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In a phase 2 trial, patients with hypercholesterolemia received 80 mg atorvastatin and placebo, 10 mg atorvastatin and an antibody to PCSK9, or 80 mg atorvastatin and an antibody to PCSK9 for 8 weeks. Reductions from baseline in LDL cholesterol were 17.3%, 66.2%, and 73.2%, respectively. Reducing levels of low-density lipoprotein (LDL) cholesterol is a cornerstone of the prevention of cardiovascular disease. 1 , 2 European and U.S. guidelines recommend lowering LDL cholesterol to less than 100 mg per deciliter (2.6 mmol per liter) in persons with established cardiovascular disease and to less than 70 mg per deciliter (1.8 mmol per liter), or by 50% or more, in those at highest risk. 3 , 4 Statins are highly efficacious in lowering LDL cholesterol. However, many patients, especially those with very high initial LDL cholesterol levels and those who have unacceptable side effects with high-dose statins, do not reach recommended target . . .

In this trial, intravascular ultrasonography was used to compare the effects of atorvastatin versus rosuvastatin on regression of coronary atherosclerosis. Both statins led to regression in two thirds of patients, with no significant difference between their effects. Randomized clinical trials have consistently shown that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce cardiovascular event rates. 1 – 9 The favorable effects of statins extend across a range of levels of low-density lipoprotein (LDL) cholesterol, with no apparent lower threshold for a benefit. 3 , 9 , 10 In parallel, imaging trials have shown that intensive statin regimens slow the progression of coronary atherosclerosis and may even result in disease regression in some patients. 11 , 12 Accordingly, guidelines for cardiovascular disease prevention have increasingly emphasized that lowering LDL cholesterol levels with statins is the primary goal of lipid-modulating therapy. 13 , 14 Available statins differ considerably . . .

In this trial, 947 patients with renal-artery stenosis were assigned to renal-artery stenting or medical therapy. At a median of 43 months, there was no significant between-group difference in the rate of a composite end point of adverse cardiovascular and renal events. Renal-artery stenosis, which is present in 1 to 5% of people with hypertension, 1 , 2 often occurs in combination with peripheral arterial or coronary artery disease. 3 , 4 Results of community-based screening suggest that the prevalence among persons older than 65 years of age may be as high as 7%. 5 Renal-artery stenosis may result in hypertension, ischemic nephropathy, and multiple long-term complications. 6 Uncontrolled studies performed in the 1990s suggested that renal-artery angioplasty or stenting resulted in significant reductions in systolic blood pressure 7 , 8 and in the stabilization of chronic kidney disease. 9 , 10 Subsequently, there were rapid increases in the rate of renal-artery . . .

Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non–high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Patients with hyperlipidemia were assigned to receive the PCSK9 antibody evolocumab or placebo on a background of lipid-lowering therapy. At 52 weeks, the least-squares mean reduction in LDL cholesterol from baseline for evolocumab versus placebo was 57%. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a major role in regulating levels of low-density lipoprotein (LDL) cholesterol by binding to hepatic LDL receptors and promoting their degradation. 1 , 2 In short-term (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels. 3 – 9 Four of these trials involved the use of evolocumab (AMG 145), a fully human monoclonal PCSK9 antibody, and assessed different doses and regimens in diverse patient populations with varying lipid phenotypes, cardiovascular disease risks, and baseline . . .

Torcetrapib, a cholesteryl ester transfer protein inhibitor, markedly raises levels of high-density lipoprotein cholesterol. Unexpectedly, in the ILLUMINATE trial, torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. The drug also raised blood pressure. Torcetrapib therapy in combination with atorvastatin, as compared with atorvastatin alone, increased the risk of death from both cardiovascular and noncardiovascular causes. Evidence supporting the proposition that high-density lipoprotein (HDL) cholesterol should be considered as a therapeutic target includes experimental models of atherosclerosis, 1 an inverse relationship to the risk of cardiovascular disease in humans, 2 clinical trials of drugs for which raising HDL cholesterol levels is a primary pharmacologic effect, 3 and the residual risk of cardiovascular disease associated with a low HDL cholesterol level after effective statin therapy. 4 Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from HDL to other lipoproteins; the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels. There is evidence . . .

Patients with stable coronary artery disease may benefit from therapy to lower low-density lipoprotein (LDL) cholesterol levels, but optimal target levels are unknown. This study showed that intensive lowering of LDL cholesterol levels to a mean of 77 mg per deciliter (2.0 mmol per liter) with 80 mg of atorvastatin per day produced greater clinical benefit than lowering levels to a mean of 101 mg per deciliter (2.6 mmol per liter) with 10 mg of atorvastatin per day. These results could affect practice patterns by redefining target levels of LDL cholesterol in patients with stable coronary disease. This study showed that intensive lowering of LDL cholesterol levels to a mean of 77 mg per deciliter with 80 mg of atorvastatin per day produced greater clinical benefit than lowering levels to a mean of 101 mg per deciliter with 10 mg of atorvastatin per day. The value of lowering low-density lipoprotein (LDL) cholesterol levels in preventing major cardiovascular events and stroke has been well documented. Recent studies have raised the issue of optimal treatment targets for patients with coronary heart disease (CHD). 1 – 4 The value of reducing LDL cholesterol levels substantially below 100 mg per deciliter (2.6 mmol per liter) in patients with CHD, particularly those with stable nonacute disease, has not been clearly demonstrated. The Third Report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel 5 and the most recent guidelines of the Third Joint Task Force of European and Other Societies on . . .

Statin therapy lowers not only low-density lipoprotein (LDL) cholesterol levels, but also levels of C-reactive protein (CRP), a marker of inflammation. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving pravastatin or atorvastatin. Lowering CRP levels reduced coronary risk irrespective of the extent of LDL cholesterol lowering. Patients with the lowest risk had the lowest levels of both LDL cholesterol and CRP after 30 days of statin therapy. This study examined the independent effects of decreasing LDL cholesterol and CRP levels on subsequent coronary risk in patients with acute coronary syndromes who were receiving statin therapy. Statin therapy lowers the risk of cardiovascular events by reducing plasma cholesterol levels, and practice guidelines for patients with known cardiovascular disease emphasize the importance of reaching target goals for low-density lipoprotein (LDL) cholesterol. 1 However, we have shown that statin therapy results in a greater clinical benefit when levels of the inflammatory biomarker C-reactive protein (CRP) are elevated 2 , 3 and that statins lower CRP levels in a manner largely independent of LDL cholesterol levels. 3 – 6 These findings, along with basic laboratory evidence, have led to the hypothesis that, in addition to being potent lipid-lowering agents, statins may also have antiinflammatory . . .

In a post hoc analysis of the Treating to New Targets study, high-density lipoprotein cholesterol levels in patients receiving statin therapy were shown to be predictive of subsequent major cardiovascular events, even when low-density lipoprotein (LDL) cholesterol levels were taken into account and even among patients with very low levels of LDL cholesterol (<70 mg per deciliter). High-density lipoprotein cholesterol levels in patients receiving statin therapy were shown to be predictive of subsequent major cardiovascular events, even among patients with very low levels of LDL cholesterol. Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease. 1 – 5 In the Framingham Heart Study, HDL cholesterol level was more potent as a risk factor for coronary heart disease than was the level of low-density lipoprotein (LDL) cholesterol. 4 An analysis of data from four large studies concluded that each increase of 1 mg per deciliter (0.03 mmol per liter) in HDL cholesterol is associated with a decrease of 2 to 3% in the risk of future coronary heart disease. 6 Intervention trials using statins to lower LDL cholesterol have consistently . . .

A monoclonal antibody to PCSK9 was studied in two single-dose trials in healthy volunteers and one multiple-dose trial in patients with familial or nonfamilial hypercholesterolemia. In all three groups, the antibody reduced levels of LDL cholesterol. In 2003, Abifadel and colleagues 1 described two families with autosomal dominant hypercholesterolemia that was associated with gain-of-function mutations in proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases. These patients had high plasma levels of low-density lipoprotein (LDL) cholesterol, which was associated with an increased incidence of coronary heart disease. Shortly thereafter, studies of animal models identified a role for PCSK9 in the post-translational regulation of LDL-receptor activity. 2 , 3 PCSK9, which is synthesized primarily in the liver, enters the circulation, where it binds to hepatic LDL receptors and targets them for degradation. This process reduces the capacity of the . . .