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Table of Contents
Year : 2013  |  Volume : 17  |  Issue : 3  |  Page : 472-479

Dyslipidemic drugs in metabolic syndrome

1 Rajiv Gandhi Center for Diabetes and Endocrinology, JNMCH, Aligarh, India
2 Department of Pharmacology, Faculty of Medicine in Rabigh, King Abdul Aziz University, Jeddah, Saudi Arabia
3 Department of Pharmacology, JNMCH, Aligarh, India
4 Deparment of Pharmacology, School of Medicine, University of Western Sydney, Australia
5 Deparment of Biotechnology, AMU, Aligarh, India

Date of Web Publication10-May-2013

Correspondence Address:
Sheelu S Siddiqi
A-2 Sami Appartment, Nagla Road, Dodhpur, Aligarh - 202 002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2230-8210.111644

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Introduction: Metabolic syndrome predisposes to diabetes and atherosclerotic vascular disease. Statins reduce cardiovascular events, so all metabolic syndrome patients should be evaluated for dyslipidemia. Many patients fail to achieve lipid goals with statin monotherapy. Co-administration of ezetimibe (EZE) and atorvastatin (ATV) may enable more patients to achievelow-density lipoproteincholesterol (LDL-C) goal while avoiding risks of high-dose statin monotherapy. Materials and Methods: The present study compares rosuvastatin (Rsv) with a combination of (Atv) and (Eze). Metabolic syndrome patients, 30-70 years with LDL-C ≥130 mg/dl and a 10-year CHD risk score of 10% were randomized to double-blind treatment with (Rsv) 5 mg (n = 67) or (Atv) 10 mg+(Eze) 10 mg (n = 68) for 12 weeks. Results: LDL-C reduced significantly; (32.3% and 30.3%, P < 0.001) in (Atv)+(Eze) and (Rsv), respectively, but there was no significant difference between two arms. More patients achieved LDL-C goal of ≤100 mg/dl with (Atv)+(Eze) compared to (Rsv) (65% vs. 58%, P < 0.05). Triglycerides (TG) were reduced more with (Atv)+(Eze) compared to (Rsv) (28.1% and 21.4%, P < 0.001). Greater increase in high-density lipoprotein cholesterol (HDL-C) was observed with (Atv)+(Eze). Both treatments were well tolerated. Conclusion: This study shows that the combination of (Atv)+(Eze) has more efficacy and comparable safety to that of (Rsv).

Keywords: 3-hydroxy-3-methyglutaryl-CoA, reductase, insulin resistance syndrome, low-density lipoproteincholesterol, statins

How to cite this article:
Siddiqi SS, Misbahuddin, Ahmad F, Rahman SZ, Khan AU. Dyslipidemic drugs in metabolic syndrome. Indian J Endocr Metab 2013;17:472-9

How to cite this URL:
Siddiqi SS, Misbahuddin, Ahmad F, Rahman SZ, Khan AU. Dyslipidemic drugs in metabolic syndrome. Indian J Endocr Metab [serial online] 2013 [cited 2021 Sep 27];17:472-9. Available from: https://www.ijem.in/text.asp?2013/17/3/472/111644

   Introduction Top

The expert panel on detection, evaluation, and treatment of high blood cholesterol defined the metabolic syndrome as a constellation of metabolic derangements that includes insulin resistance, hypertension, dyslipidemia, central or visceral obesity, impaired glucose tolerance/impaired fasting glucose that is associated with increased risk for development of type 2 diabetes and atherosclerotic vascular disease. [1],[2],[3]

Metabolic syndrome is not limited to a particular region, it has engulfed wide regions of the world and the problem is increasing at a rapid pace due to sedentary lifestyle, rapid urbanization, abnormal eating habits and behavioral changes. So it is imperative to search for the best therapy to reduce the burden of the disease.

South Asians are more predisposed to develop type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). [4],[5] Clustering of cardiovascular risk factors in South Asians was initially reported from UK. [6],[7] Since then, a number of investigators have reported a high prevalence of the metabolic syndrome in South Asian populations settled in other countries. Prevalence of the metabolic syndrome as defined by National Cholesterol Education Program, adult treatment panel III (NCEP, ATP III) [1] and other criteria ranges from about 11% to 41% in different regions of India. [8],[9],[10],[11],[12],[13]

The atherogenic dyslipidemia associated with the metabolic syndrome is characterized by low concentrations of high-density lipoprotein cholesterol (HDL-C), increased levels of triglyceride (TG); and preponderance of small low-density lipoprotein cholesterol (LDL-C) particles. [14] Many patients may also have raised LDL-C, which increases the risk of cardiovascular events. [15]

Statins are the most effective and best-tolerated agents for treating dyslipidemia and they are recognized as first-line therapy for lowering of cholesterol levels. [14],[16],[17],[18],[19] By reducing LDL cholesterol and triglyceride levels and increasing HDL cholesterol, [20] they have shown to reduce cardiovascular morbidity and mortality in large outcome trials in various populations. [21],[22],[23],[24],[25],[26] Moreover, statins have 'pleiotropic' effects, such as reducing oxidative stress and modulating inflammatory responses, [27] and these effects may improve other risk factors associated with the metabolic syndrome. Evidence suggests that High sensitive C-reactive protein, an inflammatory biomarker is a strong, independent predictor and associated with an increased risk of cardiovascular events. [28],[29],[30],[31],[32],[33],[34],[35],[36],[37] Recently conducted Justification for the use of Statins in Primary Prevention and Intervention Trial Evaluating Rosuvastatin Trial, trial has shown that rosuvastatin (Rsv) significantly reduced the incidence of major cardiovascular events even in apparently healthy population with LDL <130 mg/dl by reducing hs-CRP. Since metabolic syndrome is a pro-inflammatory state, the patients should be evaluated for statin therapy.

A large international, prospective, randomized trial, the Comparative study with Rosuvastatin in Subjects with Metabolic Syndrome study [38] and some other studies have shown that statins can improve lipid levels in patients with the metabolic syndrome. [39],[40],[41],[42] Because of the increased Cardiovascular Disease (CVD) risk associated with the metabolic syndrome and extensive clinical trial evidence documenting reduction of CVD risk with statin treatment, all patients with the metabolic syndrome should be evaluated as candidates for statin treatment as part of a multidisciplinary approach to reduce CVD risk. [43]

Despite the proven benefits of statin therapy, many patients fail to achieve lipid goals in clinical practice. [44],[45],[46],[47],[48] This may be due to inappropriate dosing of statins, increased risk of adverse effects (myopathy and hepatotoxicity) with high-dose statin monotherapy, and insufficient LDL-C-lowering efficacy of current drugs. [49],[50],[51] With recent focus on more aggressive treatment guidelines and inability of the high-risk patients to reach their target LDL-C goals with currently available lipid-lowering agents, a search for new therapies or combination therapies with improved efficacy and safety is imperative.

Co-administration of ezetimibe (EZE) with atorvastatin (ATV) may enable more patients to achieve LDL-C goals while avoiding the risks associated with high-dose statin monotherapy through dual inhibition of intestinal cholesterol absorption (EZE) and cholesterol biosynthesis (statin). In previous studies, EZE+ATV co-administration therapy was shown to produce significant incremental reductions in LDL-C with no increased risk of adverse effects compared with ATV alone in patients with raised cholesterol. [52],[53],[54]

The present study is the first study designed to evaluate the lipid-lowering effect of a newer statin, Rsv versus a combination of ATV and EZE in patients with metabolic syndrome in the Indian population. Rsv has shown to be more efficacious than ATV in the previous studies, however, the combination of ATV and EZE has also shown to produce significant reduction in LDL-C when compared to ATV alone, with no increased risk of adverse effects, enabling more patients to achieve LDL-C goals, while avoiding the risks associated with high-dose statin monotherapy. This study is designed keeping in mind the search for a better alternative in the patients with metabolic syndrome and dyslipidemia.

   Materials and Methods Top

Study design

This is a randomized, double-blind, parallel group study comparing the efficacy and safety of Rsv versus a combination of ATV and EZE in the patients with metabolic syndrome, conducted at an Indian tertiary care government teaching hospital. After institutional ethics committee approval and written informed consent, patients meeting the inclusion and exclusion criteria at enrolment entered a 6-week dietary run-in period, in which they were recommended the NCEP ATP III therapeutic life-style-change diet and all lipid-lowering therapy was withdrawn at least 14 days before the end of this period. Eligible patients were then randomized to receive Rsv 5 mg or ATV+EZE (10/10 mg) for 12 weeks [Figure 1].
Figure 1: The study of population flowchart

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{Figure 1}

Concomitant medications like erythromycin, azole antifungals, vitamin K antagonists, immunosuppressives, glitazones, systemic steroids or any medication interacting with the statin metabolism was not permitted during the study. The patient was discontinued from the trial, if the patient took lipid-lowering medication (other than the medication understudy).

Study population

Patients (male or female) ≥18 years were eligible for the study if they had metabolic syndrome as defined by the presence of at least three of the following: Abdominal obesity (waist circumference >102 cm for men and >88 cm for women); TG ≥1.70 mmol/L (150 mg/dL); HDL-C <1.04 mmol/L (40 mg/dL) for men and <1.30 mmol/L (50 mg/dL) for women; Blood Pressure ≥130/85 mmHg or receiving antihypertensive treatment; and Fasting blood glucose ≥6.11 mmol/L (110 mg/dL). [1] Patients were also required to have LDL-C ≥3.36 mmol/L (130 mg/dL) and additional multiple risk factors conferring a 10-year CHD risk score of >10%. The exclusion criteria included the following: Use of lipid-lowering agents within the past 6 months; TG ≥5.65 mmol/L (500 mg/dL); LDL-C ≥6.48 mmol/L (250 mg/dL); Documented history of CHD or other atherosclerotic disease; A history of known familial hypercholesterolemia; A history of serious or hypersensitivity reactions to other statins; Uncontrolled hypothyroidism; Uncontrolled hypertension; Acute liver disease or hepatic dysfunction [hepatic transaminases or bilirubin ≥1.5× the upper limit of normal (ULN)];unexplained serum creatine kinase (CK)>3× ULN; and use of prohibited concomitant medications.

Endpoint assessments


Blood samples were collected at6 weeks (beginning of the dietary lead-in period), 0 weeks (randomization) and 12 weeks. The primary efficacy variable was percentage change in LDL-C from baseline levels to 12 weeks of treatment (Rsv 10 mg vs. ATV+EZE 10/10 mg). Secondary endpoints included: Percentage of patients achieving the LDL-C goal of <2.59 mmol/L (100 mg/dL) at 12 weeks; percentage change in total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) from baseline to 12 weeks.

Safety and tolerability

Adverse events reported spontaneously by the patients, revealed by observation or elicited in response to an open question, were recorded. Laboratory safety variables included: Hemoglobin, platelet count, leucocyte count, serum aspartate aminotransferase (ASAT), serum alanine aminotransferase (ALAT), serum alkaline phosphatase, serum bilirubin, CK and serum creatinine. Pre-specified safety variables included the incidence of ALT and AST elevations ≥3 times ULN and CK elevations of 5-10 with muscle symptoms or ≥10 times ULN with or without muscle symptoms. Myopathy was prospectively defined as CK elevations ≥10 times ULN associated with muscle symptoms with no other plausible etiology such as exercise or trauma. Causality assessment of all the adverse events was done according to Naranjo scale. [55]

Laboratory methods

Lipids in total serum were measured using automated enzymatic methods. TC was measured by CHOD-PAP method [56] by a commercially available kit. HDL-C was measured by PEG-PAP method [57] by a commercially available kit. TG was measured by enzymatic Glycerol Phosphate Oxidase-Phenol+Aminophenazone (GPO-PAP) method [58] by a commercially available kit from Pointe Scientific Inc, USA. LDL-C is calculated using Friedewald's equation. [59] All other analyses were performed at the central laboratory.

Statistical analysis

To detect a clinically significant difference of 6% in the primary endpoint, i.e., mean percentage change in LDL-C from baseline to 12 weeks between ATV+EZE (10/10) mg and Rsv (5) mg; with a power of 90%, significance level of 5%, and a standard deviation of 10, a total of 59 patients per active treatment arm were required. Assuming a withdrawal rate of 10%, approximately 65 patients per treatment arm would need to be randomized using a ratio of 1:1. Efficacy data was evaluated on the basis of the intention-to-treat (ITT) populations, which consisted of all patients with at least one dose of study medication, a baseline reading, and at least one post-baseline assessment for one or more lipid variables in the randomized treatment period. Last observation carried forward (LOCF) was used on the ITT population for patients with missing data. Efficacy endpoint analysis was done by Students' independent t-test. The proportion of patients reaching the LDL-C goal of ≤100 mg/dl was analyzed using a Mantel-Haenszel test. Safety data were evaluated for all patients who received at least one dose of study medication.

   Results Top

Patient demographics

A total of 507 patients were screened; of which183 met the eligibility criteria and were enrolled for the dietary lead-in period. Out of this, 48 patients discontinued before randomization for various reasons like consent withdrawal, protocol violation, lost to follow-up etc., so the ITT population consisted of 135 patients [Figure 2]. Three patients from the Atv+Eze group and 4 from Rsv discontinued after randomization, so 128 patients completed the study. [Table 1] shows the demographics and baseline characteristics of the population. Both the groups were well matched.
Figure 2: Study design

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Table 1: Baseline characteristics of the ITT population

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{Figure 2}


[Table 2] shows the mean reduction in lipids at the end of 12 weeks; there was no significant difference in the percentage of LDL-C reduction between the two arms (32.3% vs. 30.3%, P > 0.05). There was also no significant difference (-3.5%, P > 0.05) regarding the percentage of TC reduction between the two arms. Both treatments increased the HDL-C level; with Atv+Eze more than Rsv group (8% vs. 3.9%) but the difference between them was not significant. Atv+Eze combination arm was significantly better than Rsv arm with reference to triglyceride and VLDL reduction (-6.7%, P < 0.05). The total percentage of patients reaching the LDL-C goal of ≤100 mg/dl was 61.7%. More patients in the Atv+Eze combination group reached the goal (65% vs. 58.3%), but this was not statistically significant. Moreover, the overall percentage of females reaching the goal was greater than males (66% vs. 56%).
Table 2: Mean percentage change in efficacy parameters from baseline to 12 weeks

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[Table 3] shows the adverse events in the treatment groups. Both the treatments were well tolerated. A total of 19.1% of the patients from Atv+Eze combination arm and 16.4% from Rsv arm experienced the events. There was no significant difference between the two arms. All the adverse events except one were in the "doubtful" or "probable" (Naranjo 0 to +2) category based on Naranjo scale. Severity was also 0 (no disability) to 1 (minor temporary) The Adverse Drug Reaction profile of both the groups was similar. The Liver Function Test (LFT), Renal Function Test (RFT), hemogramand platelet counts were within the normal limits in both the groups after 12 weeks. The most frequent adverse events were headache and loose stools which were unrelated to the medication under study. No patient in the Atv+Eze arm experienced any Side effect related to treatment but one patient in the Rsv arm experienced serious adverse event (myalgia) related to treatment causing withdrawal from the study. In this case also, there was no clinically important elevation of CK >5× ULN or any associated muscle symptoms.
Table 3: Number and percentage of patients with adverse events

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   Discussion Top

The problem of metabolic syndrome is increasing day by day in India; the South Asian population is more prone to develop diabetes and CHD. [4],[5] India especially is becoming the diabetes capital of the world. The statins are the most effective and best-tolerated agents for treating dyslipidemia and they are recognized as first-line therapy for lowering cholesterol levels. [14],[16],[17],[18],[19] Moreover, they also have pleiotropic effects which are beneficial in metabolic syndrome pathophysiology. Recent guidelines call for a more aggressive lipid lowering but still, many patients on statin monotherapy fail to achieve the optimum lipid goals. Further, the statins demonstrate only an additional 6% reduction in LDL-C for every doubling of the dose, while side-effects increase linearly with dose. This is the first study evaluating the efficacy and safety of Rsv versus a combination of ATVand EZE in patients with metabolic syndrome in the Indian population.

Results of this study show that there is no significant difference in LDL-C reduction between the two treatment arms. Many previous studies have shown a superiority of Rsv over ATV [42],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69] but when EZE is combined with ATV, we found no significant difference (32.3% vs. 30.3%, P > 0.05). This finding is consistent with the previous studies where EZE+ATV co-administration therapy was shown to produce significant incremental reductions in LDL-C with no increased risk of adverse effects when compared with ATV alone in patients with raised cholesterol. [52],[53],[54],[70],[71],[72] This may be due to dual inhibition of intestinal cholesterol absorption by EZE and cholesterol biosynthesis by ATV. High levels of HDL-C are considered to be good for CHD; in this study, both the treatment arms increased the HDL-C level but there was no significant difference between both the arms. As seen in the table, there is a significant difference in Triglyceride reduction between the two arms with Atv+Eze combination decreasing more than Rsv. EZE interferes with absorption of dietary cholesterol/TG at the intestinal brush border (exogenous pathway), thus decreasing their level. Other parameters like TC are reduced by both treatments but with no significant difference. In previous studies, patients on Rsv have consistently shown to reach target lipid goals more than ATV; but in our study, more patients in the combination arm reached the goal. Reason is the same as explained previously. Moreover, the overall percentage of females reaching the goal is higher which is consistent with previous studies but there was no subgroup-by -treatment interaction when data were stratified by age-group, baseline LDL-C levels and BMI (body mass index).

Both the therapies were well tolerated in this high-risk population. Major concerns with statin therapy include the rare occurrence of serious muscle-related adverse events (myopathy and rhabdomyolysis) and the potential for elevating serum transaminases. [73],[74] There were no clinically significant differences between EZE+ATV combination therapy and RSV with regard to the incidence of any clinical or laboratory adverse event. Safety of both the regimens has been established previously. [54],[71],[75],[76],[77]

We have chosen the minimal dose recommended for Asian population which might be the reason for absence of any serious event. Compliance of both regimens was good as the both were given once daily.

   Conclusion Top

Co-administration of EZE with statin is a treatment strategy that targets both the synthesis and intestinal absorption of cholesterol. It has been shown to produce significant incremental reductions in LDL-C beyond that achieved by either agent alone. [70],[71],[72],[78] This treatment regimen may be especially advantageous for CHD patients who frequently fail to attain optimal LDL-C levels with the highest doses of the most effective statins on one hand and minimizing adverse events on the other. In our study, the combination therapy is found to be equally safe and compliant, reducing the TG more than Rsv, and enabling more patients to reach the lipid goal.

   References Top

1.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.  Back to cited text no. 1
2.Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16.  Back to cited text no. 2
3.Ginsberg HN, Stalenhoef AF. The metabolic syndrome: Targeting dyslipidaemia to reduce coronary risk. J Cardiovasc Risk 2003;10:121-8.  Back to cited text no. 3
4.King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: Prevalence, numerical estimates, and projections. Diabetes Care 1998;21:1414-31.  Back to cited text no. 4
5.Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998;97:596-601.  Back to cited text no. 5
6.McKeigue PM, Pierpoint T, Ferrie JE, Marmot MG. Relationship of glucose intolerance and hyperinsulinaemia to body fat pattern in south Asians and Europeans. Diabetologia 1992;35:785-91.  Back to cited text no. 6
7.McKeigue PM, Marmot MG, Syndercombe Court YD, Cottier DE, Rahman S, Riemersma RA. Diabetes, hyperinsulinaemia, and coronary risk factors in Bangladeshis in east London. Br Heart J 1988;60:390-6.  Back to cited text no. 7
8.Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroja R, et al. Intra-urban differences in the prevalence of the metabolic syndrome in southern India - the Chennai Urban Population Study (CUPS No. 4). Diabet Med 2001;18:280-7.  Back to cited text no. 8
9.Gupta A, Gupta R, Sarna M, Rastogi S, Gupta VP, Kothari K. Prevalence of diabetes, impaired fasting glucose and insulin resistance syndrome in an urban Indian population. Diabetes Res Clin Pract 2003;61:69-76.  Back to cited text no. 9
10.Deepa R, Shanthirani CS, Premalatha G, Sastry NG, Mohan V. Prevalence of insulin resistance syndrome in a selected south Indian population -the Chennai urban population study-7 [CUPS-7]. Indian J Med Res2002;115:118-27.  Back to cited text no. 10
11.Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome in urban Asian Indian adults-a population study using modified ATP III criteria. Diabetes Res Clin Pract 2003;60:199-204.  Back to cited text no. 11
12.Misra A, Pandey RM, Devi JR, Sharma R, Vikram NK, Khanna N. High prevalence of diabetes, obesity and dyslipidaemia in urban slum population in northern India. Int J Obes Relat Metab Disord 2001;25:1722-9.  Back to cited text no. 12
13.Misra A, Vikram NK, Arya S, Pandey RM, Dhingra V, Chatterjee A, et al. High prevalence of insulin resistance in postpubertal Asian Indian children is associated with adverse truncal body fat patterning, abdominal adiposity and excess body fat. Int J Obes Relat Metab Disord 2004;28:1217-26.  Back to cited text no. 13
14.Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 1999;83:25F-9F.  Back to cited text no. 14
15.LaRosa JC, Hunninghake D, Bush D, Criqui MH, Getz GS, Gotto AM Jr, et al. The cholesterol facts. A summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. A joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute. The Task Force on Cholesterol Issues, American Heart Association. Circulation 1990;81:1721-33.  Back to cited text no. 15
16.Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J 1998;19:1434-503.  Back to cited text no. 16
17.A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1999. Diabet Med 1999;16:716-30.  Back to cited text no. 17
18.De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice: Third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil 2003;10:S1-10.  Back to cited text no. 18
19.American Diabetes Association: Management of Dyslipidemia in Adults With Diabetes. Diabetes Care 2002;25:s74-7.  Back to cited text no. 19
20.Sowers JR. Effects of statins on the vasculature: Implications for aggressive lipid management in the cardiovascular metabolic syndrome. Am J Cardiol 2003;91:14B-22B.  Back to cited text no. 20
21.Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S) Lancet 1994;344:1383-9.  Back to cited text no. 21
22.Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med1995;333:1301-7.  Back to cited text no. 22
23.Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-9.  Back to cited text no. 23
24.Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339:1349-57.  Back to cited text no. 24
25.Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22.  Back to cited text no. 25
26.Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentrerandomised controlled trial. Lancet 2003;361:1149-58.  Back to cited text no. 26
27.Liao JK. Beyond lipid lowering: The role of statins in vascular protection. Int J Cardiol 2002;86:5-18.  Back to cited text no. 27
28.Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003;107:363-9.  Back to cited text no. 28
29.Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9.  Back to cited text no. 29
30.Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-43.  Back to cited text no. 30
31.Koenig W, Sund M, Fröhlich M, Fischer HG, Löwel H, Döring A, et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: Results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 1999;99:237-42.  Back to cited text no. 31
32.Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002;347:1557-65.  Back to cited text no. 32
33.Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: A comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein (a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481-5.  Back to cited text no. 33
34.Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, et al. Low grade inflammation and coronary heart disease: Prospective study and updated meta-analyses. BMJ 2000;321:199-204.  Back to cited text no. 34
35.Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler ThrombVasc Biol 1997;17:1121-7.  Back to cited text no. 35
36.Albert CM, Ma J, Rifai N, Stampfer MJ, Ridker PM. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 2002;105:2595-9.  Back to cited text no. 36
37.Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;144:537-47.  Back to cited text no. 37
38.Stalenhoef AF, Ballantyne CM, Sarti C, Murin J, Tonstad S, Rose H, et al. A comparative study with rosuvastatin in subjects with metabolic syndrome: Results of the COMETS study. Eur Heart J 2005;26:2664-72.  Back to cited text no. 38
39.Hunninghake DB, Ballantyne CM, Maccubbin DL, Shah AK, Gumbiner B, Mitchel YB. Comparative effects of simvastatin and atorvastatin in hypercholesterolemic patients with characteristics of metabolic syndrome. ClinTher 2003;25:1670-86.  Back to cited text no. 39
40.Ballantyne CM, Stein EA, Paoletti R, Southworth H, Blasetto JW. Efficacy of rosuvastatin 10 mg in patients with the metabolic syndrome. Am J Cardiol 2003;91:25C-7C; discussion 28C.  Back to cited text no. 40
41.Stender S, Schuster H, Barter P, Watkins C, Kallend D, MERCURY I Study Group. Comparison of rosuvastatin with atorvastatin, simvastatin and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholesterolaemic patients with or without the metabolic syndrome in the MERCURY I trial. Diabetes Obes Metab 2005;7:430-8.  Back to cited text no. 41
42.Deedwania PC, Hunninghake DB, Bays HE, Jones PH, Cain VA, Blasetto JW, et al. Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome. Am J Cardiol 2005;95:360-6.  Back to cited text no. 42
43.Lundbye JB, Thompson PD. Statin use in the metabolic syndrome. Curr Atheroscler Rep 2005;7:17-21.  Back to cited text no. 43
44.del Cañizo-Gómez FJ, Moreira-Andrés MN. Cardiovascular risk factors in patients with type 2 diabetes. Do we follow the guidelines? Diabetes Res ClinPract 2004;65:125-33.  Back to cited text no. 44
45.Betteridge JD, Leiter LA, AUDIT Investigators: The AUDIT Study: Regional variations in physicians attitudes to diabetic dyslipidaemia. Diabetologia2004;47:A73.  Back to cited text no. 45
46.Pearson TA. The undertreatment of LDL-cholesterol: Addressing the challenge. Int J Cardiol 2000;74:S23-8.  Back to cited text no. 46
47.EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries; principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J 2001;22:554-72.  Back to cited text no. 47
48.Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459-67.  Back to cited text no. 48
49.Anonymous. Cholesterol rethink for high-risk patients. Med Lett Drugs Ther 2004;46:37-9.  Back to cited text no. 49
50.Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug Saf 1998;19:355-71.  Back to cited text no. 50
51.Hoerger TJ, Bala MV, Bray JW, Wilcosky TC, LaRosa J. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82:61-5.  Back to cited text no. 51
52.Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, et al. Effect of ezetimibecoadministered with atorvastatin in 628 patients with primary hypercholesterolemia: A prospective, randomized, double-blind trial. Circulation 2003;107:2409-15.  Back to cited text no. 52
53.Ballantyne CM, Blazing MA, King TR, Brady WE, Palmisano J. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. Am J Cardiol 2004;93:1487-94.  Back to cited text no. 53
54.Gagné C, Gaudet D, Bruckert E. Ezetimibe Study Group. Efficacy and safety of ezetimibecoadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-75.  Back to cited text no. 54
55.Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 55
56.Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470-5.  Back to cited text no. 56
57.Izzo C, Grillo F, Murador E. Improved method for determination of high-density-lipoprotein cholesterol I. Isolation of high-density lipoproteins by use of polyethylene glycol 6000. Clin Chem 1981;27:371-4.  Back to cited text no. 57
58.McGowan MW, Artiss JD, Strandbergh DR, Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem 1983;29:538-42.  Back to cited text no. 58
59.Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.  Back to cited text no. 59
60.Brown WV, Chitra RR, Zedler BK, Bays HE, Hassman HA. Long term efficacy and safety of rosuvastatin: Results of a 52 week comparator-controlled trial versus pravastatin and simvastatin [abstract] Eur Heart J 2001;22:270.  Back to cited text no. 60
61.Olsson AG, Southworth H, Wilpshaar JW. Long term efficacy and safety of rosuvastatin: Results of a 52 week comparator-controlled trial versus Atorvastatin [abstract] Eur Heart J 2001;22:253.  Back to cited text no. 61
62.Davidson M, Ma P, Stein EA, Gotto AM Jr, Raza A, Chitra R, et al. Comparision of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268-75  Back to cited text no. 62
63.Berne C, Siewert-Delle A, URANUS study investigators. Comparison of rosuvastatin and atorvastatin for lipid lowering in patients with type 2 diabetes mellitus: Results from the URANUS study. Cardiovasc Diabetol 2005;4:7.  Back to cited text no. 63
64.Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92:152-60.  Back to cited text no. 64
65.Schuster H, Barter PJ, Stender S, Cheung RC, Bonnet J, Morrell JM, et al. Effects of switching statins on achievement of lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Am Heart J 2004;147:705-13.  Back to cited text no. 65
66.Deedwania PC, Gupta M, Stein M, Ycas J, Gold A, IRIS Study Group. Comparison of rosuvastatin versus atorvastatin in South-Asian patients at risk of coronary heart disease (from the IRIS Trial). Am J Cardiol 2007;99:1538-43.  Back to cited text no. 66
67.Saito Y, Yamada N, Shirai K, Sasaki J, Ebihara Y, Yanase T, et al. Effect of rosuvastatin 5-20mg on triglycerides and other lipid parameters in Japanese patients with hypertriglyceridemia. Atherosclerosis 2007;194:505-11.  Back to cited text no. 67
68.Strandberg TE, Feely J, Sigurdsson EL, DISCOVERY study group. Twelve-week, multicenter, randomized, open-label comparison of the effects of rosuvastatin 10 mg/d and atorvastatin 10 mg/d in high-risk adults: A discovery study. Clin Ther 2004;26:1821-33.  Back to cited text no. 68
69.Clearfield MB, Amerena J, Bassand JP, Hernández García HR, Miller SS, Sosef FF, et al. Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia-Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR). Trials 2006;7:35.  Back to cited text no. 69
70.Pearson TA, Denke MA, McBride PE, Battisti WP, Brady WE, Palmisano J. A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: The ezetimibe add-on to statin for effectiveness (EASE) trial. Mayo Clin Proc 2005;80:587-95.  Back to cited text no. 70
71.Gagné C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084-91.  Back to cited text no. 71
72.Davidson MH, Ballantyne CM, Kerzner B, Melani L, Sager PT, Lipka L, et al. Efficacy and safety of ezetimibecoadministered with statins: Randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Int J Clin Pract 2004;58:746-55.  Back to cited text no. 72
73.Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995;52:1639-45.  Back to cited text no. 73
74.Tomlinson B, Chan P, Lan W. How well tolerated are lipid-lowering drugs? Drugs Aging 2001;18:665-83.  Back to cited text no. 74
75.Simons L, Tonkon M, Masana L, Maccubbin D, Shah A, Lee M, et al. Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome. Curr Med Res Opin 2004;20:1437-45.  Back to cited text no. 75
76.Bernini F, Poli A, Paoletti R. Safety of HMG-CoA reductase inhibitors: Focus on atorvastatin. Cardiovasc Drugs Ther 2001;15:211-8.  Back to cited text no. 76
77.Shepherd J, Hunninghake DB, Stein EA, Kastelein JJ, Harris S, Pears J, et al. Safety of rosuvastatin. Am J Cardiol 2004;94:882-8.  Back to cited text no. 77
78.Ballantyne CM, Lipka LJ, Sager PT, Strony J, Alizadeh J, Suresh R, et al. Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia. Int J ClinPract 2004;58:653-8.  Back to cited text no. 78


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