title: Effects of Prescription Omega-3-Acid Ethyl Esters on Fasting Lipid Profile in Subjects With Primary Hypercholesterolemia Lipoprotein Particle Profiles by Nuclear Magnetic Resonance Compared With Standard Lipids and Apolipoproteins in Predicting Incident Cardiovascular Disease in Women Low-Density Lipoprotein and High-Density Lipoprotein Particle Subclasses Predict Coronary Events and Are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial Effects of pravastatin treatment on lipoprotein subclass profiles and particle size in the PLAC-I trial. Low-Density Lipoprotein Particle Concentration and Size as Determined by Nuclear Magnetic Resonance Spectroscopy as Predictors of Cardiovascular Disease in Women Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors. Colesevelam HCl reduces LDL particle number and increases LDL size in hypercholesterolemia. Effects of pioglitazone on lipid and lipoprotein profiles in patients with type 2 diabetes and dyslipidaemia after treatment conversion from rosiglitazone while continuing stable statin therapy Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study Effectiveness of high doses of simvastatin as monotherapy in mixed hyperlipidemia. Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects. Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD. Fenofibrate effectively reduces remnants, and small dense LDL, and increases HDL particle number in hypertriglyceridemic men - a nuclear magnetic resonance study. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in type 2 diabetic patients with ischaemic heart disease. PREVENTION OF ATHEROSCLEROSIS WITH LDL-C LOWERING - LIPOPROTEIN CHANGES AND INTERACTIONS: THE SANDS STUDY. Extended-release niacin/laropiprant effects on lipoprotein subfractions in patients with type 2 diabetes mellitus. Treatment of obesity with diet/exercise versus pioglitazone has distinct effects on lipoprotein particle size. Effects of extended-release niacin on lipoprotein subclass distribution. Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy. Initial combination therapy with metformin and colesevelam for achievement of glycemic and lipid goals in early type 2 diabetes. Initial combination therapy with metformin plus colesevelam improves lipoprotein particles in patients with early type 2 diabetes mellitus.
abstract: This double-blind , r and omized crossover study investigated the effects of 6 weeks of treatment with prescription omega-3-acid ethyl esters ( POM3 , 4 g/day ) versus placebo ( soy oil ) on low-density lipoprotein cholesterol ( LDL-C ) and other aspects of the fasting lipid profile in 31 men and women with primary , isolated hypercholesterolemia ( LDL-C 130 - 220 mg/dL and triglycerides less than 150 mg/dL while free of lipid-altering therapies ) . Mean ± st and ard error of the mean baseline concentrations of total cholesterol , LDL-C , high-density lipoprotein cholesterol ( HDL-C ) , very-low-density lipoprotein cholesterol , and triglycerides were 229 ± 3 , 146 ± 3 , 60 ± 2 , 23 ± 2 , and 113 ± 8 mg/dL , respectively . POM3 produced a modest increase from baseline in LDL-C ( 3.4 % ) versus the placebo response ( -0.7 % , P = 0.010 ) . Significant changes ( P < 0.05 ) for POM3 ( placebo-corrected ) were observed for very-low-density lipoprotein cholesterol ( -18.8 % ) , triglycerides ( -18.7 % ) , and HDL-C ( 3.3 % ) . Nuclear magnetic resonance-determined very-low-density lipoprotein particle concentration and size and HDL particle concentration decreased significantly more with POM3 versus placebo , whereas LDL and HDL particle sizes increased significantly more with POM3 versus placebo . Total cholesterol , non-HDL-C , apolipoproteins A1 and B , and LDL particle concentration responses did not differ between treatments . These results did not confirm the hypothesis that POM3 treatment would lower LDL-C in primary , isolated hypercholesterolemia . Effects on other variables were consistent with prior results in mixed dyslipidemia Background — Nuclear magnetic resonance ( NMR ) spectroscopy measures the number and size of lipoprotein particles instead of their cholesterol or triglyceride content , but its clinical utility is uncertain . Methods and Results — Baseline lipoproteins were measured by NMR in 27 673 initially healthy women followed up for incident cardiovascular disease ( n=1015 ) over an 11-year period . After adjustment for nonlipid risk factors , hazard ratios and 95 % confidence intervals for the top versus the bottom quintile of NMR-measured lipoprotein particle concentration ( measured in particles per liter ) were 2.51 ( 1.91 to 3.30 ) for low-density lipoprotein ( LDLNMR ) , 0.91 ( 0.75 to 1.12 ) for high-density lipoprotein ( HDLNMR ) , 1.71 ( 1.38 to 2.12 ) for very low – density lipoprotein ( VLDLNMR ) , and 2.25 ( 1.80 to 2.81 ) for the LDLNMR/HDLNMR ratio . Similarly adjusted results for NMR-measured lipoprotein particle size ( measured in nanometers ) were 0.64 ( 0.52 to 0.79 ) for LDLNMR size , 0.65 ( 0.51 to 0.81 ) for HDLNMR size , and 1.37 ( 1.10 to 1.70 ) for VLDLNMR size . Hazard ratios for NMR measures were comparable but not superior to st and ard lipids ( total cholesterol 2.08 [ 1.63 to 2.67 ] , LDL cholesterol 1.74 [ 1.40 to 2.16 ] , HDL cholesterol 0.52 [ 0.42 to 0.64 ] , triglycerides 2.58 [ 1.95 to 3.41 ] , non-HDL cholesterol 2.52 [ 1.95 to 3.25 ] , total/HDL cholesterol ratio 2.82 [ 2.23 to 3.58 ] ) and apolipoproteins ( B100 2.57 [ 1.98 to 3.33 ] , A-1 0.63 [ 0.52 to 0.77 ] , and B100/A-1 ratio 2.79 [ 2.21 to 3.54 ] ) . Essentially no reclassification improvement was found with the addition of the LDLNMR particle concentration or apolipoprotein B100 to a model that already included the total/HDL cholesterol ratio and nonlipid risk factors ( net reclassification index 0 % and 1.9 % , respectively ) , nor did the addition of either variable result in a statistically significant improvement in the c-index . Conclusions — In this prospect i ve study of healthy women , cardiovascular disease risk prediction associated with lipoprotein profiles evaluated by NMR was comparable but not superior to that of st and ard lipids or apolipoproteins Background — Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease ( CHD ) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial ( VA-HIT ) . We examined whether measurement of low-density lipoprotein ( LDL ) and high-density lipoprotein ( HDL ) particle subclasses provides additional information relative to CHD risk reduction . Methods and Results — This is a prospect i ve nested case-control study of 364 men with a new CHD event ( nonfatal myocardial infa rct ion or cardiac death ) during a 5.1-year ( median ) follow-up and 697 age-matched controls .  Nuclear magnetic resonance ( NMR ) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo . Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models . Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles ( −5 % ) while raising numbers of HDL particles ( 10 % ) and small HDL subclass particles ( 21 % ) . Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant , independent predictors of new CHD events . For total LDL and HDL particles , odds ratios predicting CHD benefit were 1.28 ( 95 % CI , 1.12 to 1.47 ) and 0.71 ( 95 % CI , 0.61 to 0.81 ) , respectively . Mean LDL and HDL particle sizes were not associated with CHD events . Conclusions — The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses , which are not reflected by conventional lipoprotein cholesterol measures , help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol BACKGROUND Icosapent ethyl ( IPE ; formerly AMR101 ) is a high-purity prescription form of eicosapentaenoic acid ethyl ester . In the MARINE study we evaluated the efficacy and safety of IPE in patients with very high triglycerides ( TG ; ≥500 mg/dL ) and previously demonstrated significant reductions in TG levels with no significant increases in low-density lipoprotein ( LDL ) cholesterol levels  . OBJECTIVES In this follow-up , exploratory analysis , we report the effects of IPE on lipoprotein particle concentration and size . METHODS MARINE was a phase 3 , multicenter , placebo-controlled , r and omized , double-blind , 12-week study . Hypertriglyceridemic patients ( N = 229 ) were r and omized to three treatment groups : IPE 4 g/day , IPE 2 g/day , or placebo . Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy . RESULTS Compared with placebo , IPE 4 g/day significantly reduced median concentrations of large very-low-density lipoprotein ( VLDL ; -27.9 % ; P = .0211 ) , total LDL ( -16.3 % ; P = .0006 ) , small LDL ( -25.6 % ; P < .0001 ) , and total high-density lipoprotein ( HDL ; -7.4 % ; P = .0063 ) particles and reduced VLDL particle size ( -8.6 % ; P = .0017 ) . In this patient population with TG ≥500 mg/dL , IPE did not significantly change the overall sizes of LDL or HDL particles . CONCLUSION IPE 4 g/day significantly reduced large VLDL , total LDL , small LDL , and total HDL particle concentrations and VLDL particle size in patients with TG ≥500 mg/dL. Changes in VLDL particle concentration and size reflect the TG-lowering effects of eicosapentaenoic acid . The reduction in LDL particle concentration  with IPE is novel among ω-3 therapies and is consistent with the previously reported reduction in apolipoprotein B and lack of LDL-C increase with IPE in patients with very high TG levels . CLINICAL TRIAL REGISTRATION NUMBER NCT01047683 BACKGROUND To assess the lipid-lowering effects and safety of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia . METHODS We performed a r and omized , open-label , parallel- design , active-controlled , study in eight centers in the United States . We enrolled 108 patients with total cholesterol ( TC ) of > or = 200 mg/dL , serum triglycerides ( TG ) > or = 200 and < or = 800 mg/dL , and apolipoprotein B ( apo B ) > or = 110 mg/dL. Patients were r and omly assigned to receive atorvastatin 10 mg once daily ( n=55 ) or immediate-release niacin 1 g three times daily for 12 weeks ( n=53 ) . Patients were stratified based on low-density lipoprotein cholesterol ( LDL-C ) : Patients with LDL-C > or = 135 mg/dL were considered to have combined hyperlipidemia and patients with LDL-C < 135 mg/dL were considered to have isolated hypertriglyceridemia . The primary outcome measure was percent change from baseline in LDL-C. Other lipid levels were evaluated as secondary parameters . RESULTS Atorvastatin reduced LDL-C 30 % and TC 26 % from baseline , and increased high-density lipoprotein cholesterol ( HDL-C ) 4 % . Total TG were reduced 17 % . Niacin reduced LDL-C 2 % , TC 7 % , increased HDL-C 25 % , and reduced total TG 29 % from baseline . There was a significant difference in LDL-C reduction , the primary efficacy parameter , between the two treatment groups ( P < 0.05 , favoring atorvastatin ) , as well as a significant difference in the improvement in HDL-C ( P < 0.05 , favoring niacin ) . The effect of atorvastatin was relatively consistent between patients with combined hyperlipidemia and isolated hypertriglyceridemia , whereas there was more variability between these strata in the niacin treatment group . Atorvastatin was better tolerated than niacin . CONCLUSION Atorvastatin may allow patients with combined hyperlipidemia to be treated with monotherapy and offers an efficacious and well-tolerated alternative to niacin for the treatment of patients with isolated hypertriglyceridemia Aims A r and omized , double-blind , placebo-controlled study was conducted to investigate the safety and efficacy of mipomersen , an apolipoprotein B-100 ( apoB ) synthesis inhibitor , in patients who are statin intolerant and at high risk for cardiovascular disease ( CVD ) . Methods and results Thirty-three subjects , not receiving statin therapy because of statin intolerance , received a weekly subcutaneous dose of 200 mg mipomersen or placebo ( 2:1 r and omization ) for 26 weeks . The primary endpoint was per cent change in LDL cholesterol ( LDL-c ) from the baseline to Week 28 . The other efficacy endpoints were per cent change in apoB and lipoprotein a [ Lp(a ) ] . Safety was determined using the incidence of treatment-emergent adverse events ( AEs ) and clinical laboratory evaluations . After 26 weeks of mipomersen  administration , LDL-c was reduced by 47 ± 18 % ( P < 0.001 vs. placebo ) . apoB and Lp(a ) were also significantly reduced by 46 and 27 % , respectively ( P < 0.001 vs. placebo ) . Four mipomersen ( 19 % ) and two placebo subjects ( 17 % ) discontinued dosing prematurely due to AEs . Persistent liver transaminase increases ≥3 × the upper limit of normal were observed in seven ( 33 % ) subjects assigned to mipomersen . In selected subjects , liver fat content was assessed , during and after treatment , using magnetic resonance spectroscopy . Liver fat content in these patients ranged from 0.8 to 47.3 % . Liver needle biopsy was performed in two of these subjects , confirming hepatic steatosis with minimal inflammation or fibrosis . Conclusion The present data suggest that mipomersen is a potential therapeutic option in statin-intolerant patients at high risk for CVD . The long-term follow-up of liver safety is required . Clinical Trial Registration : Clinical Trials.gov identifier : Lipoprotein subclass analyses may facilitate coronary heart disease ( CHD ) risk stratification and provide insight into the cardioprotective benefits of statins ( 3-hydroxymethylglutaryl-coenzyme A reductase inhibitors ) . This study evaluated the influence of pravastatin on lipoprotein subclass profiles to determine whether subjects with predominantly large LDL ( LDL size > 20.5 nm ) or small LDL ( LDL size < or = 20.5 nm ) at baseline differ in responsiveness to drug treatment . Frozen plasma specimens were analyzed from a subset of participants in the Pravastatin Limitation of Atherosclerosis in the Coronaries ( PLAC-I ) trial at baseline and after treatment for 6 months with pravastatin ( n=154 ) or placebo ( n=138 ) .  Lipids were measured by st and ard chemical methods and lipoprotein subclasses by nuclear magnetic resonance ( NMR ) spectroscopy .  Pravastatin-induced changes in lipid levels were similar in subjects with large or small LDL at baseline . Levels of the most abundant LDL subclass were preferentially lowered by pravastatin , result ing in an increase in average LDL size for those with a predominance of small LDL . High-risk CHD subjects with small LDL particles gain at least as much pharmacological benefit from pravastatin as those with large LDL , as evidence d by reductions in the numbers of total and small LDL particles , and increases in average LDL and HDL particle size Background —Nuclear magnetic resonance ( NMR ) offers an alternative , spectroscopic means of quantifying LDL and of measuring LDL particle size . Methods and Results —We conducted a prospect i ve nested case-control study among healthy middle-aged women to assess  LDL particle size ( NMR ) and concentration ( NMR )  as risk factors for future myocardial infa rct ion , stroke , or death of coronary heart disease . Median baseline levels of LDL particle concentration ( NMR ) were higher ( 1597 vs 1404 nmol/L;P = 0.0001 ) and LDL particle size ( NMR ) was lower ( 21.5 vs 21.8 nm;P = 0.046 ) among women who subsequently had cardiovascular events ( n=130 ) than among those who did not ( n= 130 ) . Of these 2 factors , LDL particle concentration (  NMR ) was the stronger predictor ( relative risk for the highest compared with the lowest quartile=4.17 , 95 % CI 1.96–8.87 ) . This compared with a relative risk of 3.11 ( 95 % CI 1.55–6.26 ) for the ratio of total cholesterol to HDL cholesterol and a relative risk of 5.91 ( 95 % CI 2.65–13.15 ) for C-reactive protein . The areas under the receiver operating characteristic curves for LDL particle concentration ( NMR ) , total cholesterol to HDL cholesterol ratio , and C-reactive protein were 0.64 , 0.64 , and 0.66 , respectively . LDL particle concentration ( NMR ) correlated with several traditionally assessed lipid and nonlipid risk factors , and thus adjustment for these tended to attenuate the magnitude of association between LDL particle concentration ( NMR ) and risk . Conclusions —In this cohort , LDL particle concentration measured by NMR spectroscopy was a predictor of future cardiovascular risk . However , the magnitude of predictive value of LDL particle concentration  ( NMR ) was not substantively different from that of the total cholesterol to HDL cholesterol ratio and was less than that of C-reactive protein Lipoprotein subclass measurements may enhance the prediction of coronary artery disease ( CAD ) risk , but clinical application of such information has been hindered by the relatively laborious and time-consuming nature of laboratory measurement methods . In this study , lipoprotein subclass analyses were performed on frozen plasma sample s from 241 participants in the Pravastatin Limitation of Atherosclerosis in the Coronary arteries Trial using an automated nuclear magnetic resonance technique . The objective was to determine if levels of these subclasses provided additional information on the progression of CAD , based on the change in the minimum lumen diameter , over a 3-year period . After adjustment for race , sex , age , treatment group , baseline lumen diameter , and chemically measured levels of triglycerides , low-density lipoprotein ( LDL ) cholesterol , and high-density lipoprotein ( HDL ) cholesterol , on-trial predictors ( p < 0.05 ) of progression included an elevated LDL particle number , and levels of small LDL and small HDL . Within treatment groups , CAD progression was most strongly related to the LDL particle number  ( placebo ) and levels of small HDL  ( pravastatin ) . In logistic regression models that adjusted for chemically determined lipid levels and other covariates , a small LDL level > or = 30 mg/dl ( median ) was associated with a ninefold increased risk of CAD progression ( p < 0.01 ) in the placebo group . These results indicate that levels of various lipoprotein subclasses may provide useful information on CAD risk even if levels of traditional risk factors are known BACKGROUND Although recommended as initial therapy for patients with dyslipidemia who are taking human immunodeficiency virus protease inhibitors ( HIV PIs ) , the effects of pravastatin on lipoproteins and arterial reactivity have not been eluci date d. The purpose of this study was to determine the effects of pravastatin on lipoprotein subfractions and endothelial function in patients with dyslipidemia who are receiving HIV PIs . METHODS This was a placebo-controlled , double-blind , crossover study comparing pravastatin ( 40 mg ) to placebo in 20 patients who were taking HIV PIs .  Lipoprotein subfractions were measured with nuclear magnetic resonance spectroscopic analysis . Flow-mediated vasodilation ( FMD ) of the brachial artery was evaluated with high-resolution ultrasound scanning . RESULTS At baseline , subjects had an increased concentration of low-density lipoprotein ( LDL ) particles ( 1756 + /- 180 nmol/L ) , which tended to be small ( 19.9 + /- 0.2 nm ) , a low concentration of large high-density lipoproteins ( HDL ; 0.94 + /- 0.07 mmol/L ) , and an increased concentration of large very low-density lipoproteins ( VLDL ; 1.90 + /- 0.58 mmol/L ) . FMD was impaired ( 4.5 % + /- 1.1 % ) . Compared with placebo , pravastatin result ed in a 20.8 % reduction in LDL particles ( P = .030 ) , a 26.7 % reduction in small LDL ( P = .100 ) , and a 44.9 % reduction in small VLDL ( P = .023 ) . Total and non-HDL cholesterol levels decreased by 18.3 % ( P < .001 ) and 21.7 % ( P < .001 ) , respectively . FMD tended to increase in patients receiving pravastatin ( 0.7 % + /- 0.6 % ) ; however , the difference between treatment phases was not statistically significant ( P = .080 ) . CONCLUSIONS This is the first double-blind , placebo-controlled study of the effects of statin therapy on lipids , lipoprotein subfractions , and endothelial function in patients taking HIV PIs .  Pravastatin reduced concentrations of atherogenic lipoproteins , particularly those most associated with future coronary events BACKGROUND Although LDL-cholesterol ( LDL-C ) remains the target of cholesterol-lowering therapy , high levels of LDL particle numbers better differentiate cardiovascular risk than LDL-C concentrations . Colesevelam HCl , a novel bile acid sequestrant , has also been shown to reduce mean LDL-C by 18 % with the maximum dose . The effect of colesevelam HCl on LDL particle number and particle size has not been previously published . LDL particle number and particle size were measured by NMR spectroscopy . METHODS In this multi-center , double-blind , placebo-controlled study , 149 patients with moderate hypercholesterolemia ( LDL-C > 160 mg/dL [ 4.14 mmol/L ] ; triglycerides < 300 mg/dL [ 3.39 mmol/L ] ) were r and omized to colesevelam HCl ( 1.5 - 3.75 g/d ) or placebo for 6 weeks . RESULTS Colesevelam HCl reduced LDL particle number by 6.8 % at a dosage of 3.0 g/d ( P = 0.031 ) , and 13.7 % ( P = 0.0002 ) at a dosage of 3.75 g/d . Baseline levels of triglycerides or LDL size did not influence changes in LDL particle number . Further , mean LDL particle size increased with colesevelam HCl 3.75 g/d ( 1.1 % increase versus baseline , P < 0.05 ) . CONCLUSION For patients with moderate hypercholesterolemia , treatment with colesevelam HCl at the recommended starting dose of 3.75 g/d lowered LDL particle number , and increased mean LDL particle size 4The aim of this study was to evaluate changes in lipid profiles in patients with type 2 diabetes after treatment conversion from rosiglitazone to pioglitazone  while maintaining stable statin and other lipid-altering therapies . A total of 305 patients were enrolled in this open-label study . Patients had been taking stable dosages of rosiglitazone and statins for > 90 days . At baseline , patients discontinued rosiglitazone and started pioglitazone 30 mg/day , but continued statins and other lipid-altering therapies . The primary end point was change from baseline in fasting triglyceride levels . At 17 weeks after treatment conversion , patients had significant reductions in triglycerides ( -15.2 % ) , total cholesterol ( -9.0 % ) , and low-density lipoprotein ( LDL ) particle concentration ( -189 nmol/L ) , and increases in LDL cholesterol ( + 2.2 % ) , high-density lipoprotein ( HDL ) cholesterol ( + 1.8 % ) , and LDL particle diameter ( + 0.23 nm ) . In conclusion , after treatment conversion from rosiglitazone to pioglitazone while maintaining stable statin therapy , patients with type 2 diabetes had marked improvements in lipid profiles along with stable glycaemic control 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 BACKGROUND Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) increases serum LDL-cholesterol ( LDL-C ) concentrations . We assessed the effects of AMG 145 , a human monoclonal antibody against PCSK9 , in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment . METHODS In a phase 2 trial done at 52 centres in Europe , the USA , Canada , and Australia , patients ( aged 18 - 75 years ) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were r and omly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg , 105 mg , or 140 mg , or placebo every 2 weeks ; subcutaneous AMG 145 280 mg , 350 mg , or 420 mg or placebo every 4 weeks ; or oral ezetimibe 10 mg/day . The primary endpoint was percentage change from baseline in LDL-C concentration at week 12 . Analysis was by modified intention to treat . Study personnel and patients were masked to treatment assignment of AMG 145 or placebo . Ezetimibe assignment was open label . This trial is registered with Clinical Trials.gov , number NCT01375777 . FINDINGS 406 patients were assigned to AMG 145 70 mg ( n=45 ) , 105 mg ( n=46 ) , or 140 mg ( n=45 ) every 2 weeks ; AMG 145 280 mg ( n=45 ) , 350 mg ( n=45 ) , or 420 mg ( n=45 ) every 4 weeks ; placebo every 2 weeks ( n=45 ) or every 4 weeks ( n=45 ) ; or ezetimibe ( n=45 ) . AMG 145 significantly reduced LDL-C concentrations in all dose groups ( mean baseline LDL-C concentration 3·7 mmol/L [ SD 0·6 ] ; changes from baseline with every 2 weeks AMG 145 70 mg -41·0 % [ 95 % CI -46·2 to -35·8 ] ; 105 mg -43·9 % [ -49·0 to -38·7 ] ; 140 mg -50·9 % [ -56·2 to -45·7 ] ; every 4 weeks AMG 145 280 mg -39·0 % [ -44·1 to -34·0 ] ; 350 mg -43·2 % [ -48·3 to -38·1 ] ; 420 mg -48·0 % [ -53·1 to -42·9 ] ; placebo every 2 weeks -3·7 % [ -9·0 to 1·6 ] ; placebo every 4 weeks 4·5 % [ -0·7 to 9·8 ] ; and ezetimibe -14·7 % [ -18·6 to -10·8 ] ; p<0·0001 for all doses vs placebo or ezetimibe ) . Treatment-emergent adverse events occurred in 136 ( 50 % ) of 271 patients in the AMG 145 groups , 41 ( 46 % ) of 90 patients in the placebo groups , and 26 ( 58 % ) of 45 patients in the ezetimibe  group ; no deaths or serious treatment-related adverse events were reported . INTERPRETATION The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse population s including patients with documented statin intolerance . FUNDING Amgen Twenty subjects with mixed hyperlipidemia participated in a 3-arm crossover trial to evaluate the effectiveness of high-dose simvastatin as monotherapy . Significant reductions were observed in atherogenic lipids and lipoproteins . The highest dose of simvastatin also result ed in significant increases in high-density lipoprotein cholesterol ( 21 % ) with a comparable increase in large , protective high-density lipoprotein particles The effects of atorvastatin at 20 , 40 , and 80 mg/day on plasma lipoprotein subspecies were examined in a r and omized , placebo-controlled fashion over 36 weeks in 97 patients with coronary heart disease ( CHD ) with low-density lipoprotein ( LDL ) cholesterol levels of > 130 mg/dl and compared directly with the effects of fluvastatin ( n = 28 ) , pravastatin ( n = 22 ) , lovastatin ( n = 24 ) , and simvastatin ( n = 25 ) . The effects of placebo and 40 mg/day of each statin were also examined in subjects with CHD with subjects in the fasting state and in the fed state 4 hours after a meal rich in saturated fat and cholesterol and compared with results in age- and gender-matched control subjects . At all doses tested in the fasting and fed states , atorvastatin was significantly ( p < 0.01 ) more effective in lowering LDL cholesterol and non-high-density lipoprotein ( HDL ) cholesterol than all other statins , and significantly ( p < 0.05 ) more effective than all statins , except for simvastatin , in lowering triglyceride and remnant lipoprotein ( RLP ) cholesterol . At 40 mg/day in the fasting state , atorvastatin was significantly ( p < 0.01 ) more effective than all statins , except for lovastatin and simvastatin , in lowering cholesterol levels in small LDL , and was significantly ( p < 0.05 ) more effective than all statins , except for simvastatin , in increasing cholesterol in large HDL and in lowering LDL particle numbers . Our data indicate that atorvastatin was the most effective statin tested in lowering cholesterol in LDL , non-HDL , and RLP in the fasting and fed states , and getting patients with CHD to established goals , with fluvastatin , pravastatin , lovastatin , and simvastatin having about 33 % , 50 % , 60 % , and 85 % of the efficacy of atorvastatin , respectively , at the same dose in the same patients Fibrates reduce triglycerides ( TG ) and increase HDL-cholesterol levels , but there was no report showing plaque regression by fibrates . Using MRI , we investigated the effects of bezafibrate on aortic plaques in 22 dyslipidemic patients . All patients were asked to receive 400 mg bezafibrate , but 8 who declined to have bezafibrate  became the control group . Changes in vessel wall area ( VWA ) and lumen area ( LA ) from baseline to 1-year were evaluated . Bezafibrate reduced TG ( -55 % ) and increased HDL-cholesterol levels ( + 29 % ) . Bezafibrate reduced HDL size and increased LDL size . In thoracic plaques , bezafibrate reduced VWA ( -6 % , P<0.001 ) with no LA change , but VWA slightly progressed without bezafibrate ( + 5 % ) . In abdominal plaques , bezafibrate reduced VWA ( -8 % , P<0.001 ) with LA increase ( + 3 % , P<0.02 ) , but VWA progressed without bezafibrate ( + 6 % ) . VWA changes in thoracic and abdominal plaques correlated with TG reduction and HDL-cholesterol increase . Notably , VWA change in only abdominal plaques correlated with HDL size reduction and LDL size increase . Thus , bezafibrate induced plaque regression in thoracic and abdominal aortas with marked TG reduction and HDL-cholesterol increase , but the processes of plaque regression and vascular remodeling may differ between thoracic and abdominal aortas . However , because our study was not a controlled , r and omized trial , further study is needed BACKGROUND The importance of the number of circulating low-density lipoprotein ( LDL ) cholesterol particles , in addition to total LDL level , has been increasingly recognized . The effects of extended-release niacin ( ERN ) on LDL particle numbers have not been studied . OBJECTIVE To evaluate ERN 's effects on LDL particle numbers . METHODS Fifty-four patients with stable coronary artery disease ( CAD ) and well-controlled LDL levels were r and omly assigned to 3 months of ERN ( 1 g/day ) or placebo in addition to their baseline medications . Lipoprotein particle number was analyzed by proton nuclear magnetic resonance spectroscopy at baseline and after 3 months . RESULTS Compared to baseline , the addition of ERN had no significant effect on total LDL cholesterol levels ; however , ERN decreased the number of medium and small LDL particles ( P < .005 ) . After 3 months , ERN decreased the number of medium and small LDL particles compared to placebo-treated patients ( P < .05 ) . ERN raised HDL cholesterol levels by 2.7 % , significantly increased the number of large HDL particles ( P < .001 ) , and decreased the number of small HDL particles ( P = .027 ) compared to placebo . There were no significant changes in lipid values or particle numbers in the placebo-treated patients . In patients with stable coronary artery disease and well-controlled LDL cholesterol levels , ERN reduced the number of circulating particles of the more atherogenic subtypes of LDL , despite having no effect on total LDL cholesterol levels .  ERN also favorably altered the number of HDL particles . CONCLUSION ERN-induced alterations in lipoprotein particle numbers may contribute to its anti-atherosclerotic effects , and these effects may not be evident from the st and ard lipid profile Hypertriglyceridemia is often associated with small dense low density lipoprotein ( LDL ) , elevated remnants , and decreased high density lipoprotein (HDL)-cholesterol ( C ) , which comprise the dyslipidemic triad . The objective of this study was to investigate the effect of fenofibrate on the lipoprotein subfraction profile and inflammation markers in hypertriglyceridemic men . Twenty hypertriglyceridemic men were administered fenofibrate , 200 mg daily , for 8 weeks . Lipoprotein subclasses were measured by nuclear magnetic resonance ( NMR ) spectroscopy . Inflammation markers including C-reactive protein ( CRP ) , interleukin-6 ( IL-6 ) , and monocyte chemotactic protein-1 ( MCP-1 ) were also determined . Fenofibrate lowered triglyceride ( TG ) by 58 % and increased HDL-C by 18 % . NMR analysis revealed that very low density lipoprotein ( VLDL ) , particularly large VLDL , intermediate density lipoprotein ( IDL ) , and small LDL , were significantly decreased , and LDL distribution shifted towards the larger particles . HDL distribution was altered ; there was an increase in small HDL and a decrease in large HDL , result ing in a significant decrease in HDL particle size , from 9.1 to 8.9 nm , as well as a 27 % increase in HDL particle number . Among inflammation markers , CRP was significantly decreased by 42 % . In conclusion , fenofibrate effectively improves atherogenic dyslipidemia by reducing remnants and small LDL , as well as by increasing HDL particles . These effects , together with the favorable effect on inflammation , might provide a clinical benefit in hypertriglyceridemic subjects BACKGROUND Dyslipidaemia is very common in patients with HIV infection , but current therapies are often suboptimal . Since niacin may cause insulin resistance and hepatotoxicity , it has generally been avoided in this setting . METHODS Non-diabetic male subjects ( n=33 ) who had well-controlled HIV infection on antiretroviral therapy , fasting triglycerides > or = 2.26 mmol/l and non-high density lipoprotein cholesterol ( non-HDL-C ) > or = 4.66 mmol/l received escalating doses of extended-release niacin ( ERN ) up to 2,000 mg nightly for up to 44 weeks . RESULTS Fourteen subjects ( 42 % ) had pre-diabetes at entry . Twenty-three subjects ( 70 % ) received the maximum dose , eight ( 24 % ) received 1,500 mg . Niacin was well-tolerated . Only four subjects ( 12 % ) discontinued study treatment . There were small increases in fasting glycaemia and insulin resistance estimated by the homeostasis model assessment , but insulin resistance measures from the 2-h oral glucose tolerance test only transiently worsened . No subject developed persistent fasting hyperglycaemia ; one had persistently elevated 2-h glucose > 11.1 mmol/l . There were no significant changes in serum transaminases or uric acid . At week 48 , the median change in fasting lipid levels in mmol/l ( interquartile range ) were : total cholesterol -0.21 ( -1.35 , -0.05 ) , HDL-C + 0.013 ( -0.03,+0.28 ) , non-HDL-C -0.49 ( -1.37,+0.08 ) and triglycerides -1.73 ( -3.68 , -0.72 ) . Favourable changes in large HDL and large very low density lipoprotein particle concentration were observed by nuclear magnetic resonance spectroscopy . CONCLUSIONS ERN in doses up to 2,000 mg daily was safe , well-tolerated and efficacious in HIV-infected subjects with atherogenic dyslipidaemia .  Increases in glycaemia and insulin resistance tended to be transient The effect of statin therapy on subclasses of LDL , VLDL and HDL lipoproteins is unclear . We compared changes in serum lipids , apolipoproteins and nuclear magnetic resonance ( NMR ) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women . All subjects had type 2 diabetes and a modest dyslipidaemia ( mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l ) and had a previous myocardial infa rct ion . Compared with placebo , atorvastatin therapy was associated with a greater decrease in medium VLDL ( median within person change -13.4 vs. -5.9 nmol/l , P<0.001 adjusted for baseline level ) , small VLDL ( median change -17.8 vs. -8.1 nmol/l , P=0.002 ) , large LDL ( mean within person change -167.9 vs. -48.6 nmol/l , P<0.001 ) and medium LDL ( median within person change -101.8 vs. -22.3 nmol/l , P=0.017 ) . Atorvastatin therapy was also associated with a greater increase in large HDL than placebo ( median change 1.40 vs. 0.80 micromol/l , P=0.02 ) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin ( P=0.04 ) . In addition to reducing levels of ( enzymatically measured ) triglyceride , LDL-cholesterol and apolipoprotein B in diabetic patients , atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL , and increases large HDL BACKGROUND : Lowering low-density lipoprotein cholesterol ( LDL-C ) with statins reduces atherosclerosis . LDL and high-density lipoprotein ( HDL ) are commonly measured by their cholesterol content , but non-HDL cholesterol , LDL particle number ( LDL-P ) , or total apolipoprotein B ( apoB ) may better predict cardiovascular risk . Few studies have examined relations among lipoprotein levels and composition before and after interventions to lower LDL-C and non-HDL-C. OBJECTIVE : To measure changes in carotid artery intimal media thickness ( CIMT ) and lipid concentration and composition during 36 months of statin therapy . METHODS : Analyses were conducted on 418 diabetic individuals , with complete data and no prior cardiovascular events , who were r and omized to aggressive ( AG ) versus st and ard ( STD ) treatment for LDL-C , non-HDL-C , and systolic blood pressure ( SBP ) as part of the Stop Atherosclerosis in Native Diabetics Study ( S AND S ) . RESULTS : The AG group achieved average LDL-C and non-HDL-C of 71mg/dL and 100mg/dL and a decrease in CIMT . No significant interactions were observed between treatment effect and initial levels of LDL-C , non-HDL-C , HDL-C , triglycerides , apoB , or LDL-P. Decreases in LDL-C ( p<.005 ) and non-HDL-C ( p<.001 ) were independently correlated with CIMT regression in the AG group . Changes in apoB and LDL-P showed borderline correlations with CIMT regression ( p=.07 and p=.09 ) . CONCLUSIONS : In diabetic adults with no prior cardiovascular events , treatment to current targets for lipids and SBP reduces atherosclerosis progression and when more aggressive targets are met , atherosclerosis regresses . The aggressive targets for LDL-C and non-HDL-C appeared to be the main determinants of CIMT regression and were more predictive of this outcome than changes in LDL-P or BACKGROUND A potentially atherogenic lipid profile often found in patients with type 2 diabetes mellitus ( T2DM ) includes increased concentrations of small , low-density lipoprotein ( LDL ) and intermediate-density lipoprotein ( IDL ) and decreased concentration of medium/large high-density lipoprotein ( HDL ) particles . Extended-release niacin/laropiprant ( ERN/LRPT ) lowers LDL-cholesterol ( LDL-C ) and triglycerides ( TG ) , and raises HDL cholesterol ( HDL-C ) levels with attenuation of niacin-induced flushing . METHODS Plasma HDL , LDL , IDL , very-low-density lipoprotein ( VLDL ) , and chylomicron particle concentration and size at were evaluated at baseline and week 12 using nuclear magnetic resonance ( NMR ) . The data were acquired from a r and omized , multicenter , double-blind , placebo-controlled study including 796 patients with T2DM treated with either 1 tablet of ERN 1 gram/LRPT 20 mg or matching placebo  daily , increased after 4 weeks to 2 tablets daily . RESULTS ERN/LRPT significantly ( P≤0.001 for all ) reduced LDL-C 17.9 % and TG 23.1 % , and increased HDL-C levels 23.2 % . Compared to placebo , ERN/LRPT decreased LDL , IDL , VLDL , and chylomicron particle concentrations [ median concentration of smallest LDL particles decreased 16.6 % , 95 % confidence interval ( CI ) -22.3 , -10.9 , whereas the largest LDL particles decreased 11.0 % , 95 % CI -18.7 , -3.2 , and total VLDL/chylomicron mean plasma particle concentration decreased 34.7 % , 95 % CI -41.3 , -28.1 ] . Compared to placebo , ERN/LRPT shifted the distribution of HDL particle diameter from smaller to larger ( median concentration of the largest HDL particles increased 32.7 % ( 95 % CI 25.30 , 40.58 ) , whereas concentration of the smallest HDL particles decreased 8.2 % ( 95 % CI -11.29 , -5.06 ) . CONCLUSIONS Compared with placebo in patients with T2DM , ERN/LRPT shifted the lipoprotein profile toward a potentially less atherogenic pattern with reduced atherogenic LDL and IDL particle concentrations , and increased large HDL plasma particle concentrations . ( Clinical Trials.gov : NCT00485758 ) OBJECTIVE We compared the effects of diet/exercise induce weight loss versus pioglitazone on lipoprotein particle characteristics in non-diabetic , insulin resistant adults to determine whether the responses and potential mechanisms for improvement are similar between these two insulin sensitizing regimens . METHODS AND RESULTS Thirty-seven obese , insulin resistant volunteers were r and omized to 19 weeks of either pioglitazone or diet/exercise treatment .  Insulin sensitivity ( Si ) by IVGTT and lipoprotein subclass particle profiles by NMR was measured . Only diet/exercise lowered TG ( -40+/-11 mg/dL ) , total ( -29+/-4 mg/dL ) and LDL cholesterol ( -20+/-4 mg/dL ; all p<0.01 ) . Both diet/exercise and pioglitazone improved Si ( p<0.05 ) , decreased total LDL particles ( -227+/-40 and -149+/-21 nmol/L , respectively , both p<0.001 ) and small LDL particles ( -242+/-58 and -226+/-36 , respectively , both p<0.001 ) . Large LDL particle concentrations increased with both treatments . LDL particle subclasses changes correlated with changes in Si only in the diet/exercise group . CONCLUSION In obese , insulin resistant non-diabetic adults , pioglitazone improved LDL particle characteristics in a manner similar to diet/exercise without changing TG , diabetic control , total or LDL cholesterol . This effect could have implication s for atherosclerotic risk 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 BACKGROUND Niacin has multiple lipoprotein effects that may provide cardiovascular benefit when added to statin monotherapy . METHODS In this r and omized , placebo-controlled trial ( n = 75 ) of magnetic resonance imaging of carotid atherosclerosis , we performed a secondary comparison of combination niacin-statin ( simvastatin 20 mg/Niacin-ER 2 G [ S20/N ] ) to monotherapy with moderate ( 20 mg [ S20 ] ) and high-dose ( 80 mg [ S80 ] ) simvastatin on lipids , apolipoproteins ( apo ) , low density lipoprotein ( LDL ) and high density lipoprotein ( HDL ) particle subclasses , and inflammatory markers . RESULTS At baseline , average age was 71 , 72 % were male , 62.5 % used statins , and average LDL-cholesterol was 111 mg/dL. At 12 months , S20/N , compared to S80 , significantly reduced apoB ( -36.6 % vs -11.9 % ; P = .05 ) and lipoprotein(a ) ( -18 % vs + 3.5 % ; P = .001 ) and had at least an equivalent effect on LDL-cholesterol ( -39.3 % vs -24.3 % ; P = .24 ) . The combination reduced the proportion of subjects with atherogenic LDL pattern-B ( 50 % to 11.5 % ) compared to S80 ( 56 % to 56 % ) ( P = .01 ) . Despite increases in plasma free fatty acids ( + 62.4 % ; F = 5.65 , P = .005 vs S20 and S80 ) , plasma triglycerides ( -29.4 % ; F = 6.88 , P = .002 vs S20 and S80 ) , and very-low-density lipoprotein ( -44.2 % ; F = 7.94 , P < .001 vs S20 and S80 ) , levels were reduced by S20/N. S20/N increased HDL-cholesterol levels ( + 18.1 % ) as compared to S20 ( 0 % ) and S80 ( + 5.9 % ) ( P < .001 vs both statin arms ) , largely due to an increase in HDL particle size ( + 4.6 % ; P = .01 vs both statin arms ) . CONCLUSIONS We demonstrate that full-dose niacin/moderate-dose simvastatin combination has sustained benefits on atherogenic apoB lipoproteins , at least comparable to high-dose simvastatin , while also raising HDL-cholesterol . Results of large clinical trials will inform whether niacin-statin combinations reduce cardiovascular disease events OBJECTIVE To evaluate the efficacy and safety of initial combination therapy with metformin plus colesevelam in patients with early type 2 diabetes . METHODS In this 16-week , r and omized , double-blind , placebo-controlled study , adults with type 2 diabetes ( hemoglobin A1c [ A1C ] values of 6.5 % to 10.0 % ) and hypercholesterolemia ( low-density lipoprotein cholesterol [ LDL-C ] levels > or = 100 mg/dL ) were r and omly assigned ( 1:1 ) to colesevelam ( 3.75 g/d ) or placebo in combination with open-label metformin ( 850 mg/d ; uptitrated at week 2 to 1,700 mg/d ) . The primary efficacy evaluation was change in A1C from baseline to study end ( week 16 with last observation carried forward ) . RESULTS In total , 286 patients were r and omized :  metformin/colesevelam ( n = 145 ) or metformin/placebo ( n = 141 ) . Mean A1C was reduced by 1.1 % with metformin/colesevelam ( from 7.8 % at baseline to 6.6 % at study end ) and by 0.8 % with metformin/placebo ( from 7.5 % to 6.7 % ) , result ing in a treatment difference of -0.3 % at study end ( P = .0035 ) . In addition , metformin/colesevelam significantly reduced LDL-C ( -16.3 % ) , total cholesterol ( -6.1 % ) , non-high-density lipoprotein cholesterol ( -8.3 % ) , apolipoprotein B ( -8.0 % ) , and high-sensitivity C-reactive protein ( -17 % ) and increased apolipoprotein A-I ( + 4.4 % ) and triglycerides ( + 18.6 % ) versus metformin/placebo ( P<.01 for all ) . The proportions of patients who achieved recommended goals with metformin/colesevelam versus metformin/placebo , respectively , were as follows : A1C < 7.0 % ( 67 % versus 56 % [ P = .0092 ] ) , LDL-C < 100 mg/dL ( 48 % versus 18 % [ P<.0001 ] ) , and composite A1C < 7.0 % + LDL-C < 100 mg/dL ( 40 % versus 12 % [ P<.0001 ] ) . Safety and tolerability were similar between the treatment groups . CONCLUSION Metformin plus colesevelam may be a valid option for initial therapy to achieve glycemic and lipid goals safely in early type 2 diabetes BACKGROUND The bile acid sequestrant colesevelam has been shown to significantly reduce low-density lipoprotein particle concentration ( LDL-P ) in adults with primary hyperlipidemia or type 2 diabetes mellitus ( T2DM ) . OBJECTIVE To assess the effect of initial combination therapy with metformin plus colesevelam on lipoprotein particles in patients with T2DM ( secondary efficacy variables ) . METHODS This 16-week , r and omized , double-blind , placebo-controlled study enrolled drug-naïve adults with T2DM , glycated hemoglobin 6.5%-10.0 % , low-density lipoprotein cholesterol ( LDL-C ) ≥100 mg/dL , and triglycerides < 500 mg/dL. Patients were r and omized 1:1 to either open-label metformin ( titrated to 1700 mg/day ) plus double-blind colesevelam 3.75 g/day or open-label metformin plus double-blind placebo . RESULTS In total , 286 patients were r and omized  ( metformin plus colesevelam [ n = 145 ] ; metformin plus placebo [ n = 141 ] ) . Compared with metformin plus placebo , the combination of metformin plus colesevelam significantly reduced LDL-C ( mean treatment difference : -16.3 % ) , total cholesterol ( -6.1 % ) , non-high-density lipoprotein cholesterol ( -8.3 % ) , and apolipoprotein ( apo ) B ( -8.0 % ) and significantly increased triglycerides ( median treatment difference : 18.6 % ) and apoA-I ( mean treatment difference : 4.4 % ; all P < .001 ) . Metformin plus colesevelam significantly reduced total LDL-P ( mean treatment difference : absolute change -186 nmol/L [ percent change -11.7 % ] ; both P < .0001 ) , largely attributable to a reduction in small LDL-P , and increased total very-low-density lipoprotein particle concentration ( mean treatment difference : absolute change 6 nmol/L ; P = .03 [ percent change 8.3 % ; P = .06 ] ) and total high-density lipoprotein particle concentration ( 1.0 μmol/L ; P = .03 [ 4.5 % ; P = .01 ] ) versus metformin plus placebo . CONCLUSION Initial combination therapy with metformin plus colesevelam improved the atherogenic lipoprotein profile of patients with early T2DM by significantly reducing LDL-P. Clinical Trials.gov identifier : NCT00570739
target: Conclusions Study -level data from this systemic review establish that different lipid lowering agents can lead to discordance between LDL-P and LDL-C , therefore , basing LDL-lowering therapy only on the achievement of cholesterol goals may result in a treatment gap .
  Therefore , the use of LDL-P for monitoring lipid-lowering therapy , particularly for statins , can provide a more accurate assessment of residual cardiovascular risk
background: Purpose This systematic review was performed to summarize published experience using low density lipoprotein particle number ( LDL-P ) to monitor the efficacy of  lipid-lowering pharmacotherapies .