Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein

The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to elevated plasma concentrations of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP). A total of 17,802 persons with LDL cholesterol<130 mg/dl (3.36 mmol/L) and hs-CRP>or=2 mg/L were recruited from 26 countries and randomly allocated to 20 mg/day rosuvastatin or placebo. In contrast to previous studies of statin therapy in primary prevention, JUPITER is evaluating a group with modest plasma concentrations of LDL cholesterol (median 108 mg/dl, interquartile range 94 to 119). Further, the trial includes 6,801 women (38.2%) and 5,577 participants with metabolic syndrome (32.1%). Thus, in addition to broadening our understanding of statin therapy and inflammation, the JUPITER trial will provide important and clinically relevant information on primary prevention among patients who do not currently qualify for lipid-lowering therapy. In conclusion, as 20 mg of rosuvastatin can reduce LDL cholesterol by up to 50%, JUPITER will also provide crucial safety data for several thousand patients who should achieve LDL cholesterol levels<50 mg/dl on a long-term basis.     

JUPITER and satellites: Clinical implications of the JUPITER study and its secondary analyses

The justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin(JUPITER) study was a real breakthrough in primary cardiovascular disease prevention with statins,since it was conducted in apparently healthy individuals with normal levels of low-density lipoprotein cholesterol(LDL-C <130 mg/dL)and increased inflammatory state,reflected by a high concentration of high-sensitivity C-reactive protein(hs-CRP≥2 mg/L).These individuals would not have qualified for statin treatment according to current treatment guidelines.In JUPITER,rosuvastatin was associated with significant reductions in cardiovascular outcomes as well as in overall mortality compared with placebo.In this paper the most important secondary analyses of the JUPITER trial are discussed,by focusing on their novel findings regarding the role of statins in primary prevention.Also,the characteristics of otherwise healthy normocholesterolemic subjects who are anticipated to benefit more from statin treatment in the clinical setting are discussed.Subjects at"intermediate"or"high"10-year risk according to the Framingham score,those who exhibit low post-treatment levels of both LDL-C(< 70 mg/dL)and hs-CRP(<1 mg/L),who are 70 years of age or older,as well as those with moderate chronic kidney disease(estimated glomerular filtration rate <60 mL/min every 1.73 m2)are anticipated to benefit more from statin treatment.Unlikely other statin primary prevention trials,JUPITER added to our knowledge that statins may be effective drugs in the primary prevention of cardiovascular disease in normocholesterolemic individuals at moderate-to-high risk.Also,statin treatment may reduce the risk of venous thromboembolism and preserve renal function.An increase in physician-reported diabetes represents a major safety concern associated with the use of the most potent statins.     

The JUPITER Trial: Myth or Reality?

The JUPITER trial is widely hailed as a landmark trial that has the potential to dramatically change the landscape of primary prevention of cardiovascular disease. Like most trials, however, it is not without its limitations. We address some of the common myths and misunderstandings that are underscored by the JUPITER trial. First, by its intentional and ill-advised exclusion of patients with low levels of high-sensitivity C-reactive protein (hsCRP), it is not possible to assess whether baseline hsCRP modifies treatment response to statins or whether it identifies patients most likely to benefit from statin therapy. Second, by stopping the trial early, one cannot rule out the possibility that the treatment benefit was overestimated and risk was underestimated, thereby precluding a reliable estimate of benefit/risk. Finally, as a consequence of early stopping, it is not possible to reliably assess the cost-effectiveness of primary prevention with rosuvastatin. Given these limitations, the attendant societal health policy implications remain largely unknown.     

Moving toward new statin guidelines in a post-JUPITER world: Principles to consider

The recently completed study Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) demonstrates that statin therapy reduces vascular events in apparently healthy men and women with low levels of low-density lipoprotein cholesterol (mean, 104 mg/dL) who are at elevated risk due to high-sensitivity C-reactive protein levels greater than 2 mg/L. Among 17,802 trial participants, rosuvastatin resulted in a 44% reduction in the primary end point of all vascular events (P < 0.00001), a 54% reduction in myocardial infarction (P = 0.0002), a 48% reduction in stroke (P = 0.002), a 46% reduction in need for arterial revascularization (P < 0.001), and a 20% reduction in all-cause mortality (P = 0.02). All subgroups with elevated high-sensitivity C-reactive protein benefited, including those traditionally considered to be at low risk, such as women, nonsmokers, and those with Framingham risk scores less than 10%. Absolute risk reductions within JUPITER result in a number needed to treat at 5 years of 25, a value comparable or superior to that of other interventions routinely used in primary prevention, including statin therapy among those with hyperlipidemia. Although lifestyle interventions remain critical, the screening and treatment strategy tested in JUPITER is likely to impact on new guidelines for cardiovascular disease prevention.     

Surrogate markers of atherosclerosis: impact of statins

Carotid artery intima-media thickness (IMT) measured by ultrasound has been shown to be correlated with existing cardiovascular disease (CVD) and predictive of CVD in individuals without clinically evident disease. Carotid IMT is now widely used as a surrogate marker for atherosclerotic disease. A number of studies have shown that lipid-lowering therapy with a statin can reduce or reverse carotid IMT progression. The METEOR trial (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin) will examine the effects of aggressive lipid-lowering treatment with rosuvastatin on IMT in mildly hypercholesterolemic low-risk subjects with relatively high IMT values. The results will provide important information on the ability to achieve regression of abnormal IMT with robust reductions in low-density lipoprotein (LDL) cholesterol levels to below current target levels. Another study will examine the effects of potent LDL cholesterol reduction with rosuvastatin in young patients with heterozygous familial hypercholesterolemia (FH). Patients with FH are at increased risk of premature coronary heart disease in association with marked LDL cholesterol elevations, exhibiting a rate of progression of IMT 5x greater than that of low-risk controls without the disorder and early intervention may be the optimal approach to modifying atherosclerosis progression in these patients.     

Impact of statin therapy on LDL and non-HDL cholesterol levels in subjects with heterozygous familial hypercholesterolaemia

Background and aimsCardiovascular risk in heterozygous familial hypercholesterolaemia (HeFH) is driven by LDL cholesterol levels. Since lipid response to statin therapy presents individual variation, this study aimed to compare mean LDL and non-HDL cholesterol reductions and their variability achieved with different types and doses of the most frequently prescribed statins.Methods and resultsAmong primary hypercholesterolaemia cases on the Spanish Arteriosclerosis Society registry, 2894 with probable/definite HeFH and complete information on drug therapy and lipid profile were included.LDL cholesterol reduction ranged from 30.2 ± 17.0% with simvastatin 10 mg to 48.2 ± 14.7% with rosuvastatin 40 mg. After the addition of ezetimibe, an additional 26, 24, 21 and 24% reduction in LDL cholesterol levels was obtained for rosuvastatin, 5, 10, 20 and 40 mg, respectively. Subjects with definite HeFH and a confirmed genetic mutation had a more discrete LDL cholesterol reduction compared to definite HeFH subjects with no genetic mutation. A suboptimal response (<15% or <30% reduction in LDL cholesterol levels, respectively with low-/moderate-intensity and high-intensity statin therapy) was observed in 13.5% and, respectively, 20.3% of the subjects.ConclusionAccording to the LDL cholesterol reduction in HeFH patients, the ranking for more to less potent statins was rosuvastatin, atorvastatin and simvastatin; however, at maximum dosage, atorvastatin and rosuvastatin were nearly equivalent. HeFH subjects with positive genetic diagnosis had a lower lipid-lowering response. Approximately 1 in 5 patients on high-intensity statin therapy presented a suboptimal response.     

Comparison of rosuvastatin versus atorvastatin in South-Asian patients at risk of coronary heart disease (from the IRIS Trial)

In a large randomized trial of statin therapy in patients of South-Asian origin with hypercholesterolemia, 740 patients in the United States and Canada received 6 weeks of treatment with rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg. A total of 485 patients (66%) were categorized as being at high risk of coronary heart disease and had a National Cholesterol Education Program Adult Treatment Panel III treatment goal of low-density lipoprotein (LDL) cholesterol <100 mg/dl (<2.6 mmol/L). LDL cholesterol decreased by 45% with rosuvastatin 10 mg versus 40% with atorvastatin 10 mg (p = 0.0023) and by 50% with rosuvastatin 20 mg versus 47% with atorvastatin 20 mg (p = NS). National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol goal achievement rates in high-risk patients (all patients) were 76% (79%) and 88% (89%) with rosuvastatin 10 and 20 mg, respectively, compared with 70% (76%) and 81% (85%) with atorvastatin 10 and 20 mg, respectively. Rosuvastatin and atorvastatin were well tolerated. There were no clinically relevant differences between statins in adverse events or incidence of creatine kinase >10 times the upper limit of normal, alanine aminotransferase >3 times the upper limit of normal on 2 consecutive occasions, or proteinuria or hematuria over the relatively short duration of treatment. In conclusion, statin therapy was well tolerated and effective in decreasing LDL cholesterol in patients of South-Asian origin, with the 10- and 20-mg doses of rosuvastatin and atorvastatin allowing most patients to reach recommended LDL cholesterol goals.     

Proportion of oxidized LDL relative to plasma apolipoprotein B does not change during statin therapy in patients with heterozygous familial hypercholesterolemia

OBJECTIVE: Circulating oxidized low-density lipoprotein (LDL) has been shown to be a useful marker for identifying patients with coronary heart disease (CHD) and persons at high cardiovascular risk. The effect of cholesterol-lowering therapy on plasma level of oxidized LDL is not clear. METHODS AND RESULTS: We investigated effects of cholesterol lowering by therapeutic intervention (2 years) with atorvastatin (80 mg daily) and simvastatin (40 mg daily) on circulating oxidized LDL (absolute level and in proportion to plasma apolipoprotein B) in relation to atherosclerosis progression (carotid intima-media thickness, carotid IMT) and to inflammation (high-sensitivity C-reactive protein, hsCRP) in 115 stable patients with heterozygous familial hypercholesterolemia (FH). Atorvastatin and simvastatin reduced plasma-oxidized LDL (-43 and -35%, respectively) in proportion to the decrease in plasma apolipoprotein B. Neither absolute nor relative level of oxidized LDL correlated with carotid IMT or hsCRP at baseline. Also changes in levels of circulating oxidized LDL were not related to changes in carotid IMT and hsCRP. CONCLUSIONS: In familial hypercholesterolemia-oxidized LDL carried in plasma is strongly associated with apolipoprotein B but not with inflammation nor with carotid IMT, and statin treatment does not reduce oxidized LDL relative to apolipoprotein B.     

Statin Therapy in Metabolic Syndrome and Hypertension Post-JUPITER: What is the Value of CRP?

Much evidence supports a pivotal role for inflammation in atherosclerosis. C-reactive protein (CRP), the prototypic marker of inflammation in humans, is a cardiovascular risk marker and may also promote atherogenesis. CRP levels are increased in metabolic syndrome and hypertension and confer increased risk of cardiovascular events in patients in these subgroups. Statins have been shown to lower low-density lipoproteins and CRP independently, and reduce cardiovascular events in subjects with and without metabolic syndrome and hypertension. In this review, we focus on the results from the primary prevention statin trial, Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which showed reductions in LDL, CRP, and cardiovascular events. Post-JUPITER, the new guidelines will now need to consider recommending high-sensitivity CRP testing to intermediate-risk metabolic syndrome patients and those with hypertension and intermediate risk so that we can better identify candidates at greater risk and reduce cardiovascular burden in these subjects with statin therapy.     

Benefits and Risks of Statin Therapy in the HIV-Infected Population

Purpose of Review

HIV-infected patients face an increased risk for cardiovascular disease (CVD), estimated at 1.5- to 2-fold as compared to HIV-uninfected persons. This review provides a recent (within preceding 5 years) summary of the role of statin therapy and associated role in CVD risk reduction among HIV-infected patients on anti-retroviral therapy.

Recent Findings

Statins remain the preferred agents for reducing risk for CVD among HIV-infected populations based on guidance extrapolated from general population (HIV-uninfected) cholesterol treatment guidelines across different settings globally. However, HIV-infected patients are consistently under prescribed statin therapy when compared to their HIV-uninfected counterparts. The most commonly studied statins in clinical care and small randomized and cohort studies have been rosuvastatin and atorvastatin. Both agents are preferred for their potent lipid-lowering effects and their favorable or neutral pleotropic effects on chronic inflammation, renal function, and hepatic steatosis among others. However, growing experience with the newer glucuronidated pitavastatin suggests that this agent has virtually no adverse drug interactions with ART or effects on glucose metabolism—all marked additional benefits when compared with rosuvastatin and atorvastatin while maintaining comparable anti-lipid effects. Pitavastatin is therefore the statin of choice for the ongoing largest trial (6500 participants) to test the benefits of statin therapy among HIV-infected adults.

Summary

Statins are underutilized in the prevention of CVD in HIV-infected populations based on criteria in established cholesterol guidelines. There is a potential role for statin therapy for HIV-infected patients who do not meet guideline criteria which will be further delineated through ongoing clinical trials.

     

C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus

Over 20 large-scale prospective studies show that the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) is an independent predictor of future cardiovascular events that additionally predicts risk of incident hypertension and diabetes. In many studies, the relative impact of hsCRP is at least as large as that individually of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, or smoking, and knowledge of hsCRP correctly reclassifies a substantial proportion of "intermediate-risk" individuals into clinically relevant higher- or lower-risk categories. Other studies show the relative benefit of statins to be greater among those with increased hsCRP and that achieved hsCRP levels after statin therapy predict recurrent event rates as much as achieved levels of low-density lipoprotein cholesterol. Nonetheless, it remains controversial whether the time has come to modify traditional algorithms used for global risk detection. As described here, 6 areas of controversy regarding hsCRP are resolvable with a consensus position that focuses in primary prevention on selective use among individuals with 5% to 20% 10-year risk as estimated by Adult Treatment Panel III, and focuses in secondary prevention on high-risk patients being treated with statin therapy. Forthcoming trial data could expand or contract this "screen selectively" policy, and investigators should be open to the possibility that second-generation inflammatory biomarkers may be developed that supplant hsCRP altogether. In the meantime, however, this consensus position on hsCRP should be one to which both advocates and critics of the inflammatory hypothesis of atherosclerosis can adhere because it is one that can immediately improve patient care.     

Are Cardiovascular Benefits in Statin Lipid Effects Dependent on Baseline Lipid Levels?

Statins reduce coronary heart disease (CHD) morbidity and mortality over a wide range of patients. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) in subjects with elevated C-reactive protein, without vascular disease and below average low-density lipoprotein cholesterol (LDL-C) showed a 50% reduction in LDL-C with 20 mg/d of rosuvastatin and a reduction in cardiovascular events (hazard ratio 0.56 [95% CI, 0.46–0.69]; P < 0.00001), and a reduction in total mortality (20%;P < 0.02). Recent commentary has criticized perceived JUPITER design flaws and inappropriate influence. However, the Canadian 2009 guidelines cite JUPITER as class I evidence for statin benefit. Although the Cholesterol Treatment Trialists’ (CTT) Collaborators showed that, regardless of pre-treatment levels, statins can significantly reduce CHD, major vascular events, and overall mortality, a recent primary prevention meta-analysis showed no decrease in all-cause mortality. Preconceived notions on statin benefit or harm do not enhance patient care and clinicians should individualize long-term statin therapy.     

Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study)

Patients at risk of coronary heart disease may not achieve recommended low-density lipoprotein (LDL) cholesterol goals on statin monotherapy. This study was designed to investigate the efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe 10 mg in patients at high risk of coronary heart disease. Four hundred sixty-nine patients were randomly assigned to rosuvastatin alone or in combination with ezetimibe for 6 weeks. The primary end point was the percentage of patients achieving the Adult Treatment Panel III (ATP III) LDL cholesterol goal (<100 mg/dl) at week 6. Secondary end points included the percentage of patients achieving other ATP III and 2003 European lipid goals, changes from baseline in lipid, lipoprotein, and inflammatory parameters, and safety and tolerability. Significantly more patients receiving rosuvastatin/ezetimibe than rosuvastatin alone achieved their ATP III LDL cholesterol goal (<100 mg/dl, 94.0% vs 79.1%, p <0.001) and the optional LDL cholesterol goal (<70 mg/dl) for very high-risk patients (79.6% vs 35.0%, p <0.001). The combination of rosuvastatin/ezetimibe reduced LDL cholesterol significantly more than rosuvastatin (-69.8% vs -57.1%, p <0.001). Other components of the lipid/lipoprotein profile were also significantly (p <0.001) improved with rosuvastatin/ezetimibe. Both treatments generally were well tolerated. Rosuvastatin 40 mg was effective at improving the atherogenic lipid profile in this high-risk population. Combination rosuvastatin with ezetimibe 10 mg enabled greater decreases in LDL cholesterol and allowed more patients to achieve LDL cholesterol goals. In conclusion, rosuvastatin plus ezetimibe may improve the management of high-risk patients who cannot achieve goal on maximal statin monotherapy.     

Evaluation of the National Cholesterol Education Program Adult Treatment Panel III algorithm for selecting candidates for statin therapy: insights from the A to Z trial

The National Cholesterol Education Program Adult Treatment Panel III recommends an algorithm to integrate iterative risk-stratification information with low-density lipoprotein (LDL) cholesterol levels to identify candidates for statin therapy. We used the Aggrastat to Zocor (A to Z) trial, in which all patients presented with an acute coronary syndrome (ACS) event in the absence of previous statin therapy, to evaluate the performance of this algorithm. Of 1,750 patients with ACS included in this analysis, 1,126 (64%) had an indication for statin therapy before enrollment and 624 (36%) did not have a statin indication before enrollment. We estimate that initiating statin therapy at moderate dosages (decreasing LDL by 1 mmol/L) according to the National Cholesterol Education Program Adult Treatment Panel III guidelines would have prevented approximately 15% of the ACS events leading to enrollment in the A to Z trial, whereas more intensive statin therapy (decreasing LDL by 1.5 mmol/L) would have prevented >21% of events. Aspirin use before enrollment was reported in only 38% of subjects with a statin indication. In conclusion, these observations represent missed opportunities for primary and secondary prevention and highlight the need for assessment of patient risk and better adherence to existing prevention guidelines.     

The Role of Statin Therapy for Primary Prevention: What is the Evidence?

Almost one third of annual worldwide mortality is attributed to cardiovascular disease (CVD), making it the leading cause of global death. Dyslipidemia is a well-established risk factor for CVD and plays a pivotal role in the pathogenesis of atherosclerosis. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower low-density lipoprotein cholesterol, have emerged as the most effective therapy to date against atherothrombotic CVD. Although their role in secondary prevention of CVD is undisputed, it remains a topic for debate as to how widely they should be used for primary prevention. The Framingham Risk Score and the National Cholesterol Education Program Adult Treatment Panel III guidelines are the cornerstones for the current guidelines for primary prevention statin therapy. Although these guidelines serve as help to evaluate cardiovascular risk and effectively identify many patients who will benefit from statin therapy, there is a growing population of “intermediate-risk” patients who may be undertreated. Additional noninvasive tests may complement the traditional risk scores, potentially expanding the indications for statins.     

Reducing the Threshold of Primary Prevention of Cardiovascular Disease to 10% Over 10 Years: The Implications of Altered Intensity “Statin” Therapy Guidance

Cardiovascular disease (CVD) is a significant noncommunicable disease associated with high long-term mortality. In addition to more effective secondary therapies, the primary prevention of CVD has developed markedly in the past several years. This study aims to investigate the evidence and impact of reducing the threshold for primary CVD risk management to 10% over 10 years with “statin” therapy. To conduct research a systematic review utilizing 5 electronic database searches was completed for studies, analyzing the clinical effect of reducing the threshold of CVD risk to 10% over 10 years for primary prevention with statin therapy. The study included six (6) trials. Statin therapy was allocated to 31,018 participants. The mean age was 61 years and the mean follow-up was 4.6 years. The mean relative reduction in total cholesterol was 19% (from an average of), low-density lipoprotein cholesterol was 28.3% (from mmol/L to mmol/L) and triglycerides were 14.8% (from mmol/L to mmol/L). High-density lipoprotein cholesterol was observed to increase by a mean of 3.3% (from mmol/L to mmol/L). When examining all-cause mortality, statin therapy was associated with a 12% relative risk reduction compared with control, where overall rates were reduced from 1.4% to 1. % There is a 30% risk reduction in general major coronary events (from to %). There is a 19% risk reduction in general major cerebrovascular events with the statin group. While there is undoubtedly statistical evidence that supports the observation of the effectiveness of statin therapy for primary prevention, there is a risk that many hundreds of patients need to be treated to avoid a single adverse clinical outcome.     

Lowering LDL cholesterol: questions from recent meta-analyses and subset analyses of clinical trial DataIssues from the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, ninth Council meeting

The benefit of cholesterol-lowering therapy in the prevention of coronary heart disease (CHD) is well established. The secondary prevention Scandinavian Simvastatin Survival Study (4S) and the primary prevention West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated that lipid lowering with a statin can dramatically and cost-effectively reduce CHD morbidity and mortality with no increase in noncardiovascular mortality. The Cholesterol and Recurrent Events (CARE) trial extended benefit to CHD patients without high cholesterol. Post hoc analyses of data from these large trials are contributing to speculation, driven by subset analyses and meta-analyses, about whether cholesterol intervention should be target based, as current guidelines recommend. Whereas CARE data support the importance of baseline LDL cholesterol (LDL-C), with greatest clinical event risk reduction in the upper part of the LDL-C range in the trial, 4S found no difference in outcome according to baseline LDL-C in a quartile analysis, and WOSCOPS found no linear relation between decrease in LDL-C and decrease in relative risk for CHD. Furthermore, WOSCOPS showed no additional clinical benefit with LDL-C lowering beyond approximately 24%. Questions raised by such analyses require answers from prospective, hypothesis-based data, and at present there is no compelling argument for moving away from LDL-C targets. The hypothesis-based findings of 4S, CARE, and WOSCOPS support current clinical guidelines, and lowering LDL-C may reduce risk more substantially than might have been predicted.     

Rosuvastatin alone or with extended-release niacin: a new therapeutic option for patients with combined hyperlipidemia

Combination therapy with a statin and niacin may provide optimal therapy for patients with combined hyperlipidemia and low levels of high-density lipoprotein (HDL) cholesterol. The authors assessed the efficacy and safety of rosuvastatin monotherapy, extended-release (ER) niacin monotherapy, or rosuvastatin and ER niacin combined therapy in patients with atherogenic dyslipidemia. In a 24-week, open-label, multicenter trial, men and women aged > or =18 years with fasting levels of total cholesterol > or =200 mg/dL, HDL cholesterol > or =45 mg/dL, triglycerides 200-800 mg/dL, and apolipoprotein B > or =110 mg/dL were randomly assigned to one of four treatment groups: rosuvastatin 10-40 mg, ER niacin 0.5-2 g, rosuvastatin 40 mg plus ER niacin 0.5-1 g, or rosuvastatin 10 mg plus ER niacin 0.5-2 g. Daily doses of rosuvastatin 40 mg monotherapy reduced low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol levels significantly more than did either ER niacin 2 g monotherapy or rosuvastatin 10 mg combined with ER niacin 2 g. Addition of ER niacin 1 g to rosuvastatin 40 mg did not further reduce total or non-HDL cholesterol. Triglyceride reductions were similar among the four treatment groups. ER niacin mono- and combined therapy produced significantly greater rises in HDL cholesterol and apolipoprotein A-1 than did rosuvastatin monotherapy. Rosuvastatin monotherapy was better tolerated than ER niacin taken either alone or with rosuvastatin. In this study, rosuvastatin very effectively improved the three major lipoprotein-lipid abnormalities of combined hyperlipidemia.     

High-sensitivity C-reactive protein and atherosclerotic disease: From improved risk prediction to risk-guided therapy

There is compelling experimental and clinical evidence suggesting a crucial role for inflammation in the initiation and also the progression of atherosclerosis. Numerous biomarkers involved at various levels of the inflammation cascade have been shown to be associated with adverse cardiovascular outcomes. Yet, to date, it is not clear whether inflammation simply accompanies the atherosclerotic process or represents a major driver. Among all blood biomarkers, C-reactive protein (CRP), the classical acute phase reactant that can be measured with high-sensitivity (hs) assays seems to be the most promising candidate. It has already found its way into the guidelines in primary prevention. Hs-CRP can also be used to identify a high-risk group for recurrent events in patients with manifest atherosclerosis. Several post hoc analyses of large-scale randomized clinical trials testing various statins have indicated that, besides low density lipoprotein (LDL) cholesterol, hs-CRP levels might also further aid in tailoring statin treatment. The large JUPITER trial has prospectively confirmed these findings in primary prevention in patients with elevated hs-CRP but normal LDL cholesterol levels. Still, statin therapy is not a specific anti-inflammatory regime acting on the inflammation cascade. Thus, to directly test the inflammation hypothesis, a novel, more proximally located cytokine-based approach is needed. Canakinumab, a fully human monoclonal antibody against interleukin-1β, might represent a promising compound in this regard and provide a proof of concept. If successful, this may become a novel strategy to treat high-risk patients with stable atherosclerotic disease to prevent recurrent events on top of standard medical care.     

Cardiometabolic Impact of Non-Statin Lipid Lowering Therapies

There is evidence from epidemiology, pathophysiology, and clinical trials that high LDL cholesterol levels cause atherosclerotic heart disease. Current guidelines recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk. The risk imposed by LDL cholesterol is modulated by the presence of additional risk factors such as age, smoking, and indices of inflammation. Epidemiologic studies as well as rare congenital conditions (e.g., hypobetalipoproteinemia) have shown that very low LDL cholesterol (lower than 70 mg/dL) levels are associated with a very low risk of cardiovascular disease. Analyses of randomized clinical trials have shown a greater benefit in reducing the risk of cardiovascular disease (without an increase in adverse events) among those with very low achieved LDL (below 40 mg/dL). In one study of patients with achieved LDL cholesterol below 30 mg/dL, there was no increase in the usual adverse events compared to patients with LDL cholesterol levels above 30 mg/dL. High-intensity statin therapy is associated with a higher rate of transaminase elevations, but no hepatic failure, a very small risk of myopathy, and an increased risk of developing diabetes. However, the small increase in the risk of developing diabetes is much smaller than the marked lowering of cardiovascular risk. The duration of statin therapy may be important in studies of primary prevention and early, probably low-dose statin therapy, may achieve primordial prevention of atherosclerotic disease.