[Ezetimibe with statins]. / L'ézétimibe comme complément des statines?

Ezetimibe is the first cholesterol absorption inhibitor, a novel class of lipopenic drugs that inhibit intestinal absorption of biliary and dietary cholesterol. From a pathophysiological point of view, combining complementary drugs that act on different cholesterol metabolism pathways is particularly interesting. This interest has been confirmed in clinical studies combining ezetimibe and statins, which inhibit cholesterol synthesis in the liver. Adding ezetimibe (10 mg/d) to statin therapy decreased LDL cholesterol by as much as an additional 20%. It may thus be especially useful in patients who are unable to reach the LDL cholesterol target with diet and statins alone. Ezetimibe is well tolerated and is indicated alone in statin-intolerant patients.

Common promoter C516T polymorphism in the ApoB gene is an independent predictor of carotid atherosclerotic disease in subjects presenting a broad range of plasma cholesterol levels.

OBJECTIVE: A common polymorphism in the promoter of the apolipoprotein B (apoB) gene, a C to T change at position -516, increases the transcription rate of apoB, resulting in elevated circulating levels of low-density lipoprotein (LDL) cholesterol. METHODS AND RESULTS: We tested the hypothesis that carriers of the -516T allele, who may display consistent elevation in plasma cholesterol over their lifetime, may present more extensive atherosclerotic disease than noncarriers. Genotyping of the apoB 516 C/T promoter polymorphism was performed in 326 subjects at low cardiovascular risk. Homozygotes for allele T displayed higher plasma levels of apoB and LDL than did heterozygotes. Furthermore, both homozygotes and heterozygotes for allele T exhibited higher plasma levels of apoB and LDL than did homozygotes for allele C (P<0.0001). In addition, homozygotes for allele T displayed higher carotid intima-media thickness (IMT) than subjects who were heterozygous. Moreover, both groups had higher carotid IMT than subjects of genotype -516C/C (P<0.001). Only age, high-density lipoprotein, and the presence of allele T were identified as independent predictors of the presence of carotid plaque. No association existed between the polymorphism and plasma concentrations of triglycerides, high-density lipoprotein, or apoAI. CONCLUSIONS: Our data indicate that a C to T change at position -516 of the apoB gene is independently associated with the presence of carotid atherosclerotic disease. Identification of the -516C/T polymorphism may therefore contribute to the estimation of overall cardiovascular risk.

Magnitude of HDL cholesterol variation after high-dose atorvastatin is genetically determined at the LDL receptor locus in patients with homozygous familial hypercholesterolemia.

OBJECTIVE: The combination of LDL apheresis with high doses of a potent hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor, such as atorvastatin, has been the best therapy available for the prevention of cardiovascular disease in patients with homozygous familial hypercholesterolemia (HFH). However, some concerns have been made about the effect of atorvastatin on HDL cholesterol levels in these patients. METHODS AND RESULTS: HDL cholesterol levels were determined bimonthly over the course of 2 years of treatment with high-dose atorvastatin in genotypically defined HFH patients either receptor-defective (n=6) or receptor-negative (n=6) under long-term treatment with LDL apheresis. We additionally stratified the atorvastatin effect on HDL cholesterol according to the genotype as an indicator of residual in vivo LDL receptor activity. Our findings indicate that (1) an early and transitory reduction of plasma HDL cholesterol levels occurs during the first 4 weeks of atorvastatin treatment; (2) the degree of the transient HDL reduction is higher in receptor-negative than in receptor-defective patients (-21+/-11 versus -10+/-4%; P=0.01); and (3) after long-term treatment, HDL cholesterol concentration remains higher in receptor-defective than receptor-negative patients (P=0.026). CONCLUSIONS: The present study reveals that HDL cholesterol reduction after high-dose atorvastatin is an early and transient event in HFH patients which magnitude depends on the presence of a residual LDL-R activity.

Lipoprotein lipase activity and common gene variants in severely hypertriglyceridemic patients with and without diabetes.

OBJECTIVES: In severe type IV hypertriglyceridemia (triglyceride levels >10 g/l), it is yet unknown whether lipoprotein lipase (LPL) differs according to the presence or not of diabetes. METHODS: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus. RESULTS: Maximum triglyceride, cholesterol levels and distribution of apolipoprotein E phenotypes did not differ between the two subgroups. Mean post-heparin LPL activity was lower in non-diabetic compared to diabetic patients (9.74 vs. 12.98 micromol FFA/ml/h, p=0.033). Four patients were carrying a mutation in exon 9 (1 non-diabetic), 6 patients in exon 2 (4 non-diabetic) and 1 patient in the non-diabetic subgroup in exon 5. All mutations were at the heterozygous state. CONCLUSION: We found that LPL activity was lower in type IV hyperlipidemia in the absence of diabetes. Genetic defects in the LPL gene that could lead to this lower LPL tended to be more frequently observed in patients without diabetes. These data suggest that the pathomechanisms which contribute to severe type IV hyperlipidemia are different according to the presence or not of diabetes.

A comprehensive description of muscle symptoms associated with lipid-lowering drugs.

UNLABELLED: A spectrum of disease from myalgia to rhabdomyolysis exists as classic side-effect of lipid-lowering treatment (LLT). While myopathy has generated considerable interest, mild musculo-skeletal symptoms are poorly assessed. OBJECTIVE: To report on the muscular side-effects of LLT with a particular focus on the overlooked milder ones. METHODS: Hyperlipidemic patients under LLT and complaining of muscle symptoms were asked to complete a self administered questionnaire. Among the 815 adult hyperlipidemic patients under LLT and referred to the cardiovascular prevention unit of La Pitie Hospital, 165 patients answered that they experienced, or had experienced, muscle symptoms which they attributed to the LLT. One hundred and thirty three of these completed and returned a self-administered questionnaire. RESULTS: A clear chronological link between symptoms and the LLT was revealed, either because they appeared soon after drug initiation or because of an improvement after drug withdrawal. While cramps and stiffness were the most frequent symptoms, tendonitis-associated pain was surprisingly common, reported in almost half the cases. Pain was often diffuse with a focus on a given location, mainly lower limbs. 39% of patients had used analgesics for pain relief. Unpredictably, a majority of patients reported pain during rest and the lying position. In a number of cases, a family history of pain under LLT was revealed. CONCLUSION: The impact of these mild symptoms on daily activities might not be negligible in a subset of patients. The role and importance of a genetic background predisposing to low-grade myopathy deserves further investigation.

Selection of patients with solitary thyroid nodules for operation.

OBJECTIVE: To improve the preoperative selection for operation of patients with solitary thyroid nodules. DESIGN: Prospective cohort study. SETTING: University hospital, France. PATIENTS: 155 consecutive patients who presented with solitary thyroid nodules and were operated on. INTERVENTIONS: Clinical examination, ultrasound examination, fine needle aspiration biopsy, followed by total thyroid lobectomy with frozen section and final histological examination. MAIN OUTCOME MEASURE: Correct prediction of thyroid carcinoma or benign adenoma. RESULTS: A logistic regression analysis indicated that absence of rim (p < 0.002), solid and hypoechoic feature (p < 0.003) and malignant or suspicious fine needle aspiration biopsy results (p < 0.0001) were significantly associated with malignancy. Selection for operation by the logistic model would save 40 of 73 patients from operation and 40 of 59 from unnecessarily radical operation. It would detect a similar number of cancers as a strategy based solely on fine needle aspiration cytology. CONCLUSIONS: A combination of the available diagnostic methods provides substantial benefit in the preoperative selection of patients with an isolated thyroid nodule.