Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase

Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.     

Ezetimibe: the first in a novel class of selective cholesterol-absorption inhibitors

Zetia (ezetimibe) is the first medication in the novel class of selective cholesterol-absorption inhibitors to be released in the United States. Ezetimibe selectively inhibits the uptake of cholesterol from the intestinal lumen at the level of the enterocyte in the intestinal brush border while having no effect on other sterols or lipid-soluble vitamins. Ezetimibe 10 mg daily produces a consistent reduction in low-density lipoprotein cholesterol (LDL-C) by approximately 15 to 20% when used as monotherapy or in combination with 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) or fenofibrate and a 4 to 9% increase in high-density lipoprotein cholesterol. Unlike other lipid-lowering medications that act in the gastrointestinal tract, ezetimibe does not appear to worsen hypertriglyceridemia. Ezetimibe also has an adverse-event profile that is similar to placebo when used as monotherapy or in combination with statins and fenofibrate. Studies of longer duration and with niacin, bile acid sequestrants, and gemfibrozil are warranted to more completely assess the safety of ezetimibe in combination therapy. To date, no clinically significant drug-drug interactions have been noted with the use of ezetimibe; however, further studies are warranted. Ezetimibe will be useful as monotherapy in patients who need modest reductions in LDL-C or are intolerant to other lipid-lowering medication, and in combination with a statin in patients who are unable to tolerate large doses of statins or need further reductions in LDL-C despite maximum doses of a statin. The long-term safety and the effect on cardiovascular morbidity and mortality of ezetimibe are unknown.     

Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients

We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.     

The role of ezetimibe in the prevention of cardiovascular disease: Where do we stand after ARBITER 6-HALTS

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, rapidly became one of the most widely drugs in the US following its approval by the FDA in 2002. Due to its capacity to significantly lower LDL-C with few side effects, ezetimibe has been very useful in enabling patients who were statin intolerant to reach their recommended therapeutic goal for LDL-C. In addition, ezetimibe also reduces non-HDL-C and raises HDL-C, further enhancing its effectiveness in clinical practice. A significant preponderance of evidence supports the reduction of LDL-C and non-HDL-C as the most effective therapy to prevent or reverse atherosclerotic cardiovascular disease (ASCVD). However 3 recent clinical trials, ENHANCE, SEAS, and ARBITER 6-HALTS have raised questions about the efficacy and safety of ezetimibe and have led to a re-examination of its clinical use as a drug for managing lipid risk factors to prevent or manage ASCVD. An in-depth analysis of these three trials reveals methodological deficiencies and concerns with the statistical methods used which significantly diminish their indictment of the clinical utility of ezetimibe. In contrast, The SANDS trial has confirmed the effectiveness of ezetimibe in managing both LDL-C and non-HDL-C, and also demonstrated this drug’s ability to improve carotid atherosclerosis by producing regression of CIMT. One of the important conclusions of the SANDS Trail is that ezetimibe remains an effective adjunctive medication for use in patients who do not reach their LDL-C goals on statin monotherapy. However, as a significant residual risk for ASCVD remains even after aggressive goals for LDL-C and non-HDL-C are reached, current treatment strategies should emphasize managing of all cardiac risk factors and increasing HDL in addition to the attainment and maintenance of recommended goals for LDL-C and non-HDL-C. Hence, ezetimibe should be considered as an important component of broad-spectrum management of lipid risk factors with therapy that includes statins, niacin, bile acid sequestrants, fibrates and Omega 3 fatty acids in appropriate combinations in addition to therapeutic life change.     

Efficacy and safety of ezetimibe in patients undergoing hemodialysis

Patients with dyslipidemia and advanced renal failure are at markedly increased risk of cardiovascular morbidity and mortality. We evaluated the efficacy and safety of ezetimibe administration to patients with endstage renal failure (ESRF) who are undergoing hemodialysis. Ezetimibe at 10 mg/day was given to 20 patients for 12 weeks. Efficacy was determined by monitoring lipids, and safety was determined by monitoring clinical and laboratory parameters. We also evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis. Compared to baseline values, LDL-cholesterol (LDL-C) was reduced by 24.9% (p<0.005) after 12 weeks of ezetimibe administration. Treatment with ezetimibe did not change HDL-cholesterol, triglyceride and HbA1c values but caused a significant reduction in remnant like particles-cholesterol (RLP-C, p<0.05) and high-sensitive C-reactive protein (hsCRP, p<0.05). Ezetimibe therapy decreased cholesterol absorption markers (campesterol and sitosterol) and increased a marker of cholesterol synthesis (lathosterol). A highly significant correlation was observed between alterations in LDL-C and campesterol levels in response to ezetimibe therapy. No patients reported musculoskeletal symptoms. None of the patients experienced elevations in their creatine kinase or liver transaminase levels. Ezetimibe not only reduced serum LDL-C, but also RLP-C and hsCRP, in ESRF patients. Inhibition of cholesterol absorption by ezetimibe is an important therapeutic option in these patients due to its efficacy and safety.     

Efficacy of Ezetimibe is Associated with Gender and Baseline Lipid Levels in Patients with Type 2 Diabetes

Aim: The combination of ezetimibe and a statin provides greater LDL-C reduction by inhibiting both intestinal cholesterol absorption and endogenous production of cholesterol. The present study was designed to examine the influence of ageing, gender, BMI, levels of LDL-C, and HbA1c on the response to ezetimibe add-on therapy.Methods: Patients who had been taking a statin for >3 months at the usual dose and whose LDL-C was >120 mg/dL were eligible for this study. Patients were assigned to receive add-on ezetimibe at 10 mg once daily for 12 weeks.Results: Adding ezetimibe to basal statin therapy resulted in a further 15.0% reduction of TC, 20.5% reduction of LDL-C, and 19.7% reduction of non-HDL-C. The change in TC was significantly greater in males than in females. The change in TG was significantly greater in patients with a baseline TG level ≥150 mg/dL. Multivariate regression analysis showed that male sex and LDL-C ≥140 mg/dL were independent predictors of TC reduction after adjustment for age, BMI, and HbA1c. A baseline TG ≥150 mg/dL was also an independent predictor of TG reduction.Conclusion: Addition of ezetimibe to ongoing statin therapy was effective in patients with type 2 diabetes. Male sex and baseline LDL-C levels are independent predictors of marked TC reduction by ezetimibe treatment.     

Cholesterol absorption inhibitors: defining new options in lipid management

Although many studies have documented that reduction of plasma cholesterol levels decreases the risk of coronary artery disease, it remains the most common cause of death in the Western world. Current therapeutic options are effective in lowering cholesterol, especially in clinical trials, but clinical application is not optimized for many reasons. Dietary restriction for long-term management of hypercholesterolemia is helpful but usually insufficient to reduce low-density lipoprotein cholesterol (LDL-C) to goal levels. Powerful drugs are available, but these are often insufficient to meet the clinical demands for cholesterol-lowering therapy. Phytosterols and phytostanols have been partially effective by providing some inhibition of absorption of cholesterol. Compounds that specifically and more effectively block intestinal absorption of dietary and biliary cholesterol should provide a significant new agent for altering lipoprotein concentrations favorably. Ezetimibe is the first of this class of compounds that act at the gut epithelium to reduce cholesterol absorption in the milligram dose range markedly. Clinical studies indicate that ezetimibe effectively decreases LDL-C by 15 to 20% as monotherapy, with a favorable safety profile. Moreover, results from preliminary clinical trials indicate that ezetimibe given concomitantly with a statin provides additive efficacy. The combination represents a new approach to lipid management, achieving greater LDL-C and triglyceride reductions and greater improvements in HDL-C than statin monotherapy. This could offer another important option in clinical practice for management of hypercholesterolemic patients.     

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia. BACKGROUND: Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals. METHODS: After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =145 mg/dl to < or =250 mg/dl and triglycerides (TG) < or =350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups. RESULTS: Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo. CONCLUSIONS: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.     

Ezetimibe: from pharmacology to clinical trials

LDL-cholesterol (LDL-C) is a key factor in primary and secondary prevention of coronary heart disease. Statins have become a mainstay in the first-line treatment of hypercholestorelomia. Nevertheless, in clinical practice, there is a major gap between treatment guidelines and real life treatment patterns. It is not uncommon that statins lack sufficient efficacy in the most severe cases of dyslipidemia, even when the highest doses are used. Therapy combining statins with other cholesterol-lowering agents is often used, although it may be poorly tolerated. These limitations have directed research towards new mechanisms of action, additive to those of statins which inhibit the hepatic biosynthesis of cholesterol. Ezetimibe is the first once-daily potent and selective inhibitor of cholesterol absorption which has been shown to reduce the overall delivery to the liver, with a subsequent reduction of serum LDL-C. As monotherapy, mean decrease in LDL-C with ezetimibe was 19.1% versus placebo, whereas in addition to ongoing statin therapy, there was a 21.8% incremental reduction of LDL-C (p<0.001) and a 11.1% of triglycerides (p<0.001) with an increase of HDL-C of about 1.7% (p<0.05). Phase III factorial co-administration studies with various statins at increasing dosages have shown a mean supplementary decrease of LDL-C (-12.1 to -13.8%) and triglycerides (-7.4 to -10.5%) and raising HDL-C (+1.4 to 4.5%) (versus pooled statins). Co-administration of ezetimibe (10 mg once a day) with a statin permits a degree of LDL-C lowering similar to that achieved with the highest doses of statins. The efficacy of ezetimibe has also been demonstrated in familial homozygous hypercholesterolemia and sistosterolemia. In both monotherapy and combination studies, clinical and biological safety of ezetimibe was good.     

Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?

OBJECTIVES: We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose. BACKGROUND: Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy. METHODS: Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication. RESULTS: Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (-5.2 +/- 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 +/- 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin -1.01 +/- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 +/- 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin. CONCLUSIONS: Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.     

Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials

ObjectivePatients with dyslipoproteinemia constitute the largest risk group for development of atherosclerosis and cardiovascular disease (CVD). Despite extensive statin use, many patients with CVD risk do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. This pooled analysis of 27 previously published clinical trials conducted between 1999 and 2008 evaluated the lipid-altering efficacy and factors related to treatment response of ezetimibe combined with statin and statin monotherapy.MethodsPatient-level data were combined from double-blind, placebo-controlled or active comparator studies randomizing adult subjects to ezetimibe 10 mg plus statin (n = 11,714) versus statin alone (n = 10,517) for 6–24 weeks (mean = 9 weeks). Association of factors with treatment response, percent change from baseline LDL-C and other lipids, and attainment of guideline-recommended lipid and lipoprotein targets were evaluated.ResultsHigher baseline LDL-C, diabetes mellitus, Black race, greater age, and male gender were associated with small but significantly greater percent reductions in LDL-C regardless of treatment. Treatment influenced efficacy, with ezetimibe plus statin producing significantly greater reductions in LDL-C, total-cholesterol, non-HDL-C, ApoB, triglycerides, lipid ratios, hs-CRP; significantly larger increases in HDL-C and ApoA1; and significantly higher achievement of LDL-C (<70 mg/dl, <100 mg/dl), non-HDL-C (<100 mg/dl, <130 mg/dl), and ApoB (<80 mg/dl, <90 mg/dl) targets than statin monotherapy at statin potencies compared (p < 0.0001 for all). Differential treatment effects were seen with first-/second-line therapy and statin potency.ConclusionThese results suggest that patient characteristics have a limited influence on response to lipid-lowering therapy and demonstrate the consistent treatment effect of ezetimibe combined with statin and statin monotherapy across a diverse patient population.     

Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe

In addition to their expected effects on lipid profile, lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as insulin resistance and inflammation. Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol as well as plant sterols. Although it is known that an additional reduction of low-density lipoprotein cholesterol (LDL-C) levels can be induced by the combination of ezetimibe with statins, it is not known if this can enhance some pleiotropic effects, which may be useful in slowing the atherosclerotic process. This study assessed the effects of simvastatin and ezetimibe, in monotherapy or in combination, on markers of endothelial function and insulin sensitivity. Fifty prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia were randomly allocated to 2 groups receiving either ezetimibe (10 mg/d) or simvastatin (20 mg/d) for 12 weeks, after which the drugs were combined for both groups for an additional 12-week period. Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of therapy. Homeostasis model assessment of insulin resistance index and the area under the curve of insulin were calculated. As expected, both groups receiving drugs in isolation significantly reduced total cholesterol, LDL-C, apolipoprotein B, and triglyceride levels; and additional reductions were found after the combination period (P < .05). After 12 weeks of monotherapy, plasminogen activator inhibitor-1 levels and urinary albumin excretion were lower in the simvastatin than in the ezetimibe group. No change in homeostasis model assessment of insulin resistance index, area under the curve of insulin, and adiponectin levels was observed after either the monotherapies or the combined therapy. However, simvastatin combined with ezetimibe provoked significant reductions in E-selectin and intravascular cellular adhesion molecule-1 levels that were independent of LDL-C changes. Our findings support claims that simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia. Alternatively, a deleterious effect of ezetimibe on the endothelial function is suggested, considering the increase in intravascular cellular adhesion molecule-1 and E-selectin levels. Simvastatin and ezetimibe, in isolation or in combination, do not interfere with insulin sensitivity.     

Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study)

International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides for patients at moderately high to high coronary heart disease (CHD) risk. Combination therapy is often required to achieve multiple lipid treatment goals, and > or =50% reduction in low-density lipoprotein cholesterol (LDL-C) is needed in some patients to achieve aggressive LDL-C targets. In this context, we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin (niacin ER), a statin plus ezetimibe, and a highly potent statin alone. This was an open-label, multicenter, 12-week study in 292 patients (50% women) who qualified for drug therapy based on number of CHD risk factors. Patients were randomized to four parallel arms, titrated from low to moderate or high doses: atorvastatin/niacin ER, rosuvastatin/niacin ER, simvastatin/ezetimibe, or rosuvastatin alone. Baseline mean values were, for LDL-C 197 mg/dL (5.1 mmol/L), HDL-C 49 mg/dL (1.3 mmol/L), triglycerides 168 mg/dL (1.9 mmol/L). There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment. All groups lowered LDL-C by approximately 50% or more (range -49 to -57%), achieving mean levels of 82-98 mg/dL (2.1-2.5 mmol/L). Changes in non-HDL-C (range -46 to -55%) mirrored those for LDL-C and did not differ among treatment groups. Statin/niacin ER combination regimens also increased HDL-C and large HDL (HDL2) and lowered triglycerides and lipoprotein (a) significantly more than other regimens. No drug-related myopathy or hepatotoxicity was observed. In this study, low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD.     

Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease

We evaluated the effects of adding ezetimibe to statin therapy in hypercholesterolemic patients with coronary artery disease (CAD) who could not achieve the target cholesterol levels recommended in the 2007 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases on statin monotherapy. Ezetimibe (10 mg) was added to basal statin therapy for 12 weeks in 35 patients with hypercholesterolemia and a history of CAD who had not achieved their target cholesterol level with statin monotherapy. Changes in serum lipids, obesity markers, an oxidative stress marker, inflammatory markers, and laboratory values were investigated. Total cholesterol (from 200.6 ± 30.4 mg/dL in week 0 to 173.4 ± 33.3 mg/dL in week 12, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (121.3 ± 29.4 vs. 94.6 ± 30.4 mg/dL, P < 0.001), and remnant lipoprotein cholesterol (6.4 ± 3.5 vs. 5.3 ± 3.0 mg/dL, P < 0.05) all decreased significantly after addition of ezetimibe. The LDL-C/high-density lipoprotein cholesterol ratio also decreased significantly (2.5 ± 0.8 in week 0 vs. 1.9 ± 0.7 in week 12, P < 0.001). The percentage of patients achieving the target LDL-C level (<100 mg/dL) increased significantly (70.8 % in week 4 and 65.4 % in week 12, P < 0.001). There were no significant changes in the obesity or oxidative stress markers and high-sensitivity C-reactive protein (an inflammatory marker). However, another inflammatory marker (tumor necrosis factor-α) was decreased significantly by ezetimibe (1.36 ± 1.06 in week 0 vs. 0.96 ± 0.24 in week 12, P = 0.042). In conclusion, when ezetimibe was added to basal statin therapy, serum lipids improved significantly and the rate of achieving the target cholesterol level increased. Thus, ezetimibe efficiently decreases LDL-C and might prevent arteriosclerosis in hypercholesterolemic patients with CAD when added to basal statin therapy.     

Intensive statin therapy for Indians: Part-I. Benefits

The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an extremely favorable benefit-to-risk ratio of intensive statin therapy with some but not all statins. Atorvastatin 80 mg/d is 100 times safer than aspirin 81 mg/d and 10 times safer than diabetic medications. Intensive statin therapy is more effective and safe compared to intensive control of blood sugar or blood pressure in patients with diabetes.     

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.     

Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: A clinical update

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management.While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This ‘residual risk’ is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy.Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.     

Management of the Patient with Statin Intolerance

Current guidelines recommend statins as first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C) and preventing cardiovascular events. Patients taking statins frequently experience adverse effects during therapy. The first step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Strategies for managing statin intolerance include changing statins, intermittent dosing, intensification of lifestyle modifications, and using other LDL-C-lowering agents such as ezetimibe, bile acid sequestrants, and LDL apheresis in suitable patients. More controversial approaches include red yeast rice, coenzyme Q10, and vitamin D supplementation. New therapies for LDL-C lowering are in development.     

A triumvirate of targets in the prevention and treatment paradigm for cardiovascular disease

Statins have revolutionized the management of cardiovascular disease (CVD). Reductions in low-density lipoprotein cholesterol (LDL-C) with statin therapy have been shown to reduce significantly the risk of CVD in primary and secondary prevention trials. Recent evidence from clinical trials supports the concept that lower LDL-C levels, below current guideline targets, provide additional protection against cardiovascular (CV) events. In addition evidence is accumulating that increasing high-density lipoprotein cholesterol (HDL-C) and decreasing the level of chronic inflammation are important targets in CVD risk reduction. Recent studies have investigated the effectiveness of statins in terms of their ability to concomitantly reduce LDL-C, increase HDL-C and lower C-reactive protein (CRP). Results demonstrate that the more effective statins have beneficial effects on this triumvirate of potential treatment targets. Furthermore, the overall safety and tolerability profile is comparable among available statins. This paper examines recent data highlighting the role that statins and other lipid-lowering agents can play in this new treatment paradigm.     

Zetia: inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to reduce intestinal cholesterol absorption and treat hyperlipidemia

Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.