Justification For Use Of Statins Research Articles

Lipoprotein(a) and Cardiovascular Risk Prediction Among Women

BackgroundAlthough lipoprotein(a) [Lp(a)] is associated with incident cardiovascular disease (CVD), its contribution to prediction remains controversial. ObjectivesThis study examined the association and clinical utility of Lp(a) with incident CVD in women. MethodsA turbidimetric assay assessed Lp(a) in 3 cohorts of women (the WHS [Women’s Health Study] [N = 24,558], a case-cohort sample from the WHI [Women’s Health Initiative] Observational Study [n = 1,815 cases, subcohort n = 1,989], and the JUPITER [Justification for Use of Statins in Prevention] trial [n = 2,569]) and in men from JUPITER (n = 5,161). A WHS derivation sample (n = 16,400) determined the form of association with incident CVD. This was tested in WHS validation data (n = 8,158) and the other study samples. Models including traditional CV risk factors but with and without Lp(a) were compared using risk reclassification. ResultsIn the WHS, there was a curvilinear association, with increased CVD risk among those with Lp(a) >50 mg/dl, but only among women with total cholesterol (TC) >220 mg/dl. In the WHS test sample, there was a small but significant change in the C-statistic (0.790 to 0.797; p = 0.035) but no improvement in measures of reclassification. This pattern was replicated among women in the WHI and JUPITER trial. In contrast, there was a strong association of Lp(a) with CVD among men with low TC levels in JUPITER. ConclusionsIn 3 cohorts of women, Lp(a) was associated with CVD only among those with high TC, and improvement in prediction was minimal. These data have implications for Lp(a) in clinical practice among women and for trials of Lp(a)-lowering agents.

Differential Genetic Effects on Statin-Induced Changes Across Low-Density Lipoprotein-Related Measures.

Statin therapy influences not only low-density lipoprotein (LDL) cholesterol levels but also LDL-related biomarkers, including non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total number of LDL particles, and mean LDL particle size. Recent studies have identified many genetic loci influencing circulating lipid levels and statin-induced LDL cholesterol reduction. However, it is unknown how these genetic variants influence statin-induced changes in LDL subfractions and non-HDL-C. One hundred sixty candidate single-nucleotide polymorphisms for effects on circulating lipid levels or statin-induced LDL-cholesterol lowering were tested for association with response of LDL subfractions and non-HDL-C to rosuvastatin or placebo for 1 year among 7046 participants from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Of the 51 single-nucleotide polymorphisms associated with statin response for ≥ 1 of the LDL subfractions or non-HDL-C, 20 single-nucleotide polymorphisms could be clustered according to effects predominantly on LDL particle size, predominantly on LDL particle number, and on apolipoprotein B but not on LDL cholesterol or non-HDL-C. These differential associations point to pathways of LDL response to statin therapy and possibly to mechanisms of statin-dependent cardiovascular disease risk reduction. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Statin for the Primary Prevention of Cardiovascular Disease in Patients with Diabetes Mellitus

Stain is commonly used in subjects with diabetes for both primary and secondary prevention of cardiovascular diseases (CVDs) [1,2]. It is even recommended by the American Diabetes Association to be added to lifestyle therapy regardless of the baseline lipid levels for diabetic patients aged ≥40 years, even if they have no overt CVD [3], and recent guidelines from the American College of Cardiology and the American Heart Association states that statin therapy should be initiated and maintained for the primary prevention for CVD in adults 40 to 75 years of age with diabetes mellitus, regardless of their CVD risk if their low density lipoprotein cholesterol (LDL-C) level is ≥70 mg/dL [4]. The possibility of primary prevention of CVD with statin therapy for diabetic subjects with a high CVD risk has been well elucidated [1,5,6]. Collaborative Atorvastatin Diabetes Study (CARDS) [1] was a large randomized controlled trial aimed to show the efficacy of statin for the primary prevention of CVD in subjects with type 2 diabetes who had at least one or more of CVD risk factors, but the study terminated 2 years earlier than expected. This was because the statin group showed a superior risk reduction than expected: CVD event reduction of 37% (95% confidence interval [CI], -52 to -17) in statin group [1]. However, there are still insufficient evidence to show the effect of statin for the primary prevention of CVD in diabetic patients with a low risk. There have been claims that statins should be used with caution for the primary prevention in subjects with low CVD risk [7,8]. Furthermore, statin therapy has been reported to be associated with myopathy, elevated liver enzyme concentration, and incident diabetes mellitus [9,10]. However, recent meta-analysis of Cholesterol Treatment Trialists' (CTT) collaborators showed an overall relative risk reduction of major vascular events of 21% (relative risk, 0.79; 95% CI, 0.77 to 0.81) per 1 mmol/L reduction of LDL-C with statin; these benefits were similar in people with a lower CVD risk [11]. Subjects with less than 5% of CVD risk also showed a significant risk reduction of about 40% per 1 mmol/L reduction of LDL-C with statin [11]. In addition, Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) [12] showed that statin decreased the rate of CVD in healthy men and women with LDL-C level ≤130 mg/dL. Although CTT and JUPITER was not performed exclusively in diabetic patients, their results might be implicated with diabetic subjects with a low CVD risk. Moreover, diabetes is an important risk factor for CVD and is considered as an equivalent to coronary artery disease [13]. Reductions in CVD outcomes were greatest in people with high baseline CVD risk [10]. Nonetheless, subgroup analysis from the meta-analysis of CTT reported that statin could reduce CVD events in subjects with diabetes regardless of their baseline CVD risk or baseline LDL-C [6]. Lee et al. [14] reported that statin discontinuation could be considered based on the pretreatment lipid profiles, especially for subjects with baseline LDL-C less than 123 mg/dL. However, considering that statin therapy is not for reducing LDL-C itself but for reducing CVD risk, their results should be interpreted carefully to make the decision whether statin should be continued or not. As the authors mentioned, the effect of stopping statin on future CVD risk in diabetic patients with a low CVD risk remains to be elucidated. There have been obvious concerns on the cost-effectiveness of primary prevention of CVD with statin in diabetic subjects with a low CVD risk. CARDS applied the United Kingdom Prospective Diabetes Study risk engine for their study population to predict the probability of a CVD event for each CARDS patient and showed that the incremental cost-effectiveness ratio was £5,983 per event-free year for subjects with a low CVD risk and £2,077 per event-free year for subjects with a high CVD risk [15]. In addition, other issues such as feasibility and desirability should be considered to treat the majority of diabetic patients aged ≥40 years and the role of alternative public health strategies to lower blood cholesterol. In conclusion, the use of statins for the primary prevention in diabetic subjects with a low CVD risk remains suspensive in its cost-effectiveness. Considering the high risk of CVD in diabetic patients compared to non-diabetic individuals, further studies to elucidate whether statin therapy should be started and maintained for diabetic subjects with a low CVD risk should be performed.

Statins and diabetes: Are numbers tortured on JUPITER?

The purpose of preventive medicine is to avert or delay the onset of disease; importantly, the benefits accrued from the preventive treatment should outweigh any risks in both the short and long-term. Disturbingly, a wealth of evidence has established that cholesterol-lowering statin drugs, widely used for the prevention of cardiovascular disease, do increase the risk of new-onset diabetes [1,2] ,p ossibly by impairing pancreaticbetacellfunctionanddecreasingperipheralinsulinsensitivity, and it has been highlighted how lowering cholesterol at the expense of increasing diabetes might be counterproductive over the long-term [3]. Recently, the diabetogenic effect of statin therapy has been rekindled when a large randomized placebo-controlled primary prevention trial, Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), revealed that subjects randomized to rosuvastatin 20 mg daily over the 1.9-year trial developed a significantly higher incidence of new-onset diabetes [4]. In fact, a post hoc analysis of the JUPITER trial concluded that the positive, although multiple and composite, cardiovascular benefits of statin-treated subjects outweighed theriskofdevelopingdiabetes[5].However,a closerlookatthe JUPITER's data suggests that in clinical practice, the beneficial effects of statin therapy do not outweigh the risk of diabetes, even in short-term. The analysis of participants from the JUPITER trial, to address the balance of vascular benefits and diabetes hazard of statin use after a median follow-up of 2 years, found that rosuvastatin therapy was associated with 65 fewer major vascular events (MVE) or deaths at no risk of diabetes in the 6095 participants with no major diabetes risk factors, and with 93 fewer MVE or deaths at a cost of 54 new diagnoses of

Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A 2 Mass and Activity at Baseline and After Rosuvastatin Therapy

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a proinflammatory enzyme bound to low-density lipoprotein cholesterol and other circulating lipoproteins. Two measures of Lp-PLA 2 , mass and activity, are associated with increased cardiovascular risk. Data are sparse regarding genetic determinants of Lp-PLA 2 mass and activity, and no prior data are available addressing genetic determinants of statin-induced changes for this proinflammatory biomarker. Methods and Results — We performed a genome-wide association study of Lp-PLA 2 mass and activity at baseline and after 12 months of rosuvastatin therapy (20 mg/d) among 6851 participants of European ancestry from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and performed replication in a meta-analysis of 13 664 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Novel associations were identified and replicated at MS4A4E and TMEM49 for baseline Lp-PLA 2 activity with genome-wide significant joint P values ( P =2.0×10 −11 and P =2.9×10 −9 , respectively). In addition, genome-wide associations ( P <5×10 −8 ) were identified and replicated for baseline Lp-PLA 2 mass at CETP and for Lp-PLA 2 activity at the APOC1-APOE and PLA2G7 loci. Among 2673 statin-allocated participants, both Lp-PLA 2 mass and activity were reduced by >30% and low-density lipoprotein cholesterol by 50% after 12 months of statin therapy ( P <0.001 for both). Variants in ABCG2 and LPA were associated with change in statin-induced Lp-PLA 2 activity at genome-wide significance but were substantially attenuated after adjustment for statin-induced changes in lipid levels. Conclusions— Genome-wide significant associations at MS4A4E and TMEM49 may reflect novel influences on circulating levels of Lp-PLA 2 activity. In addition, genome-wide significant associations with rosuvastatin-induced change in Lp-PLA 2 activity were observed in ABCG2 and LPA , likely because of their impact on statin-induced low-density lipoprotein cholesterol lowering.

Rosuvastatin, Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations, and LDL Cholesterol Response: the JUPITER Trial

Although statin therapy is known to increase concentrations of PCSK9, whether this effect is related to the magnitude of LDL reduction is uncertain. This study was undertaken to understand the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol (LDL-C) reduction. We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 year in 500 men and 500 women participating in the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial that randomly allocated participants to rosuvastatin 20 mg daily or placebo. We also evaluated rs11591147, a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations. At baseline, median (interquartile range) PCSK9 concentrations were higher in women [73 (62-90)] ng/mL than in men [69 (57-81) ng/mL] (P<0.005). During 1 year, there was no change in PCSK9 concentrations in the placebo arm, suggesting stability in time. In contrast, the rosuvastatin increased PCSK9 by 35% in women [101 (82-117) ng/mL] and 28% in men [89 (71-109) ng/mL] (P<0.0001). Among those allocated to rosuvastatin, greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales (r=-0.15, P<0.0005). Furthermore PCSK9 (rs11591147) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use. In this randomized trial, rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction; the LDL-C response to statin could not be inferred by PCSK9 concentrations.

Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective.

The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with “intermediate risk” as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with “normal” lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes.

Rosuvastatin for Primary Prevention Among Individuals With Elevated High-Sensitivity C-Reactive Protein and 5% to 10% and 10% to 20% 10-Year Risk

Recent primary prevention guidelines issued in Canada endorse the use of statin therapy among individuals at "intermediate risk" who have elevated levels of high-sensitivity C-reactive protein (hsCRP). However, trial data directly addressing whether this recommendation defines a patient population in which statin therapy is effective have not previously been published. In the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which demonstrated a 44% reduction in first vascular events when rosuvastatin 20 mg was compared with placebo among 17 802 primary prevention patients with LDL cholesterol <130 mg/dL and hsCRP ≥2 mg/L, 6091 participants (2525 women, 3566 men) had baseline estimated 10-year Framingham risks of 5% to 10% and 7340 participants (1404 women, 5936 men) had baseline estimated Framingham risk of 11% to 20%. In these 2 "intermediate risk" subgroups, relative risk reductions consistent with the overall trial treatment effect were observed (hazard ratio, 0.55; 95% confidence interval, 0.36 to 0.84; 5-year number needed to treat=40, P=0.005 for those with 5% to 10% risk; hazard ratio, 0.51; 95% confidence interval, 0.39 to 0.68, 5-year number needed to treat=18, P<0.0001 for those with 11% to 20% risk). Use of the Reynolds Risk Score to stratify the study population gave similar results but reclassified large numbers of individuals into lower- or higher-risk groups. The majority of women with elevated hsCRP who benefited from rosuvastatin were at 5% to 10% 10-year risk at study entry using either global risk scoring system. Consistent with recent evidence-based Canadian Cardiovascular Society guidelines for primary prevention, the JUPITER trial demonstrates that rosuvastatin 20 mg significantly reduces major cardiovascular events among men and women with elevated hsCRP and "intermediate risk" defined either as 5% to 10% or 10% to 20% 10-year risk.

Relation of Baseline High-Sensitivity C-Reactive Protein Level to Cardiovascular Outcomes With Rosuvastatin in the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)

In the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), random allocation of rosuvastatin compared to placebo among primary prevention patients with a low-density lipoprotein cholesterol level of <130 mg/dl and a high-sensitivity C-reactive protein (hs-CRP) level of > or =2 mg/L resulted in a highly significant 44% reduction in major vascular events. However, the relation of baseline hs-CRP levels to risk within JUPITER has not previously been described and has been an area of controversy for study interpretation. As reported in the present study for the first time, despite enrolling patients with a constrained range of values, increasing baseline hs-CRP levels within JUPITER were nonetheless associated with increasing vascular risk in analyses treating hs-CRP as a continuous variable, as an ordinal variable, and as a threshold variable. As anticipated, the relative risk reduction associated with rosuvastatin was similar in magnitude across the tertile and threshold levels of entry hs-CRP. In conclusion, as the absolute risk increased with increasing hs-CRP, the absolute risk reduction associated with rosuvastatin within JUPITER was also greatest among those with the greatest entry hs-CRP levels.

Statin Therapy for Low-LDL, High-hsCRP Patients: From JUPITER to CORONA

In the recently completed Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)1 trial, which was conducted with 17 802 primary-prevention patients with LDL cholesterol concentrations <3.37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) concentrations ≥2 mg/L, random allocation to treatment with 20 mg rosuvastatin was associated with a 54% reduction in the incidence of myocardial infarction, a 48% reduction in stroke, a 47% reduction in the need for angioplasty or bypass surgery, a 43% reduction in venous thrombosis, and a 20% reduction in all-cause mortality (1). These effects were consistent in all of the evaluated subgroups, including among women as well as men, among minority populations, at all levels of Framingham risk, and among those with and without metabolic syndrome. Within the JUPITER trial, as had previously been shown in high-risk patients with acute coronary ischemia and among those with stable coronary disease, the clinical benefits of statin therapy compared with placebo were greatest among patients who reduced not only their LDL cholesterol concentration but also their hsCRP value (2). On the basis of these data, an advisory panel to the US Food and Drug Administration recently voted in favor of expanding the labeling for statin therapy to include those with low LDL cholesterol and increased hsCRP. Furthermore, 2009 guidelines from the Canadian Cardiovascular Society—the first national guidelines to appear since publication of the JUPITER trial data—now explicitly endorse hsCRP screening among “intermediate risk” patients, including those with low LDL cholesterol concentrations (3). The concept that low-LDL, high-hsCRP patients are at a higher than anticipated vascular risk and thus good candidates for statin therapy has also recently been confirmed in the multiethnic Atherosclerosis Risk in Communities (ARIC) study, in which patients with low LDL cholesterol values but high hsCRP concentrations had a substantially …

Relating statin therapy to C-reactive protein levels

Inflammation is pivotal in atherosclerosis, and C-reactive protein (CRP) is an inflammatory marker that predicts cardiovascular events. The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the standard lowering of low-density lipoprotein (LDL)-cholesterol with pravastatin 40 mg/day, with the intense lowering of LDL-cholesterol with atorvastatin 80 mg/day on atheroma volume in patients with coronary artery disease, and showed that the atheroma progressed by 2.7% in the pravastatin group, and remained unchanged in the atorvastatin group. At 18 months follow-up, the CRP levels were reduced from a baseline level of 2.8 mg/l to 1.8 mg/l by atorvastatin, whereas pravastatin had little effect, and there was a good correlation between both the ultrasonographic progression of disease and the reduction in CRP levels. The Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial compared the long-term effects of the standard lowering of LDL-cholesterol with pravastatin, with the intense lowering of LDL-cholesterol with atorvastatin in patients with an acute coronary syndrome. The primary end point was the first of death, myocardial infarction, unstable angina requiring hospitalisation, revascularisation or stroke, and, at the end of 2 years, was greater in the pravastatin than the atorvastatin group (26.3 versus 22.4%, respectively). Patients with CRP levels of 2 mg/l had lower rates of recurrent myocardial infarction or death from coronary causes than patients with higher levels. Further analysis should be undertaken to assess cardiovascular risk at different levels of CRP, including assessing cardiovascular risk at different levels in men and women. Definitive results about the importance of lowering CRP levels are not likely to be obtained until the results of the Justification for Use of Statins in Primary Prevention, an Intervention Trial in Evaluating Rosuvastatin (JUPITER) study are published.