Influence of etofibrate on LDL-subtype distribution in patients with diabetic dyslipoproteinemia.

Low density lipoprotein (LDL-) particles can be subfractionated in large-buoyant (lb), intermediate-dense (id) and small-dense (sd) LDL-subtypes. Fibrates improve the LDL-subtype profile by reducing proatherogenic sd-LDL which are prominent in diabetic dyslipoproteinemia. We evaluated the effect of etofibrate on the LDL-subtype distribution in patients with type 2 diabetes mellitus (n = 13, 55 +/- 18 years, BMI 27.9 +/- 5.5 kg/m2, HbA1c 10.1 +/- 3.9 %) and diabetic dyslipoproteinemia (triglycerides 343 +/- 253 mg/dl, HDL-cholesterol 36 +/- 7 mg/dl, LDL-cholesterol 110 +/- 37 mg/dl). Plasma lipids (enzymatic methods) and LDL-subtypes (7 LDL-subfractions, density gradient ultracentrifugation) were measured before and during etofibrate therapy (500 mg/d, 7 - 16 weeks). Etofibrate significantly (p < 0.05, Wilcoxon-test) reduced triglycerides (- 31 +/- 60 %) and increased HDL-cholesterol (+ 24 +/- 22 %), whereas total cholesterol and LDL-cholesterol did not change. Cholesterol concentration decreased in sd-LDL by 12 % (p < 0.05), while it increased in id- and lb-LDL (+ 26 %,+ 39 %, respectively). Thus, the LDL-subtype profile showed a relative increase of the fraction of lb- (+ 13 +/- 32 %, n.s.) and id-LDL (+ 23 +/- 33 %, p < 0.05) and a relative decrease of the fraction of sd-LDL (- 19 +/- 18 %, p < 0.05). We conclude that etofibrate not only decreases triglycerides and increases HDL-cholesterol but also improves the LDL-subtype profile and thus may reduce the cardiovascular risk in patients with an abundance of sd-LDL such as diabetic patients.     

Hyperinsulinemia in patients with hypercholesterolemia.

An independent association between hypercholesterolemia and high insulin levels has not consistently emerged from large-scale epidemiologic observations. We selected 39 patients with elevated low-density (LDL) cholesterol levels but normal body weight, blood pressure, and glucose tolerance, and compared them to 36 normocholesterolemic, healthy control subjects accurately matched to the patients for age, gender, body mass index, and mean arterial blood pressure. Fasting serum total cholesterol concentrations and levels of LDL cholesterol, triglycerides, and apoprotein B were all higher in the patients with hypercholesterolemia than in controls (P < 0.025 or less), whereas high-density lipoprotein cholesterol and apoprotein A levels were significantly lower (P < 0.05 or less). Plasma insulin concentrations were elevated in hypercholesterolemic patients vs. controls both in the fasting state (86 +/- 6 vs. 59 +/- 8 pmol/L) and 2 h after a 75-g oral glucose load (412 +/- 16 vs. 276 +/- 18 pmol/L, P < 0.02 for both). Two-hour plasma glucose concentrations were also significantly raised in the patients (7.8 +/- 0.2 mmol/L) compared to controls (6.4 +/- 0.1 mmol/L, P < 0.025). In a multiple regression model including serum triglyceride concentrations, LDL cholesterol was still significantly related to both fasting and 2-h plasma insulin concentrations, contributing approximately 20% to the overall variability of these measures. Thus, in this group of patients with type IIa familial combined hyperlipoproteinemia hypercholesterolemia was associated with hyperinsulinemia even when controlling for other confounders (age, gender, body mass, glucose tolerance, and blood pressure).     

Effect of atorvastatin on low-density lipoprotein subtypes in patients with different forms of hyperlipoproteinemia and control subjects

Atorvastatin is a potent hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, but little is known about its effects on LDL subtype distribution in different types of hyperlipoproteinemia. Thus, we evaluated the influence of atorvastatin (10 mg/d, 4 weeks) on lipid concentrations and LDL subtype distribution in patients with hypercholesterolemia (n = 9; LDL cholesterol, 227 +/- 30 mg/dL; triglycerides, 137 +/- 56 mg/dL), patients with type 2 diabetes and dyslipoproteinemia (n = 11; LDL cholesterol, 163 +/- 34 mg/dL; triglycerides, 260 +/- 147 mg/dL), and controls (n = 10; LDL cholesterol, 116 +/- 20 mg/dL; triglycerides, 130 +/- 47 mg/dL). Cholesterol concentration was determined in 7 LDL subfractions isolated by density gradient ultracentrifugation before and during atorvastatin treatment. Atorvastatin decreased LDL cholesterol (-36%, -28%, and -41%, all P <.01) and triglyceride (-4%, NS; -2%, NS; -24%, P <.05) concentrations but had little effect on high-density lipoprotein (HDL) cholesterol (-1%, NS; +10%, P <.05; +6%, NS) in hypercholesterolemic, diabetic, and control subjects, respectively. In all 3 groups, a significant reduction in cholesterol in each LDL subfraction was observed. Large-buoyant (LDL-1, LDL-2) and intermediate-dense (LDL-3, LDL-4) LDL were reduced more than small-dense (LDL-5 through LDL-7) LDL in hypercholesterolemic (-45%, -35%, and -32%, P <.05) and control subjects (-48%, -44%, and -25%, P <.05), but in diabetic patients cholesterol reduction was uniform in all LDL subtypes (-32%, -27%, and -29%, P =.45). Thus, atorvastatin decreases cholesterol concentration in all LDL subfractions in hypercholesterolemic, diabetic, and control subjects. However, the relative reduction of individual LDL subtypes differed between these groups. This finding suggests that the effect of atorvastatin on LDL subtype distribution depends on the type of underlying hyperlipoproteinemia.     

Effects of simvastatin (40 and 80 mg/day) in patients with mixed hyperlipidemia

Mixed hyperlipidemia is characterized by both elevated total cholesterol and triglycerides. It is estimated to account for 10% to 20% of patients with dyslipidemia. This study assessed the lipid-altering efficacy and tolerability of simvastatin 40 and 80 mg/day as monotherapy. One hundred thirty patients (62 women [48%], 24 [16%] with type 2 diabetes mellitus, mean age 53 years) with mixed hyperlipidemia (baseline low-density lipoprotein [LDL] cholesterol 156 mg/dl [mean], and triglycerides 391 mg/dl [median) were randomized in a multicenter, double-masked, placebo-controlled, 3-period, 22-week, balanced crossover study, and received placebo, and simvastatin 40 and 80 mg/day each for 6 weeks. Compared with placebo, simvastatin produced significant (p <0.01) and dose-dependent changes in all lipid and lipoprotein parameters (LDL cholesterol 2.1%, -28.9%, and -35.5%; triglycerides -3.5%, -27.8%, and -33.0%; high-density lipoprotein cholesterol 3.3%, 13.1%, and 15. 7%; apolipoprotein B 3.8%, -23.1%, and -30.6%; and apolipoprotein A-I 4.0%, 8.2%, and 10.5% with placebo, and simvastatin 40 and 80 mg/day, respectively). The changes were consistent in patients with diabetes mellitus. One patient taking simvastatin 80 mg/day had an asymptomatic and reversible increase in hepatic transaminases 3 times above the upper limit of normal. Simvastatin 40 and 80 mg/day is effective in patients with mixed hyperlipidemia across the entire lipid and lipoprotein profile. The reductions in LDL cholesterol and triglycerides are large, significant, and dose dependent. The increase in high-density lipoprotein cholesterol was greater than that observed in patients with hypercholesterolemia, and appears dose dependent.     

Serum lipids and lipoproteins in type 2 diabetic patients with persistent microalbuminuria

To investigate whether persistent microalbuminuria is related to altered levels of both lipids and apolipoproteins in Type 2 diabetes mellitus serum total-cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, apolipoprotein A-I, and apolipoprotein B were measured by standard methods in a group of Type 2 diabetic patients affected by persistent microalbuminuria (albumin excretion rate (AER) 20-200 micrograms min-1) as compared with a group of sex- and age-matched non-microalbuminuric patients (AER less than 20 micrograms min-1). The groups were stratified according to a short (less than or equal to 5 years) or a longer (greater than 5 years) duration of diagnosed diabetes. Microalbuminuria was not associated with significant changes of serum total-cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, and apolipoproteins in the group of patients with a duration of disease greater than 5 years, while microalbuminuric patients less than or equal to 5 years from diagnosis (n = 11) had serum total-cholesterol, triglycerides, LDL-cholesterol, and apoprotein B higher than non-microalbuminuric control patients (n = 26) (cholesterol 6.2 +/- 0.9 vs 5.1 +/- 1.0 mmol l-1 (p = 0.003); triglycerides 2.1 +/- 0.7 vs 1.7 +/- 1.3 mmol l-1 (p = 0.03); LDL-cholesterol 4.1 +/- 0.8 vs 3.0 +/- 0.7 mmol l-1 (p less than 0.001); apo-B 1.3 +/- 0.3 vs 1.1 +/- 0.3 g l-1 (p = 0.02). In these patients with shorter duration of diabetes many of the serum lipid measures correlated positively with AER.     

Effect of pioglitazone on lipids in well controlled patients with diabetes mellitus type 2 -- results of a pilot study.

INTRODUCTION: Patients with diabetes mellitus type 2 are characterized by a typical dyslipoproteinemia. Improvement in glucose control usually also ameliorates this dyslipoproteinemia. It is unclear whether different antidiabetic strategies differ in their effects on the lipid profile. Particularly, it is unknown whether glitazones improve lipid values independently of their effects on glucose metabolism. METHODS: Ten patients well controlled on sulfonylureas (HbA1c 6.9 +/- 0.5 %) with diabetic dyslipoproteinemia were treated with additional pioglitazone (30 mg/d) for 3 months. Every 4 weeks the sulfonylurea dose was adjusted to keep HbA1c and fasting glucose constant. Before and after 3 months of pioglitazone therapy lipid metabolism was determined in detail (cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, VLDL-triglycerides, lipoprotein(a), LDL-subtype distribution by isopycnic density gradient ultracentrifugation). RESULTS: Although glucose control remained unchanged (HbA1c 6.9 +/- 0.5 % vs. 6.8 +/- 0.6 %; fasting glucose concentration 7.7 +/- 1.1 vs. 7.3 +/- 1.3 mmol/l) we observed a significant reduction in triglyceride concentration (1.9 +/- 0.6 vs. 1.4 +/- 0.5 mmol/l, - 26 %, p < 0.01), a significant increase in HDL-cholesterol concentration (1.2 +/- 0.2 vs. 1.4 +/- 0.2 mmol/l, + 14 %, p < 0.05), a significant decrease in LDL/HDL-ratio (3.03 +/- 0.77 vs. 2.51 +/- 0.61, - 24 %, p < 0.05) and non-significant improvements in total cholesterol, LDL-cholesterol, VLDL-triglycerides, and VLDL-cholesterol concentrations. The LDL-subtype profile improved (significant reduction [- 20 %] in small dense LDL). CONCLUSIONS: This pilot study indicates that at comparable fasting glucose concentration and at comparable HbA1c value pioglitazone is superior to sulfonylureas concerning the improvement of diabetic dyslipoproteinemia. Whether this relates to indirect effects (improvement in insulin sensitivity) or direct effects (stimulation of PPARalpha) remains to be determined.     

Intensive lipid-lowering strategy in patients with diabetes mellitus.

AIMS: To assess the feasibility of an intensive lipid-lowering strategy in diabetic subjects pursuing target plasma lipid levels. METHODS: Patients with diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target values (LDL-cholesterol <2.6 mmol/l, triglycerides < 1.7 mmol/l, HDL-cholesterol > 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks of diet and glycaemic control, lipid-lowering medication (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages and combinations for 30 weeks. RESULTS: Of all eligible clinic patients, 25% initially responded and finally 12% were entered. Thirty-six patients with Type 1 and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type 2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7 and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and 1.2 mmol/l, respectively. All three target values were reached in 66% of the patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l, respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2 diabetes and increased significantly in HDL in Type 2 DM. CONCLUSIONS: A minority of subjects eligible for intensive lipid lowering agreed to participate in a feasibility study, suggesting a potentially large compliance problem for a general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive lipid lowering with drug combinations can attain the recommended target lipid levels in 66% of subjects with diabetes. With this strategy the plasma lipoprotein composition shifts towards a less atherogenic profile. Subjects with diabetes should therefore receive lipid-lowering therapy tailored to reach target levels, rather than standard dosages, in order to reduce atherogenic risk.     

Lipid and lipoprotein profiles in Ethiopian patients with diabetes mellitus

The association between dyslipidemia and diabetes mellitus is well established. Although various lipoprotein abnormalities have been described in patients with diabetes mellitus elsewhere, there is limited information from African patients. We undertook a cross-sectional study to assess the prevalence of dyslipidemia in Ethiopian patients with types 1 and 2 diabetes. A total of 193 subjects were included in the study (54 patients had type 1 diabetes mellitus, 92 patients had type 2 diabetes mellitus, and 47 were nondiabetic controls). Of these, 93 (48.6%) were men and 103 (51.4%) were women. The mean age+/-SEM for patients with type 1 diabetes mellitus, type 2 diabetes mellitus, and controls were 29.8+/-1.4, 51.2+/-1.1, and 29.0+/-1.7 years, respectively. Hypercholesterolemia and hypertriglyceridemia, defined as cholesterol level of greater than 5.2 mmol/L and triglyceride level of greater than 1.8 mmol/L, were found in 47.3% and 41.8% of patients with diabetes mellitus compared with 27% and 17% in controls (P<.05 for both). The mean total cholesterol level+/-SEM was significantly higher in patients with type 1 or 2 diabetes mellitus than controls (5.76+/-0.27 mmol/L in type 1 diabetes mellitus, 5.25+/-0.2 mmol/L in type 2 diabetes mellitus, and 4.67+/-0.28 mmol/L in healthy controls, P<.02). Triglycerides and low-density lipoprotein levels were also significantly higher in patients with diabetes than in controls, whereas high-density lipoprotein levels were significantly lower in patients with diabetes. In conclusion, our study demonstrates that in Ethiopians with diabetes mellitus, dyslipidemia occurs more frequently than in controls. Thus, we recommend periodic screening for dyslipidemia in all Ethiopian patients with diabetes. Other studies are needed to assess the potential negative effect of dyslipidemia and obesity on morbidity and mortality in Ethiopians with diabetes.     

Comparison about the efficacy and tolerability between simvastatin and bezafibrate in the treatment of hypercholesterolemia]

Simvastatin and bezafibrate actions on blood lipids and their side effects were compared in a double-blind trial involving 24 adults with severe type IIa or IIb primary hypercholesterolemia (mean plasma cholesterol = 4.35 g/l). During a 12-week period, the patients received either bezafibrate, 600 mg 3 times a day, or simvastatin, 10 or 20 mg once a day, with a doubling of the dosage at week 6 if the LDL-cholesterol level remained above 1.40 g/l. Simvastatin significantly reduced LDL-cholesterol by -39.5% (p less than 0.001), total cholesterol by 33.9% (p less than 0.005) and apoprotein B by -28% (p less than 0.001). Bezafibrate significantly reduced LDL-cholesterol (-19.8%, p less than 0.001) and total cholesterol (-17.5%, p less than 0.002), but not apoprotein B. Bezafibrate also reduced triglycerides by -26.6% and raised HDL-cholesterol by +27.6%. Simvastatin was more effective than bezafibrate in lowering LDL-cholesterol (p less than 0.002), total cholesterol (p less than 0.005) and apoprotein B (p less than 0.05). Tolerance of both drugs was considered excellent.     

Efficacy and tolerability of combined treatment with L-carnitine and simvastatin in lowering lipoprotein(a) serum levels in patients with type 2 diabetes mellitus

Lipoprotein(a) [Lp(a)] concentration is generally related to coronary artery disease (CAD) and cerebrovascular disease. However, at present, few interventions are available to lower Lp(a) concentrations. We investigated the effects of l-carnitine, co-administered with simvastatin, on hyper-Lp(a) in patients with type 2 diabetes mellitus. We conducted an open, randomised, parallel-group study, in one investigational center (University hospital). Fifty-two patients with type 2 diabetes mellitus, a triglyceride serum levels <400mg/dL (<4.5 mmol/L), and Lp(a) serum levels >20mg/dL (0.71 mmol/L) were randomised to receive simvastatin alone (n=26) or simvastatin plus l-carnitine (n=26) for 60 days. Simvastatin was administered, in both groups, at a dosage of 20 mg/day, while l-carnitine was administered at a dosage of 2g/day once daily. Both treatments were given orally. Serum levels of triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol (total cholesterol minus HDL cholesterol), apolipoprotein B, and Lp(a) were measured at baseline and 60 days after starting treatment. No difference in time by groups (simvastatin and simvastatin plus l-carnitine) were observed in the reduction of LDL cholesterol, non-HDL cholesterol, and apoB serum levels. On the other hand, Lp(a) serum levels increase from baseline to 60 days in the simvastatin group alone versus a significant decrease in the combination group. Our findings provide support for a possible role of combined treatment with l-carnitine and simvastatin in lowering Lp(a) serum levels in patients with type 2 diabetes mellitus than with simvastatin alone. Our results strongly suggest that l-carnitine may have a role among lipid-lowering strategies.     

Effect of fluvastatin slow-release on low density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action

The objective of this study was to determine the effect of slow-release (XL) fluvastatin on low density lipoprotein (LDL) subfractions in type 2 diabetes. A multicenter, double-blind, randomized, parallel-group comparison of fluvastatin XL 80 mg (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with type 2 diabetes (HbA1c: 7.2 +/- 1.0%, LDL cholesterol (LDL-C): 3.4 +/- 0.7 mmol/liter, high density lipoprotein cholesterol: 1.1 +/- 0.3 mmol/liter, and triglycerides (TG): 2.4 +/- 1.4 mmol/liter). At baseline and on treatment, plasma lipoproteins were isolated and quantified. Eight weeks of fluvastatin treatment decreased total cholesterol (-23.0%, P < 0.001), LDL-C (-29%, P < 0.001) and TG (-18%, P < 0.001), compared with placebo. At baseline, there was a preponderance of dense LDL (dLDL) (apolipoprotein B in LDL-5 plus LDL-6 > 25 mg/dl) in 79% of patients, among whom fluvastatin decreased all LDL subfractions, reductions in dLDL being greatest (-28%, P = 0.001; cholesterol in dLDL -29%). In patients with low baseline dLDL (apolipoprotein B in LDL-5 plus LDL-6 相似文献   

Ethnicity and glycaemic control are major determinants of diabetic dyslipidaemia in Malaysia.

AIMS: To define the prevalence of dyslipidaemia in young diabetic patients in Peninsular Malaysia and the contributory factors of dyslipidaemia in these subjects. METHODS: This is a cross-sectional study involving 848 young diabetic patients from seven different centres, with representation from the three main ethnic groups. Clinical history and physical examination was done and blood taken for HbA1c, fasting glucose, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglycerides. RESULTS: The overall lipids were suboptimal, worse in Type 2 diabetes mellitus (DM) patients compared with Type 1 DM patients. Of the Type 2 patients, 73.2% had total cholesterol > 5.20 mmol/l, 90.9% had LDL-cholesterol > 2.60 mmol/l, 52.6% had HDL-cholesterol < 1.15 mmol/l and 27.3% had serum triglycerides > 2.30 mmol/l. There were ethnic differences in the lipid levels with the Malays having the highest total cholesterol (mean 6.19 mmol/l), and the highest LDL-cholesterol (mean 4.16 mmol/l), while the Chinese had the highest HDL-cholesterol (geometric mean 1.24 mmol/l). Ethnicity was an important determinant of total, LDL- and HDL-cholesterol in Type 2 DM, and LDL- and HDL-cholesterol and triglycerides in Type 1 DM. Glycaemic control was an important determinant of total, LDL-cholesterol and triglycerides in both Type 1 and Type 2 DM. Waist-hip ratio (WHR) was an important determinant of HDL-cholesterol and triglycerides in both types of DM. Gender was an important determinant of HDL-cholesterol in Type 2 DM, but not in Type 1 DM. Socioeconomic factors and diabetes care facilities did not have any effect on the dyslipidaemia. CONCLUSIONS: The prevalence of dyslipidaemia was high especially in Type 2 DM patients. Ethnicity, glycaemic control, WHR, and gender were important determinants of dyslipidaemia in young diabetic patients. Diabet. Med. 18, 501-508 (2001)     

Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.     

Long-term effects of simvastatin in familial dysbetalipoproteinaemia

The long-term effects (66 weeks) of simvastatin (40 mg in one or two doses per day), an inhibitor of HMG CoA-reductase, were evaluated in 12 patients with familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia). Simvastatin had a persistent hypolipidaemic effect; the mean reduction in serum cholesterol was 36-51%, and the mean reduction in serum triglycerides was 32-55%. The decrease in serum lipids was caused by a decline in VLDL-cholesterol and LDL-cholesterol levels; the mean ratio between VLDL-cholesterol and serum triglycerides decreased significantly from 1.06 to 0.73. There was no significant difference between the once-a-day and twice-a-day regimens. Simvastatin was well tolerated; no serious side-effects were observed. These data demonstrate the usefulness of simvastatin in the therapy of familial dysbetalipoproteinaemia.     

The influence of simvastatin on adrenal corticosteroid production and urinary mevalonate during adrenocorticotropin stimulation in patients with heterozygous familial hypercholesterolemia.

The adrenal gland requires a continuous supply of cholesterol for the biosynthesis of adrenal corticosteroids, which can be supplied by low density lipoprotein receptor-mediated uptake or local synthesis. The present study examined whether hypolipidemic therapy with a potent HMG CoA reductase inhibitor, simvastatin, compromises the adrenal response to ACTH stimulation in adult patients with heterozygous familial hypercholesterolemia. The adrenal response to a 36-h continuous ACTH infusion was determined at baseline and after 2 months of simvastatin treatment (40 mg, twice daily) in eight patients. Simvastatin reduced total and low density lipoprotein cholesterol levels by 36% and 45%, respectively. The time course of the increase in serum cortisol concentrations with continuous ACTH infusion was the same before and during simvastatin therapy, as were the rates of urinary excretion of free cortisol, 17-hydroxycorticosteroids, and 17-ketosteroids. Urinary excretion of mevalonate, which correlates with rates of whole body cholesterol synthesis, decreased from 3.8 +/- 0.42 (+/- SEM) mu,ol/24 h at baseline to 2.75 +/- 0.56 on simvastatin; no significant changes were seen in the urinary mevalonate levels before and after simvastatin therapy during ACTH stimulation. We conclude that the hypolipidemic effects of simvastatin in patients with heterozygous familial hypercholesterolemia are paralleled by a decrease in urinary mevalonate, but that the drug does not adversely affect ACTH-stimulated adrenal corticosteroid production.     

Lipid-lowering effect of simvastatin in patients of type 2 diabetes mellitus.

BACKGROUND: Dyslipidemia is an important factor in causation of macrovascular disease in type 2 diabetics. The role of simvastatin in the management of dyslipidemia in patients with type 2 diabetes mellitus is not very well elucidated, particularly in the context of the recent American Diabetes Association criteria 2001. The American Diabetes Association suggests that aggressive therapy of diabetic dyslipidemia will reduce the risk of coronary heart disease in diabetics and that optimal levels are serum low-density lipoprotein cholesterol <2.60 mmol/L (< 100 mg/dl), high-density lipoprotein cholesterol >1.1 5 mmol/L (>45 mg/dl) and triglycerides <2.30 mmol/L, (<200 mg/dl).This study was planned to compare the effect of simvastatin together with behavioral modification and behavioral modification alone, in age, sex and body mass index matched patients with type 2 diabetes mellitus with dyslipidemia, in reaching the target levels of various lipids as suggested by the American Diabetes Association criteria 2001. METHODS AND RESULTS: An open-label, prospective study was conducted on 80 patients with type 2 diabetes mellitus, who had fair to moderate glycemic control with a total glycated hemoglobin < 10%. The patients in the control group (n=40) were treated with only behavioral modifications like calorie control and daily walking for 30 minutes, and no lipid-lowering agent was given. The lipid profile was re-evaluated after 6 and 12 weeks. The patients in the test group (n=40) were advised behavioral modification and given simvastatin. The starting dose was 10 mg at bed time. After 6 weeks of simvastatin therapy, a lipid profile was done. If the goal of low-density lipoprotein cholesterol < 100 mg/dl and/or triglycerides <200 mg/dl and/or high-density lipoprotein cholesterol >45 mg/dl was not achieved, the dose of simvastatin was increased to 20 mg at bedtime for another 6 weeks. It was observed that low-density lipoprotein dyslipidemia was most prevalent. In the control group, a favorable alteration in lipid levels was brought about but none was statistically significant and the American Diabetes Association goals were not achieved in any of the patients. In the test group, there was a significant and favorable alteration in all lipid moieties, and the target levels were achieved in 80% of patients after 12 weeks. There was no significant alteration in glycemic control and liver functions. Myopathy and epigastric pain were seen in 1 patient in each group. CONCLUSIONS: In our study, behavioral modification alone did not achieve the target levels of various lipids in diabetic dyslipidemia as per the American Diabetes Association guidelines. Hence, pharmacological therapy with statins should be resorted to in patients with type 2 diabetes mellitus who carry a high risk of coronary heart disease. Simvastatin is a safe and efficacious lipid-lowering drug.     

Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study

Aortic valve stenosis and atherosclerotic disease have several risk factors in common, in particular, hypercholesterolemia. Histologically, the diseased valves appear to have areas of inflammation much like atherosclerotic plaques. The effect of lipid-lowering therapy on the progression of aortic stenosis (AS) is unclear, and there are no randomized treatment trials evaluating cardiovascular morbidity and mortality in such patients. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) Study is a randomized, double-blind, placebo-controlled, multicenter study of a minimum 4 years' duration investigating the effect of lipid lowering with ezetimibe/simvastatin 10/40 mg/day in patients with asymptomatic AS with peak transvalvular jet velocity 2.5 to 4.0 m/s. Primary efficacy variables include aortic valve surgery and ischemic vascular events, including cardiovascular mortality, and second, the effect on echocardiographically evaluated progression of AS. The SEAS Study randomly assigned 1,873 patients (age 68+/-10 years, 39% women, mean transaortic maximum velocity 3.1+/-0.5 m/s) from 173 sites. Other baseline characteristics were mean blood pressure of 145+/-20/82+/-10 mm Hg (51% hypertensive); 55% were current or previous smokers; and most were overweight (mean body mass index 26.9 kg/m2). At baseline, mean total cholesterol was 5.7+/-1.0 mmol/L (222 mg/dl), low-density lipoprotein cholesterol was 3.6+/-0.9 mmol/L (139 mg/dl), high-density lipoprotein cholesterol was 1.5+/-0.4 mmol/L (58 mg/dl), and triglycerides were 1.4+/-0.7 mmol/L (126 mg/dl). The SEAS Study is the largest randomized trial to date in patients with AS and will allow determination of the prognostic value of aggressive lipid lowering in such patients.     

Comparison of the efficacy and tolerability of simvastatin and atorvastatin in the treatment of hypercholesterolemia

BACKGROUND: Simvastatin and atorvastatin are effective statins for treating hypercholesterolemia. HYPOTHESIS: The study was undertaken to compare the efficacy and tolerability of simvastatin 20 and 40 mg/day and atorvastatin 10 and 20 mg/day. METHODS: In this multinational, open-label, crossover study, 258 patients with primary hypercholesterolemia were randomized after 4 weeks of diet plus placebo to once-daily administration of a starting dose sequence of simvastatin (20 mg) or atorvastatin (10 mg), or a higher dose sequence of simvastatin (40 mg) or atorvastatin (20 mg) for 6 weeks. Patients were then switched after a 1-week washout to the corresponding starting or higher dose of the alternate drug for a second 6-week period. The primary endpoint was the mean percent change from baseline to Week 6 in low-density lipoprotein (LDL) cholesterol; percent changes from baseline in total cholesterol, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were also compared. Safety was assessed through adverse experiences and laboratory measurements. RESULTS: Both statins produced statistically significant improvements in all measured plasma lipids and lipoproteins. The main treatment comparison showed no statistically significant difference in changes in LDL cholesterol and triglycerides, whereby the overall effects were comparable when doses of 20 mg and 40 mg of simvastatin were compared with atorvastatin 10 mg and 20 mg. The mean percent reductions for LDL cholesterol from baseline to Week 6 ranged from 35-42% for the entire study cohort. An LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) was achieved in approximately 70% of patients treated with both drugs in this study. Simvastatin and atorvastatin were well tolerated at the doses studied. CONCLUSION: In patients with hypercholesterolemia, the most commonly used doses of simvastatin and atorvastatin produced similar changes in LDL cholesterol and achieved an LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) in a similar number of patients. Both statins were well tolerated.     

Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia

Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10–40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p ? 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day. Furthermore, approximately 90% of patients treated once daily with simvastatin experienced an at least 20% decrease in plasma LDL cholesterol compared with only 36 to 68% of patients treated with the individual fibrate agents (p ? 0.05). The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides. In contrast, the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished (p ? 0.05) among patients with triglyceride concentrations > 1.7 mmol/1. Plasma highdensity lipoprotein (HDL) cholesterol levels were increased by approximately 10% after treatment with simvastatin or the fibrates. Although fibrate therapy was more effective overall in lowering plasma triglyceride levels, the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2- to 4-fold greater in patients with hypercholesterolemia associated with triglyceride levels ? 2.3 mmol/1 than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/1. The results of these studies confirm the superiority of simvastatin to standard fibrate therapy in reducing plasma levels of total and LDL cholesterol. They further indicate that once-daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels.     

Treatment of hyperlipidemia in primary practise in Germany: sub-group analyses from the 4E-registry with particular emphasis on men and women with diabetes mellitus.

AIMS: To investigate the achievement of treatment goals for low density lipoprotein (LDL) cholesterol in men and women with diabetes mellitus receiving statins in a primary-care setting in Germany. METHODS: 6,827 men and 5,989 women with diabetes mellitus were recruited from among the 28,200 men and 24,200 women participating in the 4E registry of patients being treated with statins for primary hypercholesterolemia unresponsive to diet and lifestyle. Participants were assessed after 6 weeks and 9 months of statin therapy. Attainment of treatment targets was assessed (i) using individual LDL goals based on each participant's individual level of risk and (ii) based on the 2.6 mmol/L target recommended by current European and U.S. guidelines for persons with diabetes. RESULTS: At baseline, patients with and without diabetes mellitus had similar LDL cholesterol levels patients (men: 4.5+/-1 vs. 4.7+/-1 mmol/L, women: 4.7+/-1 vs. 4.9+/-1 mmol/L respectively). The mean drop in LDL cholesterol on statin therapy was similar in men and women with and without diabetes, ranging from 26-27 percent all subgroups. After 9 months of statins, individual LDL goals were achieved by 25% of men and 24% of women with diabetes, while only 16% of diabetic men and 12% of diabetic women achieved the 2.6 mmol/L LDL target. These success rates were similar to those of non-diabetics, including those at high risk, in 4E. CONCLUSIONS: Patients with diabetes mellitus in 4E responded just as well to statins as patients without diabetes. However, achievement of treatment goals in patients with diabetes was just as poor as in other high-risk groups in the 4E cohort.