Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia. A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events Effects of extended-release niacin on lipoprotein subclass distribution. Impact of Increases in High-Density Lipoprotein Cholesterol on Cardiovascular Outcomes During the Armed Forces Regression Study Combined use of extended-release niacin and atorvastatin: safety and effects on lipid modification. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. Normalization of low-density-lipoprotein levels in heterozygous familial hypercholesterolemia with a combined drug regimen. Plasma phospholipid transfer protein activity in patients with low HDL and cardiovascular disease treated with simvastatin and niacin. Lipid lowering agents, cognitive decline, and dementia: the three-city study. 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. Effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by virtual histology intravascular ultrasound. Influence of Low High-Density Lipoprotein Cholesterol and Elevated Triglyceride on Coronary Heart Disease Events and Response to Simvastatin Therapy in 4S Lipoprotein profile, plasma Ischemia Modified Albumin and LDL density change in the course of postprandial lipemia. Insights from the LIPGENE study Heart positive: design of a randomized controlled clinical trial of intensive lifestyle intervention, niacin and fenofibrate for HIV lipodystrophy/dyslipidemia. Clinical trial experience with extended-release niacin (Niaspan): dose-escalation study. Niacin, but Not Gemfibrozil, Selectively Increases LP-AI, a Cardioprotective Subfraction of HDL, in Patients With Low HDL Cholesterol Effects of extended-release niacin with laropiprant in high-risk patients.
This study was conducted to determine the efficacy of atorvastatin and niacin on lipoprotein subfractions in patients with atherogenic dyslipidemia . This was a multicenter , r and omized , open-label , parallel- design study of patients with total cholesterol > 200 mg/dl , triglycerides between 200 and 800 mg/dl , and apolipoprotein B > 110 mg/dl . Patients were r and omly assigned to atorvastatin 10 mg or immediate release niacin 3,000 mg daily for 12 weeks following a low-fat diet stabilization period . Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy . Atorvastatin and niacin both significantly reduced the concentrations of very low-density lipoprotein ( VLDL ) particles ( -31 % and -29 % , respectively ) and small low-density lipoprotein ( LDL ) particles ( -44 % and -35 % , respectively ) . Niacin increased the concentration of large LDL ( + 75 % ) . Atrovastatin reduced the number of LDL particles more than niacin ( 31 % vs 14 % ) . In patients with atherogenic dyslipidemia , both drugs had important effects on lipoprotein subfractions , which contributed to a reduction in coronary heart disease risk . The drugs equally reduced VLDL subclass levels . Niacin shifted the LDL subclass distribution toward the larger particles , more effectively converted patients from LDL phenotype B to phenotype A , and increased levels of the larger and perhaps more cardioprotective high-density lipoprotein particles . In contrast , atorvastatin preferentially lowered the concentration of small LDL particles without increasing levels of large LDL , and more effectively , reduced LDL particle numbers .  Atorvastatin had a preferred LDL effect , whereas niacin had a preferred high-density lipoprotein effect Context Most trials that address lipid management focus on reducing low-density lipoprotein ( LDL ) cholesterol levels rather than increasing high-density lipoprotein ( HDL ) cholesterol levels . Contribution In this double-blind trial , 143 military retirees with low HDL cholesterol levels and coronary artery disease were r and omly assigned to placebo or aggressive HDL cholesterolincreasing therapy with gemfibrozil , niacin , and cholestyramine for 30 months . All participants received diet and exercise counseling . Compared with the placebo group , the treated group had a 20 % decrease in total cholesterol level ; a 36 % increase in HDL cholesterol level ; less focal coronary stenosis ; fewer total cardiovascular events ; and more flushing , skin rashes , and abdominal symptoms . Caution s The small trial had limited ability to assess clinical outcomes . The Editors Large epidemiologic studies have repeatedly demonstrated that cardiovascular risk increases proportionally with increasing total cholesterol and low-density lipoprotein ( LDL ) cholesterol levels and decreasing high-density lipoprotein ( HDL ) cholesterol levels ( 1 , 2 ) . Although many studies have documented that statins , drugs that primarily reduce LDL cholesterol levels , significantly reduce the risk for cardiovascular events ( 3 - 7 ) , prospect i ve studies that examine the clinical effects of increasing HDL cholesterol levels have been more limited . The Coronary Drug Project first reported evidence of a mortality benefit in patients treated with niacin ; however , the difference was seen long after withdrawal of the study drug , making the mechanism of benefit less clear ( 8) . The Helsinki Heart Study ( 9 ) examined the use of gemfibrozil in primary prevention . Coronary events were reduced by 34 % , but the increase in HDL cholesterol level was modest ( only 11 % ) . The Bezafibrate Infa rct ion Prevention Trial failed to show a reduction in cardiovascular events in the composite population , although a recent re analysis of the data suggests an improved outcome in patients experiencing a greater increase in HDL cholesterol level ( 10 ) . The Veterans Affairs HDL Intervention Trial ( VA-HIT ) ( 11 ) demonstrated a modest reduction in coronary events when gemfibrozil was used in patients with normal levels of LDL cholesterol and low levels of HDL cholesterol . The authors ascribed most of the reduction in clinical events to the improvement in HDL cholesterol , although the overall improvement was only approximately 6 % with drug therapy . More recently , a combination of a statin ( simvastatin ) with niacin was found to favorably modify both HDL cholesterol and LDL cholesterol levels and reduce cardiovascular events compared with both placebo therapy and underlying treatment with antioxidants in a cohort of 160 patients with coronary disease ( 12 ) . Despite a significant increase in mean HDL cholesterol levels , the overwhelming treatment effect in this study was the reduction in LDL cholesterol level ( 42 % in the treatment group ) . The most suggestive evidence of benefit from an increase in HDL cholesterol level has come from trials assessing the effect on coronary stenosis . Trials of quantitative angiography after monotherapy with fibrates ( 13 ) , as well as combinations of medications that both reduce LDL cholesterol levels and increase HDL cholesterol levels ( 14 - 18 ) , have shown an attenuation in angiographic progression . Nissen and colleagues ( 19 ) recently took this theory a step further by demonstrating that an infusion of a recombinant form of HDL , apolipoprotein A-I Milano , can lead to regression of angiographic stenosis as assessed by intravascular ultrasonography . We undertook the Armed Forces Regression Study ( AFREGS ) in 1993 to determine whether coronary atherosclerosis , assessed by quantitative coronary angiography and clinical coronary events , would improve when combination drug therapy focused on increasing HDL cholesterol levels in a sample of patients with fairly normal LDL cholesterol levels and low HDL cholesterol levels . A pilot study by Whitney and colleagues ( 20 ) showed the feasibility of this trial design , and the safety of using these drugs in combination has been previously established ( 21 ) . Methods Patients Participants living within a 150-mile radius of Wilford Hall Medical Center in San Antonio , Texas , who could provide written informed consent were eligible for enrollment . We recruited men and women younger than 76 years of age who had established or suspected coronary artery disease ( positive results on an exercise treadmill test or classic angina ) and did not have unstable symptoms . We allowed LDL cholesterol levels up to 4.1 mmol/L ( 160 mg/dL ) with HDL cholesterol levels less than 1.0 mmol/L ( 40 mg/dL ) after adherence to the American Heart Association ( AHA ) step II diet for at least 6 months . We set no lower limit to either HDL cholesterol or LDL cholesterol level . Each patient was required to have measurable stenosis between 30 % and 80 % of the luminal diameter within the coronary tree by caliper inspection . Patients with stenosis greater than 80 % were eligible if they had a favorable prognosis based on functional testing ( ability to exercise for > 9 minutes on a full Bruce protocol exercise treadmill test ) . Exclusions included a major vascular event ( myocardial infa rct ion , cerebrovascular accident , coronary artery bypass grafting , or other coronary catheterbased intervention ) within 6 months , a history of congestive heart failure ( other than in the setting of myocardial infa rct ion ) , or a left ventricular ejection fraction less than 0.4 on ventriculography . Other exclusion criteria included alcohol or substance abuse within the past year , uncontrolled arrhythmias , resistant hypertension , diabetes , uncontrolled gout , uncontrolled thyroid disease , liver or gall bladder disease , renal dysfunction ( creatinine concentration > 176.8 mol/L [ > 2.0 mg/dL ] or proteinuria greater than 2 + by dipstick or 500 mg/24 h ) , uncontrolled peptic ulcer disease , or pancreatic disorders . In addition , we excluded patients taking any lipid-modifying medications within 4 weeks of r and omization , heparin or coumarin-type anticoagulants , long-term oral corticosteroid therapy , or other immunosuppressive agents . We also excluded patients if they had hypersensitivity to or history of intolerance that required cessation of therapy for any component of gemfibrozil , nicotinic acid , cholestyramine , aspirin , or nitrates . Other exclusion criteria were the potential for childbearing , technically inadequate coronary arteriography for stenosis quantification , or any serious condition that we thought would compromise participation in the study or preclude survival for the duration of the study . We thoroughly informed participants of the details of the study . Each patient voluntarily enrolled and signed an informed consent statement that the Wilford Hall Medical Center Institutional Review Board review ed and approved . From screening laboratory records , we identified 1290 participant c and i date s and invited them to participate ( Figure 1 ) . Of the 847 patients who attended the introductory briefing , 671 met LDL cholesterol and HDL cholesterol entry criteria on fasting lipid analysis . Of the 269 participants who eventually provided informed consent , 55 subsequently withdrew for personal reasons , most commonly citing a fear of cardiac catheterization , and an additional 27 met an exclusion criterion . Of the 187 participants who completed the 6-month lifestyle modification phase and underwent coronary angiography  , 44 were excluded after initial coronary arteriography ; 27 had extensive coronary disease necessitating revascularization ( percutaneous coronary intervention in 3 patients and coronary artery bypass grafting in 24 patients ) , and 17 had insignificant coronary disease on angiography . Thus , we eventually r and omly assigned 143 patients ( 11 % of those initially contacted ) to either pharmacologic therapy or placebo . Figure 1 . Flow of patients through the study . Protocol After inclusion and exclusion criteria were met , a 6- to 8-month run-in period was performed to ensure that patients could adhere to the prescribed diet . During this phase , all patients received diet counseling from a study dietitian , exercise guidance from an exercise specialist , and smoking cessation advice . All study participants committed to attending a bimonthly food show for training in the AHA step II diet , with reinforcing presentations from the dietitian , exercise specialist , and cardiologist that discussed cardiac risk factor modification . We r and omly assigned each participant by using a computer-generated r and omization schedule . The central pharmacy held the code , and the information was not shared with physicians or patients until the completion of the protocol . Patients were r and omly assigned to 1 of 2 treatment groups : pharmacologic therapy with gemfibrozil , niacin , and cholestyramine or conventional therapy . The goal of therapy was to increase HDL cholesterol level by at least 25 % . The study was double-blind and placebo-controlled . The pharmaceutical company prepared all medications and placebos , and the central pharmacy dispensed them at 30-day intervals . The pharmacologic therapy group began receiving gemfibrozil , 600 mg twice per day . Short-acting niacin was added in the third month at a dosage of 250 mg/d and was titrated to 3000 mg/d as tolerated . Cholestyramine was added in the sixth month , and the dosage was titrated to 16 g/d as tolerated . The conventional therapy group was maintained on the AHA step II diet and applicable matching placebos for the duration of the investigation . If LDL cholesterol levels exceeded 4.14 mmol/L ( 160 mg/dL ) during the trial , cholestyramine was administered in an open-label fashion . Participants visited 1 clinic on a monthly basis for the duration of the study . At each monthly visit , clinicians measured vital signs and weight , counted unused study drugs , review ed changes in medications or medical status , provided The efficacy of extended-release niacin ( niacin ER ) on lipoprotein subclasses was evaluated in patients with primary hypercholesterolemia using a proton nuclear magnetic resonance method . Paired plasma sample s collected at baseline and after 12 weeks ' treatment with niacin ER 1,000 ( n = 21 ) or 2,000 ( n = 20 ) mg/day or placebo ( n = 19 ) were available for 60 eligible patients from a previous multicenter , r and omized , controlled trial .  Niacin ER increased high-density lipoprotein ( HDL ) cholesterol and decreased low-density lipoprotein ( LDL ) cholesterol and very low-density lipoprotein triglycerides in a dose-dependent manner relative to placebo . Niacin ER increased large HDL particles ( H5 and H4 , corresponding to the HDL(2ab ) fraction ) without having a net effect on small HDL particles ( H3 , H2 , and H1 , corresponding to the HDL(3abc ) fraction ) . It also decreased smaller , denser LDL particles ( L1 and L2 ) and increased the larger , more buoyant L3 subclass . The inhibitory effect of niacin ER on very low-density lipoprotein was evident on the larger particles ( V6 , V5 , V4 , and V3 subclasses ) rather than the smaller ones ( V2 and V1 ) . The results show that niacin ER produces a beneficial effect on lipoprotein subclasses , specifically decreasing the more atherogenic small , dense LDL particles and enhancing the cardioprotective large HDL particles Introduction : High-density lipoprotein ( HDL ) cholesterol is a well-established inverse risk factor for cardiovascular disease . The extent to which cardiovascular risk can be modified through changes in HDL , however , is less clear . We further examined the role of aggressive HDL raising therapy on cardiovascular outcomes in the 143 patients enrolled in the Armed Forces Regression Study ( AFREGS ) . Methods : Re analysis of the AFREGS population . Patients with stable coronary disease were r and omized to receive gemfibrozil , niacin , and cholestyramine in combination or matching placebos , on top of aggressive dietary and exercise modification for a 30-month period . Blood work was performed at baseline and repeated after 1 year of therapy . Results : Patients were divided into 3 groups based on their therapeutic response : no HDL increase , mild HDL increase , and large HDL increase ( % change in HDL ≤0 , ≤ the lower 2 tertiles of HDL increase , and > the upper tertile of HDL increase , respectively ) . A progressive decrease in cardiovascular events was noted across these groups ( 30.4 % , 19.4 % , and 3.2 % , respectively , P = .01 ) . Kaplan-Meier analysis according to percentage change in HDL demonstrated a similar improvement in event-free survival ( P = .01 ) . Proportional hazards modeling also demonstrated that increasing HDL predicted a lower hazard of cardiovascular events , even after adjusting for changes in low-density lipoprotein ( [ LDL ] P < .01 ) . For every 1 % increase in HDL achieved , a 2 % decrease in events was recognized . Conclusions : These data suggest that in a population of patients with stable atherosclerosis , the greater the percentage increase in HDL achieved , the greater the cardioprotective benefit . This further supports HDL raising as a beneficial therapeutic strategy BACKGROUND Cholesterol-lowering therapy with statins has been reported to reduce the morbidity and mortality of cardiovascular diseases . This study aim ed to investigate the effects of combined application of extended-release niacin and atorvastatin on lipid profile modification and the risks of adverse events in patients with coronary artery disease . METHODS Consecutive 108 patients with coronary artery disease and serum total cholesterol ( TC ) > or = 3.5 mmol/L were r and omized into two groups : group A using atorvastatin and group B using extended-release niacin ( niacin ER ) and atorvastatin .  Plasma lipid profile , glucose , and adverse events were assessed at the hospitalization , and 6 and 12 months after treatment . In addition , clinical cardiovascular events were evaluated after 12 months of treatment . RESULTS The levels of TC , low density lipoprotein cholesterol ( LDL-C ) were significantly decreased ( P < 0.05 ) in groups A and B , but the levels of high density lipoprotein cholesterol ( HDL-C ) and ApoA increased by 29.36 % and 40.81 % respectively after 12 months of treatment in group B ( P < 0.01 ) . The medications were generally well tolerated in the two groups . No significant difference of adverse events was found between the two groups ( group A : 3.2 % vs group B 5.1 % , P > 0.05 ) . CONCLUSIONS Combined use of extended-release niacin with atorvastatin was superior to atorvastatin monotherapy alone in lipid profile regulation . Combination therapy with niacin ER and atorvastatin was well tolerated and safe in patients with coronary artery disease BACKGROUND AND METHODS The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography . Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter , documented coronary artery disease , and a family history of vascular disease , 120 completed the 2 1/2-year double-blind study , which included arteriography at base line and after treatment . Patients were given dietary counseling and were r and omly assigned to one of three treatments : lovastatin ( 20 mg twice a day ) and colestipol ( 10 g three times a day ) ; niacin ( 1 g four times a day ) and colestipol ( 10 g three times a day ) ; or conventional therapy with placebo ( or colestipol if the low-density lipoprotein [ LDL ] cholesterol level was elevated ) . RESULTS The levels of LDL and high-density lipoprotein ( HDL ) cholesterol changed only slightly in the conventional-therapy group ( mean changes , -7 and + 5 percent , respectively ) , but more substantially among patients treated with lovastatin and colestipol ( -46 and + 15 percent ) or niacin and colestipol ( -32 and + 43 percent ) . In the conventional-therapy group , 46 percent of the patients had definite lesion progression ( and no regression ) in at least one of nine proximal coronary segments ; regression was the only change in 11 percent . By comparison , progression ( as the only change ) was less frequent among patients who received lovastatin and colestipol ( 21 percent ) and those who received niacin and colestipol ( 25 percent ) , and regression was more frequent ( lovastatin and colestipol , 32 percent ; niacin and colestipol , 39 percent ; P less than 0.005 ) . Multivariate analysis indicated that a reduction in the level of apolipoprotein B ( or LDL cholesterol ) and in systolic blood pressure , and an increase in HDL cholesterol correlated independently with regression of coronary lesions . Clinical events ( death , myocardial infa rct ion , or revascularization for worsening symptoms ) occurred in 10 of 52 patients assigned to conventional therapy , as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol ( relative risk of an event during intensive treatment , 0.27 ; 95 percent confidence interval , 0.10 to 0.77 ) . CONCLUSIONS In men with coronary artery disease who were at high risk for cardiovascular events , intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions , increased the frequency of regression , and reduced the incidence of cardiovascular events We studied the effect of th bite acid sequestrant colestipol , alone and in combination with clofibrate or niacin , in patients with heterozygous familial hypercholesterolemia who were given a diet low in cholesterol and saturated fat . With colestipol alone , mean cholesterol levels in serum decreased 16 to 25 per cent . The addition of clofibrate produced a total mean decrement of only 28 per cent . In contrast , serum cholesterol levels fell 45 per cent when colestipol as combined with niacin .  Low-density-lipoprotein ( LDL ) cholesterol decreased 55 per cent with colestipol and niacin , whereas high-density-lipoprotein ( HDL ) cholesterol increased . Mean LDL cholesterol was lower in patients given this regimen than in matched normal controls eating an unrestricted diet . Tendinous xanthomas , measured by quantitative xeroradiography , were significantly reduced ( P < 0.01 ) , indicating that this regimen mobilized cholesterol from tissue pools with slow turnover . Colestipol plus niacin promises to be useful in the treatment of patients at high risk from elevated levels of LDL Plasma phospholipid transfer protein ( PLTP ) is an important modulator of high-density lipoprotein ( HDL ) metabolism , regulating its particle size , composition , and mass . In patients with low HDL and cardiovascular disease ( CVD ) , plasma PLTP activity is positively correlated with the concentration of HDL particles containing apo A-I but not apo A-II ( Lp(A-1 ) ) . We recently completed a study to determine the effect of simvastatin and niacin ( S-N ) therapy on disease progression/regression in these patients , and found that this therapy selectively increased Lp(A-I ) . To determine if PLTP was also increased with this drug therapy , we measured the  PLTP activity  in the plasma of 30 of these patients obtained at baseline and after 12 months of therapy , and compared the changes to a similar group of 31 patients who received placebo for the drugs . No significant increase in PLTP activity was observed in either group of patients . However , changes in apo A-I and A-II between these two time points were correlated with the corresponding change in PLTP activity . The correlation coefficients were r=0.57 ( P=0.001 ) and r=0.43 ( P=0.02 ) for apo A-I , and r=0.54 ( P=0.002 ) and r=0.41 ( P=0.02 ) for apo A-II in the placebo and S-N group , respectively . At baseline , PLTP activity correlated positively with the percent of plasma apo A-I associated with Lp(A-I ) ( r=0.38 , P=0.04 ) and the amounts of apo A-I in these particles ( r=0.43 , P=0.02 ) . These relationships persisted in patients who took placebo for 12 months ( r=0.46 , P=0.009 and r=0.37 , P=0.04 , respectively ) , but was attenuated in those treated with S-N. These data indicate that S-N-induced increase in Lp(A-I ) was PLTP-independent . It also confirms our previous observation that an interrelationship exists between PLTP and apo-specific HDL particle subclasses in CVD patients with low HDL , and that this relationship is altered by drug intervention The aim of this prospect i ve cohort study was to evaluate the effects of lipid lowering agent ( LLA ) intake on cognitive function in 6,830 community-dwelling elderly persons .  Cognitive performance ( global cognitive functioning , visual memory , verbal fluency , psychomotor speed , and executive function ) , clinical diagnosis of dementia , and fibrate and statin use , were evaluated at baseline , and 2 , 4 , and 7 year follow-up . Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics , mental and physical health including vascular risk factors , and genetic vulnerability ( apolipoprotein E and cholesteryl ester transfer protein ) . For women but not men , fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only ( HR = 1.29 , 95 % CI = 1.09 - 1.54 , p = 0.004 ) , and did not increase risk for incident dementia . This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate ( HR = 1.39 , 95 % CI = 1.08 - 1.79 , p = 0.01 ) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment . For both genders , no significant associations were found between statins ( irrespective of their lipophilicity ) and either cognitive decline or dementia incidence . This prospect i ve study , adjusting for multiple confounders , found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia , but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory The efficacy , safety , and tolerability of a moderate dose , 3-drug lipid-lowering regimen were evaluated among 29 male patients with hyperlipidemia and coronary artery disease . In an initial 12-month phase , regular niacin , 500 mg qid , lovastatin , 20 mg bid , and colestipol , 10 g/bid , were given with dose adjustment for lipid targets and side effects . This was followed by 2 r and om sequence crossover phases ( 8 months each ) alternating regular niacin with a polygel controlled-release formulation of niacin for use in this regimen . Lipid , lipoprotein , apoprotein , and clinical chemistry determinations were obtained at baseline , during the initial phase , at the 2 crossover phases , and at 6 weeks after therapy . A final question naire queried specific side effects and overall preferences . Low-/high-density lipoprotein ( LDL/HDL ) changed from means of 215/46 mg/dl at baseline , to 94/59 mg/dl after run-in , to 85/52 mg/dl after 8 months of controlled-release niacin , and to 98/56 mg/dl after 8 months of regular niacin ( regular niacin vs controlled-release niacin , p < 0.005/<0.05 ) . The target of LDL < or = 100 mg/dl was achieved at 8 months by 83 % of these patients with controlled-release niacin and by 52 % with regular niacin ( p < 0.01 ) . Compliance was 95 % with controlled-release niacin versus 85 % with regular niacin ( p < 0.001 ) . The controlled-release niacin and regular niacin regimens did not differ in terms of uric acid , glucose , insulin , or asparate aminotransferase levels . Overall , 21 % of patients called the 3 drugs " very easy " and 72 % " fairly easy " to take . The controlled-release niacin-containing regimen was preferred by 21 patients and the regular niacin by 4 . In conclusion , these regimens achieve striking lipid changes among hyperlipidemic patients . Controlled release is the preferred niacin preparation in terms of LDL reduction , compliance , patient preference , and achieving the National Cholesterol Education Program guideline of LDL < or = 100 mg/dl . The 2 niacin preparations did not differ in evidence of toxicity OBJECTIVES The aim of this study was to evaluate the effect of treatment with statins on the progression of coronary atherosclerotic plaques of a nonculprit vessel by serial volumetric virtual histology ( VH ) intravascular ultrasound ( IVUS ) . BACKGROUND Recent clinical trials have demonstrated a reduction of atherosclerotic plaque , yet whether statin therapy affects the change in components of plaque remains unknown . METHODS This study was a nonr and omized and nonblinded design . Eighty patients with stable angina pectoris were divided into either the fluvastatin group ( n = 40 ) or the control group ( n = 40 ) according to their total or low-density lipoprotein ( LDL ) cholesterol level . The volume of each plaque component ( dense calcium , fibrous tissue , fibro-fatty , or necrotic core ) was evaluated at baseline and at 12-month follow-up . RESULTS The LDL cholesterol and high-sensitivity C-reactive protein ( hsCRP ) levels in the fluvastatin group were significantly decreased at time of follow-up . In VH IVUS findings , fibro-fatty volume was significantly decreased ( baseline 80.1 + /- 57.9 mm(3 ) vs. follow-up 32.5 + /- 27.7 mm(3 ) , p < 0.0001 ) and fibrous tissue volume was increased ( baseline 146.5 + /- 85.6 mm(3 ) vs. follow-up 163.3 + /- 94.5 mm(3 ) , p < 0.0001 ) in the fluvastatin group . In the control group , the volumes of all plaque components without fibrous tissue were significantly increased . Change in fibro-fatty volume has a significant correlation with a change in LDL cholesterol level ( R = 0.703 , p < 0.0001 ) and change in hsCRP level ( R = 0.357 , p = 0.006 ) . CONCLUSIONS One-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume Background — Patients with low HDL cholesterol ( HDL-C ) and elevated triglyceride had an increased  risk for coronary heart disease ( CHD ) events and received the greatest benefit with fibrate therapy in sub study analyses of the Helsinki Heart Study and the Bezafibrate Infa rct ion Prevention Study . Methods and Results —In this post hoc analysis of the Sc and inavian Simvastatin Survival Study , which enrolled patients with elevated LDL cholesterol ( LDL-C ) and CHD , subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy . Patients in the lowest HDL-C ( < 1.00 mmol/L [ 39 mg/dL ] ) and highest triglyceride ( > 1.80 mmol/L [ 159 mg/dL ] ) quartiles ( lipid triad ; n=458 ) had increased proportions of other features of the metabolic syndrome ( increased body mass index , hypertension , diabetes ) , men , prior myocardial infa rct ion , prior revascularization , and & bgr;-blocker use than patients in the highest HDL-C ( > 1.34 mmol/L [ 52 mg/dL ] ) and lowest triglyceride ( < 1.11 mmol/L [ 98 mg/dL ] ) quartiles ( isolated LDL-C elevation ; n=545 ) . The major coronary event rate was highest in lipid triad patients on placebo ( 35.9 % ) , and this subgroup had the greatest event reduction ( relative risk 0.48 , 95 % CI 0.33 to 0.69 ) ; a significant treatment-by-subgroup interaction ( P = 0.03 ) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup . Conclusions — Patients with elevated LDL-C , low HDL-C , and elevated triglycerides  were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome , had increased risk for CHD events on placebo , and received greater benefit with simvastatin therapy Abstract Postpr and ial lipemia is associated with elevated risk of cardiovascular disease . Very little data exists regarding postpr and ial response in subjects with metabolic syndrome ( MetS ) . The current study was conducted within the LIPGENE EU Integrated Project . Patients were r and omized to one of the four isocaloric fatty meals ( Oral Fat Tolerance Tests , OFTT ) : ( A ) high-fat , saturated fatty acid (SFA)-rich ( HFSA ) , ( B ) high-fat , monounsaturated fatty acid (MUFA)-rich ( HFMUFA ) , ( C ) low-fat , high-complex carbohydrate with 1.24 g high oleic sunflower oil supplement ( LFHCC ) and ( D ) low-fat high-complex carbohydrate with 1.24 g long chain n-3 poly-unsaturated fatty acid ( LC n-3 PUFA ) supplement ( LFHCCn-3 ) . The total and incremental areas under the curve ( tAUC and iAUC ) of plasma lipid and lipoprotein , Ischemia Modified Albumin ( IMA ) and LDL density were examined in patients with MetS to define effect of OFTT . All types of OFTT transiently increased plasma triglyceride and LDL density ( LDLdens ) . It was paralleled by temporal decrease in total cholesterol ( TC ) , LDL cholesterol ( LDL-C ) , and HDL cholesterol ( HDL-C ) . This last effect was partly alleviated in LFHCCn-3 test . A reversible increase of IMA was statistically significant only in the course of HSFA and HMUFA tests . EPA and DHA supplement in combined high complex-carbohydrate meal may attenuate adverse effect of tested meal on LDL particle profile and plasma ischemia modified albumin . No expected associations between measures of central adiposity ( waist , WHR ) , adipose tissue insulin resistance ( Adipo-IR ) , and postpr and ial responses of TG , TC , LDL-C , HDL-C , LDLdens and IMA/Alb ratio were found in subgroup analysis . Trial registration : Clinical Trials.gov identifier : NCT00429195 Dyslipidemia and insulin resistance occur in a large proportion of HIV-infected patients treated with highly active antiretroviral therapy ( HAART ) ; anthropomorphic changes , such as lipoatrophy and central obesity , occur in a subset of patients . This cluster of clinical features , which is termed HIV lipodystrophy , places patients at increased risk for cardiovascular disease . Currently , there is no consensus on the appropriate therapy for the management of HIV lipodystrophy for which the underlying defects are enhanced lipolysis , impaired fat oxidation , increased hepatic VLDL-triglyceride synthesis and secretion , and impaired disposal of intestinally-derived lipoprotein-triglycerides . We describe the design of a r and omized , placebo-controlled trial to compare the effects of usual care to diet , exercise and lipid-lowering drugs on lipid profiles of patients with HIV lipodystrophy . The trial will r and omize 200 patients into five groups . Outcomes of usual care , diet and exercise alone or in combination with  niacin , fenofibrate or both medications will be compared after six months . Unique aspects of the design include an interactive Internet Diet Management system to increase ATP-III recommended dietary compliance for metabolic syndrome , and a supervised program of aerobic and resistance exercises . The study is powered to detect a 20 % decrease in triglycerides with the lifestyle intervention and an additional 20 % improvement with the addition of niacin and /or fenofibrate . Secondary outcomes include assessment of lipid profile changes , LDL and HDL particle size , plasma cholesterol ester transport protein activity , visceral and subcutaneous fat distribution , glucose tolerance , insulin resistance , and leptin and adiponectin levels Niacin is a useful lipid-modifying drug because it ( 1 ) decreases low-density lipoprotein ( LDL ) cholesterol , total cholesterol , triglycerides , and lipoprotein(a ) , and ( 2 ) raises high-density lipoprotein ( HDL ) cholesterol . Its use tends to be limited by side effects and inconvenient dosing regimens . The availability of an extended-release preparation ( Niaspan-which has safety and efficacy similar to immediate-release niacin but which can be given once a day ) provides an opportunity to increase the use of this effective lipid-modifying agent . To study the safety and efficacy of escalating doses of extended-release niacin , hyperlipidemic patients were r and omly assigned to  placebo or Niaspan . A forced dose-titration was done with the dosage increasing by 500 mg every 4 weeks to a maximum of 3,000 mg/day . Niaspan showed dose-related changes in total , LDL , and HDL cholesterol levels , triglycerides , cholesterol/HDL ratio , and lipoprotein(a ) . At a dosage of 2,000 mg/day , total cholesterol decreased by 12.1 % , LDL cholesterol by 16.7 % , triglycerides by 34.5 % , and lipoprotein(a ) by 23.6 % ; HDL cholesterol increased by 25.8 % . Flushing was the most commonly reported side effect ; flushing episodes tended to decrease with time despite an increasing dose of niacin . Of the reported side effects , only pruritus and rash were significantly different between the 2 groups . Aspartate aminotransferase , lactate dehydrogenase , and uric acid increased in a dose-dependent fashion , but fasting blood sugar increased by about 5 % across most dosages . Two subjects had aspartate aminotransferase levels greater than twice the upper limit of normal , but there were no subjects in whom transaminases increased to 3 times the upper limit of normal . Women tended to have a greater LDL cholesterol response to the medication and also experienced more side effects , especially at higher dosages . Thus , the use of lower dosages of niacin may be desirable in women . The results of this dose-escalation study show beneficial effects of Niaspan on the entire lipid profile . At the maximum recommended dosage of 2,000 mg/day , all lipid and lipoprotein levels changed in desirable directions . Side effects ( other than flushing ) and blood chemistries were comparable to those seen with immediate-release niacin Evidence indicates that the high density lipoprotein ( HDL ) subfraction containing apolipoprotein A-I without apolipoprotein AII ( LP-AI ) is more antiatherogenic than HDL particles containing apolipoprotein A-I and apolipoprotein A-II ( LP-AI+AII ) . This study examined the effect of extended-release niacin ( niacin-ER ) and gemfibrozil on LP-AI and LP-AI+AII particles in patients with low levels of HDL cholesterol ( HDL-C ) . Mechanisms by which these agents modulate HDL particles were investigated by in vitro studies using human hepatoblastoma ( Hep G2 ) cells . A total of 139 patients with low HDL-C ( ≤40 mg/dL ) were r and omized  to niacin-ER or gemfibrozil in a multicenter double-blind trial . Patients were dose-escalated with once-nightly niacin-ER ( 1 to 2 g ) or gemfibrozil ( 1.2 g ) for 19 weeks . Niacin-ER had a greater effect in raising HDL-C and apolipoprotein A-I levels than did gemfibrozil . Niacin-ER at 1- and 2-g doses increased LP-AI levels by 8.7±4.0 % ( P = 0.033 ) and 24.0±4.4 % ( P < 0.001 ) , respectively . Gemfibrozil had no consistent effect on LP-AI levels . LP-AI+AII levels increased 5 % to 8 % by both agents . In vitro studies showed that niacin , but not gemfibrozil , selectively decreased the uptake of 125I-labeled LP-AI holoparticles by Hep G2 cells . The uptake of [3H]cholesterol ester was ≈75 % greater from LP-AI versus LP-AI+AII particles , but neither niacin nor gemfibrozil  affected cholesterol ester uptake . These data indicate that unlike gemfibrozil , niacin selectively increases LP-AI compared with LP-AI+AII particle concentration in patients with low HDL-C levels . The mechanism of action of increased LP-AI concentration appears to be mediated by decreased hepatic removal of LP-AI particles , which are more efficient in reverse cholesterol transport , thus suggesting an additional mechanism by which niacin mediates its antiatherogenic properties BACKGROUND Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein ( LDL ) cholesterol level . Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein ( HDL ) cholesterol level , but its clinical efficacy and safety are uncertain . METHODS After a prer and omization run-in phase to st and ardize the background statin-based LDL cholesterol-lowering therapy and to establish participants ' ability to take extended-release niacin without clinical ly significant adverse effects , we r and omly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily . The primary outcome was the first major vascular event ( nonfatal myocardial infa rct ion , death from coronary causes , stroke , or arterial revascularization ) . RESULTS During a median follow-up period of 3.9 years , participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter ( 0.25 mmol per liter as measured in the central laboratory ) lower and an HDL cholesterol level that was an average of 6 mg per deciliter ( 0.16 mmol per liter ) higher than the levels in those assigned to placebo . Assignment to niacin-laropiprant , as compared with assignment to placebo , had no significant effect on the incidence of major vascular events ( 13.2 % and 13.7 % of participants with an event , respectively ; rate ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.90 to 1.03 ; P=0.29 ) . Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious ( absolute excess as compared with placebo , 3.7 percentage points ; P<0.001 ) and with an increased incidence of diabetes diagnoses ( absolute excess , 1.3 percentage points ; P<0.001 ) , as well as increases in serious adverse events associated with the gastrointestinal system ( absolute excess , 1.0 percentage point ; P<0.001 ) , musculoskeletal system ( absolute excess , 0.7 percentage points ; P<0.001 ) , skin ( absolute excess , 0.3 percentage points ; P=0.003 ) , and unexpectedly , infection ( absolute excess , 1.4 percentage points ; P<0.001 ) and bleeding ( absolute excess , 0.7 percentage points ; P<0.001 ) . CONCLUSIONS Among participants with atherosclerotic vascular disease , the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events . ( Funded by Merck and others ; HPS2-THRIVE Clinical Trials.gov number , NCT00461630 . )
This significant effect was derived by the use of fibrates ( RR 0.80 , 95 % CI 0.73–0.87 , P < 0.001 , I2 = 22 % ) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol .
Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints .
Conclusion The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality , stroke or all-cause mortality .
The beneficial effect on myocardial infa rct ion was lost when drugs were used with statin therapy
Background The effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain .
Design We conducted a meta- analysis to investigate the effects of high-density lipoprotein cholesterol modifiers ( niacin , fibrates and cholesteryl ester transfer protein inhibitors ) on cardiovascular outcomes .