Type IIa Hypercholesterolemia Research Articles

A Case Report of Giant Tuberous Xanthoma with Type IIa Familial Hypercholesterolemia

Abstract Tuberous xanthomas are nontender, yellow to red papules to nodules that occur on the extensor surface, and trauma-prone areas such as the elbows, knees, Achilles tendon, and buttocks. A 10-year-old female child born out of second-degree consanguineous marriage presented with multiple skin-colored nodular lesions on axillary folds, both elbows, cubital fossa, medial side of the wrist, interphalangeal joints, buttocks, knees, popliteal fossa, and Achilles tendons. After complete evaluation, diagnosis of familial hypercholesterolemia type IIa with tuberous xanthoma was made. Tuberous xanthoma usually presents in combined type III dyslipidemias, but in our case, it is presented in type IIa familial hypercholesterolemia. Early diagnosis and treatment of familial hypercholesterolemia are important for preventing complications.

Plasminogen Deficiency Significantly Reduces Vascular Wall Disease in a Murine Model of Type IIa Hypercholesterolemia.

The fibrinolytic system has been implicated in the genesis and progression of atherosclerosis. It has been reported that a plasminogen (Pg) deficiency (Plg−/−) exacerbates the progression of atherosclerosis in Apoe−/− mice. However, the manner in which Plg functions in a low-density lipoprotein-cholesterol (LDL-C)-driven model has not been evaluated. To characterize the effect of Pg in an LDL-C-driven model, mice with a triple deficiency of the LDL-receptor (LDLr), along with the active component (apobec1) of the apolipoprotein B editosome complex, and Pg (L−/−/A−/−/Plg−/−), were generated. Atherosclerotic plaque formation was severely retarded in the absence of Pg. In vitro studies demonstrated that LDL uptake by macrophages was enhanced by plasmin (Pm), whereas circulating levels of LDL were enhanced, relative to L−/−/A−/− mice, and VLDL synthesis was suppressed. These results indicated that clearance of lipoproteins in the absence of LDLr may be regulated by Pg/Pm. Conclusions: The results from this study indicate that Pg exacerbates atherosclerosis in an LDL-C model of atherosclerosis and also plays a role in lipoprotein modification and clearance. Therefore, controlling the Pg system on macrophages to prevent foam cell formation would be a novel therapeutic approach.

Evaluation of the efficacy of plant sterols supplement sterolip® ESI in patients with type IIA hypercholesterolemia in relation to Genetic variants modulating intestinal absorption of cholesterol

Background and aim: Phytosterols (PS) are recommended by European Guidelines for the treatment of hypercholesterolemia. This study aims to evaluate the lipid-lowering activity of a PS supplement (STEROLIP® ESI) in subjects with hypercholesterolemia and the influence of genetic variants involved in cholesterol absorption in the modulation of the individual response to PS.

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Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection

BackgroundFamilial hypercholesterolemia type IIA (FH) is due to mutations in the low-density lipoprotein receptor (LDLR) resulting in elevated levels of low-density lipoprotein cholesterol (LDL-c) in plasma and in premature cardiovascular diseases. As hepatocytes are the only cells capable of metabolizing cholesterol, they are therefore the target cells for cell/gene therapy approaches in the treatment of lipid metabolism disorders. Furthermore, the LDLR has been reported to be involved in hepatitis C virus (HCV) entry into hepatocytes; however, its role in the virus infection cycle is still disputed.MethodsWe generated induced pluripotent stem cells (iPSCs) from a homozygous LDLR-null FH-patient (FH-iPSCs). We constructed a correction cassette bearing LDLR cDNA under the control of human hepatic apolipoprotein A2 promoter that targets the adeno-associated virus integration site AAVS1. We differentiated both FH-iPSCs and corrected FH-iPSCs (corr-FH-iPSCs) into hepatocytes to study statin-mediated regulation of genes involved in cholesterol metabolism. Upon HCV particle inoculation, viral replication and production were quantified in these cells.ResultsWe showed that FH-iPSCs displayed the disease phenotype. Using homologous recombination mediated by the CRISPR/Cas9 system, FH-iPSCs were genetically corrected by the targeted integration of a correction cassette at the AAVS1 locus. Both FH-iPSCs and corr-FH-iPSCs were then differentiated into functional polarized hepatocytes using a stepwise differentiation approach (FH-iHeps and corr-FH-iHeps). The correct insertion and expression of the correction cassette resulted in restoration of LDLR expression and function (LDL-c uptake) in corr-FH-iHeps. We next demonstrated that pravastatin treatment increased the expression of genes involved in cholesterol metabolism in both cell models. Moreover, LDLR expression and function were also enhanced in corr-FH-iHeps after pravastatin treatment. Finally, we demonstrated that both FH-iHeps and corr-FH-iHeps were as permissive to viral infection as primary human hepatocytes but that virus production in FH-iHeps was significantly decreased compared to corr-FH-iHeps, suggesting a role of the LDLR in HCV morphogenesis.ConclusionsOur work provides the first LDLR-null FH cell model and its corrected counterpart to study the regulation of cholesterol metabolism and host determinants of HCV life cycle, and a platform to screen drugs for treating dyslipidemia and HCV infection.

Foam cell formation is regulated by plasmin in a murine model of type IIa hypercholesterolemia

Foam cell formation is regulated by plasmin in a murine model of type IIa hypercholesterolemia

The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine

Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic α cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and ARG1 sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the Gcgr−/− knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in GCGR. Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease.

Improved Hepatocyte Engraftment after Portal Vein Occlusion in LDL Receptor-Deficient WHHL Rabbits and Lentiviral-Mediated Phenotypic Correction in Vitro

Innovative cell-based therapies are considered as alternatives to liver transplantation. Recent progress in lentivirus-mediated hepatocyte transduction has renewed interest in cell therapy for the treatment of inherited liver diseases. However, hepatocyte transplantation is still hampered by inefficient hepatocyte engraftment. We previously showed that partial portal vein embolization (PVE) improved hepatocyte engraftment in a nonhuman primate model. We developed here an ex vivo approach based on PVE and lentiviral-mediated transduction of hepatocytes from normal (New Zealand White, NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbits: the large animal model of familial hypercholesterolemia type IIa (FH). FH is a life-threatening human inherited autosomal disease caused by a mutation in the low-density lipoprotein receptor (LDLR) gene, which leads to severe hypercholesterolemia and premature coronary heart disease. Rabbit hepatocytes were isolated from the resected left liver lobe, and the portal branches of the median lobes were embolized with Histoacryl® glue under radiologic guidance. NZW and WHHL hepatocytes were each labeled with Hoechst dye or transduced with lentivirus expressing GFP under the control of a liver-specific promoter (mTTR, a modified murine transthyretin promoter) and were then immediately transplanted back into donor animals. In our conditions, 65-70% of the NZW and WHHL hepatocytes were transduced. Liver repopulation after transplantation with the Hoechst-labeled hepatocytes was 3.5 ± 2%. It was 1.4 ± 0.6% after transplantation with either the transduced NZW hepatocytes or the transduced WHHL hepatocytes, which was close to that obtained with Hoechst-labeled cells, given the mean transduction efficacy. Transgene expression persisted for at least 8 weeks posttransplantation. Transduction of WHHL hepatocytes with an LDLR-encoding vector resulted in phenotypic correction in vitro as assessed by internalization of fluorescent LDL ligands. In conclusion, our results have applications for the treatment of inherited metabolic liver diseases, such as FH, by transplantation of lentivirally transduced hepatocytes.

Diagnosis Scoring for Clinical Identification of Children With Heterozygous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a frequent monogenic condition characterized by progressive atherosclerosis requiring preventive therapy from childhood. In a pediatric setting, heterozygous FH (hFH) in children may not be identified from common forms of hypercholesterolemia (HC). To elaborate a clinical scoring system for the diagnosis of hFH, defined by the presence of a disease-causing mutation of the gene for the low-density lipoprotein receptor (LDLR). A total of 100 unrelated children (6 +/-3 years old, 43 boys, 57 girls) with type IIa HC (LDLC >130 mg/dL) and complete genetic testing (at loci for genes for LDLR, apolipoprotein B, proprotein convertase subtilisin-like kesin type 9, and apolipoprotein E) were selected for score elaboration. Of 60 criteria from clinical records and family questionnaires, predictors of having hFH were estimated by logistic regression analysis. Scores were validated in 38 other unrelated children with HC. Three independent predictors of hFH were identified according to the LDLR genotype (50 Microt+/50 Microt-): low-density lipoprotein cholesterol before (262 vs 178 mg/dL, P < 0.001) and after (225 vs 142 mg/dL, P < 0.001) 3 months or more of a lipid-lowering diet, combined with parental statin usage (odds ratio 6.2; 95% confidence interval 1.4-28.3; P = 0.018). High precision and accuracy of the scoring system (area under the receiver operating characteristic curve = 0.94; 95% confidence interval 0.91-0.98) were translated into 4 probability classes (definite/probable/possible/improbable hFH) with a false-negative rate of 12%. A score distinguishing hFH from common HC provides a simple tool for appropriate clinical decision and care in high-risk children.

Atorvastatin effect on the distribution of high-density lipoprotein subfractions and human paraoxonase activity

Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (LDL); therefore, it may protect against atherosclerosis. Changes in the ratio of high-density lipoprotein (HDL) subfractions may alter the stability and the antioxidant capacity of PON1. The aim of the study was to examine the effect of atorvastatin treatment on the distribution of HDL subfractions, LDL size, cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and PON1 activity. In all, 33 patients with type IIa and IIb hypercholesterolemia were involved in the study. LDL sizes and HDL subfractions were determined by gradient gel electrophoresis. CETP, LCAT, and PON1 activities were measured spectrophotometrically. Three months of treatment with atorvastatin 20 mg daily significantly increased the HDL3 (+8.13%) and decreased the HDL2a and HDL2b subfractions (-1.57% and -6.55%, respectively). The mean LDL size was significantly increased (+3.29%). The level of oxidized LDL was significantly decreased (-46.0%). The PON1 activity was augmented by the atorvastatin treatment (+5.0%). The CETP activity positively correlated with the HDL2b level and negatively correlated with the HDL3 and HDL2a levels. Atorvastatin alters the HDL subfractions, which may improve its antiatherogenic effect via enhancement of the PON1 activity.

Efficacy and safety of ursodeoxycholic acid in primary, type IIa or IIb hypercholesterolemia: A multicenter, randomized, double-blind clinical trial

Background Ursodeoxycholic acid (UDCA) is a therapeutic bile acid used in dissolution of gallstones and treatment of several cholestatic liver diseases. Results obtained from primary biliary cirrhosis patients treated with UDCA suggested that this agent exerts significant cholesterol-lowering effects and justifies evaluation in primary hypercholesterolemic patients without liver disease. Purpose of this study was to determine whether UDCA had potential to be an effective, safe cholesterol-lowering agent in primary type IIa or IIb hypercholesterolemia. Methods This was a multicenter randomized, double blind, placebo-controlled trial. After a 6-week placebo lead-in period during which two qualifying lipid profiles were obtained, patients with a mean serum LDL-cholesterol (LDL-C) between 130 and 190 mg/dL, triglycerides <400 mg/dL and HDL-cholesterol >30 mg/dL were randomized to UDCA or matching placebo for 24 weeks. Results Seven sites screened 200 patients with 134 patients meeting the entry criteria who were randomized to the two treatments. There were 125 patients meeting the efficacy evaluation criteria, 57 on UDCA and 68 on placebo. LDL-C change from weeks 0 to 24 showed no significant difference between groups. No significant differences in changes for total cholesterol, HDL-cholesterol and triglycerides were observed. Both groups had similar adverse event profiles. Conclusions UDCA did not show intrinsic cholesterol-lowering properties and therefore is not a useful therapy in treating type IIa or type IIb hypercholesterolemic patients. UDCA was confirmed as a well tolerated and safe drug in this population.

Statin Therapy Alters the Relationship Between Apolipoprotein B and Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol Targets in High-Risk Patients: The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) Trial

The purpose of this analysis was to compare concentrations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apoB) before and during statin therapy. Reducing LDL-C to a pre-determined goal may still leave an excess of atherogenic lipoproteins, as reflected in apoB levels. The MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial examined the effects of statin treatment in patients with high coronary heart disease (CHD) risk, LDL-C > or =130 and <250 mg/dl, and triglycerides <400 mg/dl. Therapy consisted of rosuvastatin (10 or 20 mg), atorvastatin (10 or 20 mg), or simvastatin (20 or 40 mg). The apoB and LDL-C or non-HDL-C at baseline and after 16 weeks of therapy were compared using linear regression. In untreated patients, the apoB target of <90 mg/dl was roughly equivalent to an LDL-C level <100 mg/dl and a non-HDL-C level <130 mg/dl, which is consistent with existing apoB and lipoprotein guidelines. However, during statin therapy, to reach an apoB target of <90 mg/dl it was necessary to reduce non-HDL-C to <100 mg/dl or to reduce LDL-C to <70 mg/dl (in high-triglyceride patients) or <80 mg/dl (in lower-triglyceride patients). The tight correlation seen for non-HDL-C with apoB while on statin therapy (R(2) = 0.92) implies that non-HDL-C may be an acceptable surrogate for direct apoB measurement. These data are consistent with the more aggressive cholesterol goals suggested for CHD patients, because achieving such targets also reduced apoB to the recommended level. (Mercury II-Compare the Efficacy and Safety of Lipid Lowering Agents Atorvastatin and Simvastatin With Rosuvastatin in High Risk Subjects With Type IIa and IIb Hypercholesterolemia; NCT00654407).

Genetic analysis of Indian subjects with clinical features of possible type IIa hypercholesterolemia

We performed genetic analysis in 55 patients with clinical features of possible type IIa hypercholesterolemia and 76 normolipemic healthy subjects for mutations and polymorphisms in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B-100 (APOB), apolipoprotein E (APOE), and hepatic lipase (LIPC) genes to elucidate the important genetic factors that can influence cholesterol levels in our population. None of the subjects showed mutations in part of exon 26 of the APOB gene, whereas two class 5 mutations were identified in exon 9 of the LDLR gene. First, an E387K mutation was observed in a Gujarati family in which both the parents were heterozygous for the mutation. Second, a L393R mutation was observed in a 38-year-old female. We found no correlation between LIPC -514C/T genotypes and cholesterol levels whereas the apoepsilon4 allele frequency was significantly higher in cases and the apoE4 genotype was found to influence total cholesterol levels.

Anesthetic Management of Combined Heart-Liver Transplantation

COMBINED HEART AND LIVER transplantation (CHLT), initially reported by Starzl et al 1 Starzl T. Hakala T.R. Shaw B.W. et al. Heart-liver transplantation in a patient with familial hypercholesterolemia. Lancet. 1984; 3: 1382-1383 Abstract Scopus (211) Google Scholar in 1984, has been successfully performed in adults and children. 2 Figuera D. Ardaiz J. Martin-Judez V. et al. Combined transplantation of heart and liver from two different donors in a patient with familial type IIa hypercholesterolemia. J Heart Transplant. 1986; 5: 327-329 PubMed Google Scholar , 3 Wallwork J. Williams R. Calne R. Transplantation of liver, heart, and lungs for primary biliary cirrhosis and primary pulmonary hypertension. Lancet. 1987; 2: 182-184 Abstract PubMed Scopus (79) Google Scholar , 4 Olivieri N. Liu P.P. Sher G.D. et al. Brief report: Combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med. 1994; 330: 1125-1127 Crossref PubMed Scopus (66) Google Scholar , 5 Couetil J. Soubrane O. Houssin D.P. et al. Combined heart-lung-liver, double lung-liver, and isolated liver transplantation for cystic fibrosis in children. Transplant International. 1996; 10: 33-39 Crossref Google Scholar , 6 Dennis C.M. McNeil K.D. Dunning J. et al. Heart-lung-liver transplantation. J Heart Lung Transplant. 1996; 15: 536-538 PubMed Google Scholar , 7 Detry O. Honore P. Meurisse M. et al. Advantages of inferior vena cava flow preservation in combined transplantation of the liver and heart. Transpl Int. 1997; 10: 150-151 Crossref PubMed Google Scholar , 8 Surakomol S. Olson L.J. Rastogi A. et al. Combined orthotopic heart and liver transplantation for genetic hemochromatosis. J Heart Lung Transplant. 1997; 16: 573-575 PubMed Google Scholar , 9 Offstad J. Schrumpf E. Geiran O. et al. Plasma exchange and heart-liver transplantation in a patient with homozygous familial hypercholesterolemia. Clin Transpl. 2001; 15: 432-436 Crossref Scopus (30) Google Scholar , 10 Eckhoff D. Frenette L. Sellers M.T. et al. Combined cardiac surgery and liver transplantation. Liver Transpl. 2001; 7: 60-61 Crossref PubMed Scopus (46) Google Scholar , 11 Ruygrok P. Gane E.J. McCall J.L. et al. Combined heart and liver transplantation for familial amyloidosis. Intern Med J. 2001; 31: 66-67 Crossref PubMed Scopus (22) Google Scholar , 12 Praseedom R. McNeil K.D. Watson C.J. et al. Combined transplantation of the heart, lung, and liver. Lancet. 2001; 358: 812-813 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar , 13 Pirenne J. Verleden G. Nevens F. et al. Combined liver and (heart-) lung transplantation in liver transplant candidates with refractory portopulmonary hypertension. Transplantation. 2002; 73: 140-156 Crossref PubMed Scopus (45) Google Scholar , 14 Gandhi S. Reyes J. Webber S.A. et al. Case report of combined pediatric heart-lung-liver transplantation. Transplantation. 2002; 73: 1968-1969 Crossref PubMed Scopus (18) Google Scholar , 15 Grazi G. Cescon M. Salvi F. et al. Combined heart and liver transplantation for familial amyloidotic neuropathy: Considerations from the hepatic point of view. Liver Transpl. 2003; 9: 986-992 Crossref PubMed Scopus (40) Google Scholar CHLT is an uncommon procedure, with only 37 procedures reported in the United States by the United Network for Organ Sharing Scientific Registry of Transplant Recipients (SRTR) database. 16 UNOS, United Network for Organ Sharing. Available at: http://www.UNOS.org. Accessed February 1, 2006 Google Scholar Historically, there are few indications for CHLT and definitive dual-organ candidacy criteria have not been established. Previous case reports and small series have detailed the surgical procedure and outcomes; however, no reports have detailed intraoperative management strategies to optimize the physiologic support and function of each organ. This manuscript highlights unique anesthetic considerations for the intraoperative management of the CHLT recipient.

Achieving lipid goals in real life: the Dutch DISCOVERY Study

DISCOVERY Netherlands was an open-label, randomised, multicentre study (D3560/L00003) designed to compare the effects of rosuvastatin with those of atorvastatin, simvastatin or pravastatin on low-density lipoprotein cholesterol (LDL-C) goal achievement in a primary care setting. Patients (n = 1,215) with type IIa or type IIb hypercholesterolaemia and cardiovascular risk of >20% or a history of coronary heart or other atherosclerotic vascular disease were randomised to receive treatment with rosuvastatin 10 mg (n = 621), atorvastatin 10 mg (n = 189), simvastatin 20 mg (n = 194) or pravastatin 40 mg (n = 211) for 12 weeks. Significantly, more patients achieved 1998 and 2003 European LDL-C goals with rosuvastatin than with other statins after 12 weeks (p < 0.001). Rosuvastatin reduced LDL-C and total cholesterol levels significantly more than other statins, both in patients who were statin-naïve and in patients who had received previous statin treatment (p < 0.05). All treatments were similarly well tolerated. In conclusion, greater reductions in LDL-C were achieved with rosuvastatin compared with atorvastatin, simvastatin and pravastatin, enabling more patients to achieve European LDL-C goals.

Effects of Colesevelam HCl on Sterol and Bile Acid Excretion in Patients with Type IIa Hypercholesterolemia

Colesevelam HC1 is a potent bile acid-binding polymer. This study's aim was to determine effects of colesevelam HCl on sterol and bile acid excretion in patients with type IIa hypercholesterolemia. Twenty-four patients (low-density lipoprotein cholesterol, 130 to 220 mg/dL) enrolled in an open-label, parallel-design study, entered an American Heart Association/National Cholesterol Education Program diet for 6 weeks and were randomized to colesevelam HCl, 2.3 or 3.8 g/day for 4 weeks. In an apparent dose-related manner, respective mean serum concentrations HCl of low-density lipoprotein cholesterol decreased by 10% (P < 0.01) and 13% (P = 0.05), mean total cholesterol levels decreased by 4.9% (P = 0.05) and 6.1% (P = 0.09), and total fecal bile acid excretion showed median changes of +324% (P < 0.05) and +316% (P < 0.05). Colesevelam HCl did not affect fecal neutral sterol or fecal fatty acid excretion; however, 24-hr urinary mevalonic acid levels significantly increased in both treatment groups (P < 0.05). The cholesterol-lowering action of colesevelam HCl appears to be mediated through increased bile acid excretion.

Effects of Colesevelam HCl on Sterol and Bile Acid Excretion in Patients with Type IIa Hypercholesterolemia

Effects of Colesevelam HCl on Sterol and Bile Acid Excretion in Patients with Type IIa Hypercholesterolemia

W16-O-003 Efficacy and safety of rosuvastatin 40 MG in patients with severe type IIA and IIB hypercholesterolaemia

W16-O-003 Efficacy and safety of rosuvastatin 40 MG in patients with severe type IIA and IIB hypercholesterolaemia

Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia

This randomized, double-blind, placebo-controlled trial was conducted in 52 centers in North America to compare the effects of the new, highly effective statin, rosuvastatin, with atorvastatin and placebo in hypercholesterolemic patients. After a 6-week dietary run-in, 516 patients with low-density lipoprotein (LDL) cholesterol ≥4.14 mmol/L (160 mg/dl) and <6.47 mmol/L (250 mg/dl) and triglycerides ≤4.52 mmol/L (400 mg/dl) were randomized to 12 weeks of once-daily placebo (n = 132), rosuvastatin 5 mg (n = 128), rosuvastatin 10 mg (n = 129), or atorvastatin 10 mg (n = 127). The primary efficacy end point was percent change in LDL cholesterol. Secondary efficacy variables were achievement of National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II), ATP III, and European Atherosclerosis Society LDL cholesterol goals and percent change from baseline in high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I. Rosuvastatin 5 and 10 mg compared with atorvastatin 10 mg were associated with greater LDL cholesterol reductions (−40% and −43% vs 35%; p <0.01 and p <0.001, respectively) and HDL cholesterol increases (13% and 12% vs 8%, p <0.01 and p <0.05, respectively). Total cholesterol and apolipoprotein B reductions and apolipoprotein A-I increases were also greater with rosuvastatin; triglyceride reductions were similar. Rosuvastatin 5 and 10 mg were associated with improved achievement in ATP II (84% in both rosuvastatin groups vs 73%) and ATP III (84% and 82% vs 72%) LDL cholesterol goals, and rosuvastatin 10 mg was more effective than atorvastatin in achieving European Atherosclerosis Society LDL cholesterol goals. Both treatments were well tolerated.

Four cases of tendinopathy in patients on statin therapy

During the last decade, statins have been widely prescribed as lipid-lowering drugs. Their overall safety profile is good. The main musculoskeletal side effects have consisted of muscle pain and weakness, peripheral neuropathy, and a few cases of drug-induced lupus. We report the first four cases of tendinopathy in patients receiving statin therapy. There were three men and one woman. The diagnoses were extensor tenosynovitis at the hands (case 1), tenosynovitis of the tibialis anterior tendon (case 2), and Achilles tendinopathy (cases 3 and 4). Two patients were on simvastatin and two on atorvastatin. The tendinopathy developed 1 to 2 months after treatment initiation. The outcome was consistently favorable within 1 to 2 months after discontinuation of the drug. Similar cases have been reported to French pharmacovigilance centers. This report of four cases of tendinopathy draws attention to a possible and heretofore unrecognized side effect of a drug class that is becoming increasingly popular. Statins are effective in lowering high cholesterol levels in patients with type IIa or IIb hypercholesterolemia. They have been widely used for the last decade, particularly in the secondary and primary prevention of major coronary events. Statins act by inhibiting the enzyme hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase. Although most patients tolerate statins extremely well, a few experience side effects requiring treatment discontinuation. Reported musculoskeletal side effects include myalgia and a few cases of rhabdomyolysis and polymyositis. Induced lupus and peripheral neuropathy are exceedingly rare.