHA Clofibrate guidelines should suggest never monitoring be used to renal target function low HDL prior as to it the is their lipid profiles. The groups were hypertriglyceridemia with J Family Med Community Health 2(3): 1037 (2015) 8/12 Jain S et al. (2015) Email: Central

1.1; p=0.001) resulted in the early termination of this study. The every 6 months thereafter [15]. major contributors to increased non-cardiovascular deaths were initiation of fenofibrate therapy, at the 3 month mark and then cancer and infection [44]. CETP inhibitors The Dal OUTCOMES trial [21] studied cardiovascular risk The CETP inhibitors prevent the transfer of cholesteryl ester reduction in patients with recent ACS through the use of another from HDL to other lipoproteins, resulting in increased HDL and CETP inhibitor, dalcetrapib. 15,871 patients from over 935 decreased LDL levels44.These are developing medications in sites and 27 countries were randomized to either 600 mg of phase three testing and are not currently available for widespread dalcetrapib or placebo. All patients were at least 45 years old clinical use. and had an LDL of less than or equal to 2.6 mmol/L with statin use. The patients were largely Caucasian men from Europe, Israel inhibitors, torcetrapib, were published. Initially, ILLUSTRATE or North America. Approximately 25% had diabetes, 67% had [45], InRADIANCE 2007 several 1 [46] publicationsand RADIANCE regarding 2 [47] all the demonstrated first of the hypertension and 63% had metabolic syndrome. Randomization

LDL (17% to 20%). When combined with a statin however, no biomarkers at the index event. The primary outcome was a additionalsignificant reduction increases in HDLthe progression (53% to 63.4%) of coronary and decreases or carotid in compositewas stratified of based coronary on country heart and disease presence death, of majorelevated non-fatal cardiac atherosclerosis was seen [45-47]. coronary event or ischemic stroke. Discontinuation rates were comparable in both groups (21% in the treatment group vs. 19% A larger trial, ILLUMINATE, randomized 15,067 patients with in placebo).All patients except 1.6% in the dalcetrapib group known cardiovascular disease on atorvastatinto either torcetrapib and 1.3% in placebo were accounted for at the end of the study. or placebo. After 12 months, there was a 72.1% increase in HDL An intention to treat protocol was used. Dal OUTCOMES was (p<0.001) and a 24.9% decrease in LDL (p<0.001). However, terminated after 31 months of follow up due to futility. Despite increased risk of all cause death (HR: 1.58; 95% CI: 1.14 to 2.19; p=0.006) and major cardiac events including hospitalization for primary end point (HR: 1.04; 95% CI: 0.93 to 1.16; p=0.52) or unstable angina, stroke and death (HR: 1.25; 95% CI: 1.09 to anya 31-40% of its individualincrease in components. HDL, there was Effect no significanton LDL with effect treatment on the

Table 3: Summary of all included CETP inhibitor studies. Summary of Included CETP Inhibitor Studies Follow Up Study Population Therapy Primary outcome Results (months) ILLUSTRATE[45] 1 188 patients 24 Torcetrapib 60 mg daily and Change in percent Torcetrapib and atorvastatin: between 18 to 75 atorvastatin 10-80 mg daily atheroma volume HDL: 61% increase 2007 years of ago with Change in atheroma volume: 0.07% cardiac stenosis on Placebo and atorvastatin 10- decrease compared to placebo (p= 0.72) angiography 80 mg daily RADIANCE 1[46] 850 patients with 24 Torcetrapib 60 mg daily and Annualized change Torcetrapib and atorvastatin: heterozygous familial atorvastatin 20-80 mg daily in maximum HDL: 54% increase in HDL (p<0.001) 2007 hypercholesterolemia carotid intima- Primary outcome: 11% decrease compared Placebo and atorvastatin 20- media thickness to placebo (p=0.87) 80 mg daily for 12 carotid artery segments RADIANCE 2[47] 752 aged 18-70 years 20 Torcetrapib 60 mg daily and Yearly change in Torcetrapib and atorvastatin: old atorvastatin 10-80 mg daily maximum intima- HDL: 63.4% increase (p<0.0001) 2007 media thickness Primary outcome: 17% decrease compared Placebo and atorvastatin 10- for 12 carotid to the placebo group (p= 0.46) 80 mg daily artery segments ILLUMINATE[44] 15 067 between 40 18 Torcetrapib 60 mg daily and Torcetrapib and atorvastatin: and 75 years old with atorvastatin (variable dose) occurrence HDL: 72.1% increase (p<0.001) 2007 a history of CVD ofTime a major to first Primary outcome: 25% increase with Placebo and atorvastatin cardiovascular treatment (p=0.001) event Dal OUTCOMES[21] 15 871 patients 45 31 Dalcetrapib 600 mg daily Composite of Dalcetrapib: years or older with death from HDL: 31-40% increase 2012 acute ACS Placebo coronary heart Primary outcome: 0.3% increase in number disease, major of events compared to placebo (p=0.52) non-fatal coronary event or ischemic stroke TC = Total Cholesterol; TG = Triglycerides; HDL = High-Density Lipoprotein; LDL = Low-Density Lipoprotein RCT = Randomized Controlled Trial nfMI = non-fatal Myocardial Infarction; PE = Pulmonary Embolus; TIA = Transient Ischemic Attack; CAD = Coronary Artery Disease; IHD = Ischemic Heart Disease

J Family Med Community Health 2(3): 1037 (2015) 9/12 Jain S et al. (2015) Email: Central was minimal but a 4-10% increase in triglycerides was seen. The To conclude, the principal lipid target, as outlined in both the Canadian and AHA cholesterol treatment guidelines [15,16], [21]. remains LDL. Currently available agents that alter HDL offer no side effect profile included increased systolic blood pressure Other CETP inhibitors include anacetrapib and evacetrapib (significant increase of 0.6 mmHg), diarrhea and insomnia therapies designed to alter HDL form and function and reassess both of which have been found to decrease LDL (11.2% to 39.8%) cumulative benefit in addition to statin therapy. We await new and increase HDL (78.5% to 138.1%) [48,49]. Phase 3 testing is its role in cardiovascular disease prevention. currently underway in the REVEAL and ACCELERATE trials [51]. REFERENCES Data from these trials is summarized in Table 3. 1. World Health Statistics 2014. Geneva. 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Cite this article Jain S, Ward MA (2015) HDL and its Role in Cardiovascular Disease: A Primary Care Perspective. J Family Med Community Health 2(3): 1037.

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