Insulin-induced glucose control improves HDL cholesterol levels but not reverse cholesterol transport in type 2 diabetic patients

Type 2 diabetes (T2D) is characterized by low HDL cholesterol (HDL-C) and HDL dysfunction. We herein tested whether lowering HbA1c affects HDL-C and reverse cholesterol transport (RCT). Forty-two uncontrolled T2D patients initiating basal insulin were included. HbA1c, HDL-C and RCT were assessed at baseline and after 6 months. At baseline, HDL-C and RCT were directly correlated (r = 0.50; p < 0.001). After 6 months of insulin therapy, HbA1c dropped from 8.8 ± 0.16% to 7.1 ± 0.1%, while average HDL-C and RCT did not change. Follow-up HDL-C and RCT were still correlated (r = 0.31; p = 0.033) and ΔHDL-C correlated with ΔRCT (r = 0.32; p = 0.029). ΔHbA1c correlated with ΔHDL-C (r = 0.43, p = 0.001), but not with ΔRCT. In patients with ΔHbA1c above the median value (1.3%), HDL-C (but not RCT) increased significantly. In conclusion, glucose control correlates with increased HDL-C, but not with improved RCT. Thus, persistent HDL dysfunction despite improved HbA1c and HDL-C can contribute to residual cardiovascular risk in T2D.     

Effects of simvastatin,an HMG-CoA reductase inhibitor,in patients with hypertriglyceridemia

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.     

Postprandial reverse cholesterol transport in type 2 diabetic patients: effect of a lipid lowering treatment

Deterioration of reverse cholesterol transport (RCT), an important anti-atherogenic process, may contribute to the largely unexplained severity of cardiovascular risk in type 2 diabetic patients. Among other relevant metabolic perturbations is the impairment in type 2 patients of the postprandial increase in RCT which, in normal subjects, is associated with the transfer to HDL of PL from lipolyzed chylomicrons. We have explored the possibility that improvement of postprandial lipolysis by bezafibrate might also restore the stimulated level of postprandial RCT. Twelve male patients (HbA1c 7.6 +/- 1.6% triglycerides (TG) 4.5 +/- 2.4 mmol/l) were treated for 4 weeks with 400 mg bezafibrate and compared with seven age-matched controls. Lipoproteins were analyzed over 8 h after a 1000 Kcal fat load (80% lipid), serum mediated cholesterol efflux was evaluated using 3H-cholesterol labelled Fu5AH cells. Fasting efflux was lower in patients (17.9 +/- 3.3 vs 19.9 +/- 3.0 a. units, P < 0.05) and decreased postprandially in most instead of increasing, so that area under the time-curve (AUC) was 23% lower than in controls (140 +/- 23 vs 170 +/- 25 units x h, P < 0.001) The patients' HDL failed to acquire PL and gained TG in proportion to lipemia (r = 0.660, P < 0.001). Bezafibrate restored fasting efflux (19.6 +/- 3.6 units, P < 0.005 vs pretreatment) but not postprandial increase of efflux or HDL-PL. AUC of efflux was however improved to 155 +/- 23 units h (P < 0.02). Postprandial efflux related mainly to HDL-PL in controls and patients before treatment. HDL-TG emerged as a significant negative correlate common to all groups (r = -0.674, P < 0.001 8 h after the meal). Impairment of reverse cholesterol transport in diabetic patients might therefore be due to combined postprandial deficit of PL transfer and excess accumulation of TG in HDL. The significant improvement due to fibrate treatment might thus be related to the reduction of HDL-TG contents associated with the improvement of postprandial hyperlipemia.     

The HMG-CoA reductase inhibitor cerivastatin lowers advanced glycation end products in patients with type 2 diabetes.

Although the association between type 2 diabetes mellitus (DM) and cardiovascular diseases is well-documented, current knowledge regarding reasons for the increased prevalence of atherosclerosis in DM is incomplete. Advanced glycosylation end-products (AGE) may play an important role in the development of atherosclerosis in diabetic patients. We examined the effect of the HMG-CoA reductase inhibitor (HMGRI) cerivastatin on serum concentration of AGE-CML in patients with elevated fasting glucose, impaired glucose tolerance or DM. The study was a multicenter, double-blind, randomized, parallel-group comparison of cerivastatin at 0.4 mg daily for 12 weeks (n=34) and placebo (n=35). Patients were characterized by combined hyperlipoproteinemia and the preponderance of dense LDL. Primary objective of the study was the effect of cerivastatin on the concentration of dense LDL subfractions. Here we report on the effect of cerivastatin on the concentration of AGE-CML. After 12 weeks of treatment cerivastatin reduced cholesterol, apolipoprotein B, LDL cholesterol and the concentration of dense LDL. Furthermore, cerivastatin significantly lowered the concentration of AGE-CML by 21% ( P=0,005; compared to -7,5% in the placebo group). The effect on AGE-CML was correlated with the reduction in LDL cholesterol (r=0.355, P=0.003) and LDL apoB (r=0.239, P=0.05). In addition to the lipid-lowering effects of HMGRI, the reduction of AGE-CML observed in our study may entail an improvement of the cardiovascular prognosis in patients with chronic hyperglycemia.     

HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients

Recently, it was reported that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors increased bone mineral density (BMD) in mice. We studied the effect of HMG-CoA reductase inhibitors on BMD of type 2 diabetes mellitus by a retrospective review of medical records. Sixty-nine type 2 diabetic patients were included. The control group (n = 33) did not take HMG-CoA reductase inhibitors. The treatment group (n = 36) was administered either lovastatin, pravastatin, or simvastatin. BMD of the spine, femoral neck, femoral trochanter, and total hip were measured by dual-energy X-ray absorptiometry. There were no significant differences between control and treatment groups in age, sex, body mass index, glycemic control, and serum insulin levels. In the control group, BMD of the spine significantly decreased (from 1.116 +/- 0.165 to 1.081 +/- 0.178 g/cm2) after 14 months. In the treatment group, BMD of the femoral neck significantly increased (from 0.853 +/- 0.139 to 0.878 +/- 0.147 g/cm2) after 15 months. In male subjects treated with HMG-CoA reductase inhibitors, there was a significant increase in BMD of the femoral neck and femoral trochanter (from 0.899 +/- 0.139 to 0.934 +/- 0.139 and from 0.801 +/- 0.145 to 0.833 +/- 0.167 g/cm2, respectively), but in female subjects, only BMD of the femoral neck increased (from 0.819 +/- 0.132 to 0.834 +/- 0.143 g/cm2). Percentage increments of BMD of the femoral neck, femoral wards triangle, femoral trochanter, and total hip in the treatment group were significantly higher than in the control group (2.32% vs. -0.99, 1.77% vs. -1.25%, 1.40% vs. -1.21%, 0.88% vs. -1.03%, respectively). The proportion of subjects who had an increase in BMD of the spine and total hip more than two percentages was significantly larger in the treatment group than in the control group (30.6% vs. 15.2% and 30.6% vs. 9.1%, respectively). The increased increment in BMD of the treatment group was significantly greater than those in the control group after adjustment for age and body mass index (P < 0.05). These results suggest that HMG-CoA reductase inhibitors may increase BMD of the femur in male patients with type 2 diabetes mellitus.     

Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus

Aims/Introduction:  Endothelial lipase (EL) plays an important role in high‐density lipoprotein (HDL) metabolism and experimental data suggest that EL might be proatherogenic. We have investigated whether serum EL concentration is associated with changes in serum capacity to induce cholesterol efflux and arterial stiffness in type 2 diabetes.Materials and Methods:  Serum EL was assayed by ELISA in 172 diabetic patients and 175 controls. The ability of serum to induce cholesterol efflux was measured using a cell culture system and arterial stiffness was determined by measuring pulse wave velocity (PWV) between carotid and femoral arteries.Results:  Diabetic patients had significantly higher C‐reactive protein (CRP) and EL (27.7 ± 16.6 ng/mL vs 24.0 ± 11.3, P < 0.05). Cholesterol efflux to serum mediated through scavenger receptor class B type I was impaired (15.1 ± 2.5%vs 16.7 ± 3.1, respectively, P < 0.01). In controls, serum EL correlated with cholesterol efflux to serum (r = −0.16, P = 0.025), but only a trend was seen in the diabetic patients. Linear regression showed that in controls, HDL, serum EL and waist circumference were major independent determinants of cholesterol efflux; whereas in the diabetic cohort, the major independent determinants of cholesterol efflux were HDL, CRP and age. PWV was increased in the diabetic patients (P < 0.01), but no association between serum EL and PWV was seen in either groups.Conclusions:  Serum EL was increased in diabetic patients, but impaired serum capacity to induce cholesterol efflux in these patients was mainly related to low HDL and subclinical inflammation. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00016.x, 2010)     

Effects of fluvastatin in type 2 diabetic patients with hyperlipidemia: reduction in cholesterol oxidation products and VCAM-1

The purpose of this study was to investigate the lipid-lowering and anti-oxidative effects of fluvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in type 2 diabetic patients. Six patients (3 men and 3 women, mean age = 56.2) took 20 mg of fluvastatin once daily (at night) for 12 weeks. Several markers of oxidative stress were then measured in these patients including plasma cholesterol oxidation products, i.e. oxysterols, and the levels of circulating adhesion molecules. Plasma total cholesterol levels were reduced by 12.3% in these individuals after 4 weeks of treatment, with levels remaining below 220 mg/dl for the entire treatment period. LDL levels were significantly reduced at 4 (18.1%) and 12 weeks (16.1%), and triglyceride levels were significantly reduced after 8 (22.5%) and 12 (37.7%) weeks of treatment. HDL-C levels increased from 50.7 +/- 15.4 prior to treatment to 63.8 +/- 24.3 mg/dl after 12 weeks of treatment, though this increase was not statistically significant. Lipid hydroperoxide, thiobarbituric acid-reactive substance (TBARS), and oxysterol levels were also reduced, suggesting that fluvastatin also had anti-oxidative effects. Finally, VCAM-1 levels were similarly reduced by fluvastatin treatment. We conclude that fluvastatin safely improves the plasma lipid profile in type 2 diabetic patients with hyperlipidemia. We speculate that this drug might be doubly effective in reducing atherosclerosis and cardiac events in these patients as a result of its demonstrated anti-oxidative effects and its ability to reduce VCAM-1 levels.     

Hemodynamic changes associated with reduction in total cholesterol by treatment with the HMG-CoA reductase inhibitor pravastatin

Hemodynamic changes associated with the lowering of total cholesterol (TC) by the water-soluble HMG-COA reductase inhibitor pravastatin were investigated in 59 patients with hypercholesterolemia (TC level at least 220 mg/dl) who received pravastatin therapy for 6 months. The patients were divided into two groups according to the reduction in TC: a 15% reduction group and a <15% reduction group. The changes in hemodynamics were compared before and after pravastatin treatment. No changes in blood pressure, heart rate or aortic damping factor were found in either group. However, significant decreases in pulse wave velocity and total peripheral resistance, and increase in cardiac output were seen in the 15% reduction group. All these hemodynamic parameters remained unchanged in the <15% reduction group. The 12 patients with a clear pravastatin-induced reduction in TC maintained over a 5-year period showed no changes in blood pressure, heart rate or aortic damping factor, but the reductions in pulse wave velocity and total peripheral resistance, and increase in cardiac output were maintained. These changes in hemodynamics were not dependent on aortic elasticity, and appeared to result from improved peripheral hemodynamics. Lowering of TC levels by pravastatin results in improvement in the peripheral endothelium-dependent vasodilation disorder associated with hypercholesterolemia.     

基础血脂水平对HMG—CoA还原酶抑制剂降脂作用的影响

目的　观察治疗前基础血脂水平对HMG CoA还原酶抑制剂降低血清总胆固醇 (TC)、低密度脂蛋白胆固醇(LDL C)以及血清甘油三酯 (TG)作用的影响。方法　分析1994～ 1999年期间进行的 3项多中心临床药物试验 :辛伐他汀试验 (16 6例 ,平均年龄 5 8 9岁± 9 2岁 ) ,洛伐他汀试验(146例 ,平均年龄 5 7 9岁± 8 7岁 ) ,阿伐他汀试验 (10 5例 ,平均年龄 5 7 8岁± 9 3岁 )。治疗前血清TC≥ 5 98mmol·L-1,血清TG≤ 4 5 2mmol·L-1。按治疗前基础血脂水平分组。分别口服辛伐他汀 10mg·d-1,疗程 8周 ;或洛伐他汀2 0mg·d-1,疗程 8周 ;或阿伐他汀 10mg·d-1,疗程 6周。结果　治疗前基础血清TC、LDL C以及TG水平越高 ,HMG CoA还原酶抑制剂降低相应血脂的作用越明显。辛伐他汀、洛伐他汀或阿伐他汀降低血清TC、LDL C以及TG的幅度分别与治疗前相应的基础血脂水平呈正相关。结论　HMG CoA还原酶抑制剂降低血脂的作用与治疗前相应的基础血脂水平有关     

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia

In a genetically heterogeneous group of 109 patients with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH), the influence of gender, apolipoprotein (apo) E genotype and the type of molecular defect in the LDL-receptor (LDLR) gene on the reduction of plasma LDL-cholesterol levels to treatment with a HMG-CoA reductase inhibitor (simvastatin) were studied. Response was determined as the percentage fall in LDL-cholesterol from untreated levels and as the proportion of patients where levels fell below 4.9 or 4.1 mmol/l. Of the patients, 86 individuals had tendon xanthomata (TX+) and a diagnosis of 'definite' FH and these individuals presented with a significantly higher untreated LDL-cholesterol compared to the 23 individuals who did not have xanthomas (TX-) and a diagnosis of 'probable' FH (8.14+/-0.19 vs. 6.81+/-0.25, P= 0.001). Overall, HMG-CoA reductase inhibitor doses of 10, 20 or 40 mg/day resulted in a significant fall of LDL-cholesterol levels of 29, 39 and 49%, but at all doses those with TX had significantly higher levels than those without, and significantly fewer TX + patients achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l than the TX - group (P < 0.05 at each dose). In the TX+ group the response to treatment was of similar magnitude in men and women and in patients with different apoE genotype. In the 'probable' FH probands only three mutations were identified (detection rate 13%), one in the LDLR gene and two in the APOB gene, a detection rate significantly lower (P= 0.02) than in the 'definite' FH probands where 28 mutations were detected (detection rate 37%). In the TX + patients where no mutation was detected, treatment resulted in a greater proportion achieving LDL-cholesterol levels below 4.9 and 4.1 mmol/l compared to those with any LDLR mutation, this difference was close to statistical significance at the 4.9 mmol/l threshold at 10 mg/day (41 vs. 13%, P = 0.058). For the 14 patients with an LDLR mutation that was predicted to be 'severe', fewer achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l at each dosage compared to the 16 individuals with 'mild' mutations, and this difference was statistically significant at the maximal dosage of 40 mg/day (P = 0.018). Thus although characterisation of the molecular defect in FH patients may not be relevant to their immediate clinical management, those with a particular mutation may need more aggressive lipid-lowering treatment to reach LDL-cholesterol levels recommended to reduce the risk of coronary heart disease (CHD).     

Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile

We tested the possibility that simvastatin, a competitive inhibitor of HMG-CoA reductase related to mevinolin, might alter cholesterol saturation of gallbladder bile. Ten patients with Type IIa or IIb hypercholesterolemia underwent bile sampling before, and again after, treatment with 20 or 40 mg per day simvastatin for 7 to 13 weeks. Mean cholesterol saturation index of gallbladder bile fell from 1.01 to 0.77 during simvastatin treatment (p less than 0.01). This finding strongly suggests that treatment with HMG-CoA reductase inhibitors will not predispose to development of cholesterol gallstones. Indeed, it raises the possibility that such inhibitors might have a future role to play in treatment of gallstones.     

The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia

In type 2 diabetics, the progression of atherosclerosis is more rapid than the general population and 80% of these patients will die of an atherosclerotic event. Since in these patients hyperglycemia per se confers increased risk for cardiovascular disease (CVD), the presence of even borderline-high-risk LDL-C signals the need for more aggressive LDL-lowering therapy. Most of the lipid lowering agents, currently in use in the treatment of dyslipidemia in type 2 diabetics, have a host of side effects. In contrast, dietary tocotrienols are Vitamin E and have effective lipid lowering property in addition to their potent antioxidant activity. In this study, we have investigated the therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients. Based on known tocotrienol rich fraction (TRF)-mediated decrease on elevated blood glucose and glycated hemoglobin A(1C) (HbA(1C)) in diabetic rats, we have also investigated the effect of TRF on these parameters. A randomized, double blind, placebo-controlled design involving 19 type 2 diabetic subjects with hyperlipidemia was used. After 60 days of TRF treatment, subjects showed an average decline of 23, 30, and 42% in serum total lipids, TC, and LDL-C, respectively. The goal in type 2 diabetics is to reduce LDL-C levels < or = 100mg/dl. In the present investigation tocotrienols mediated a reduction of LDL-C from an average of 179 mg/dl to 104 mg/dl. However, hypoglycemic effect of TRF was not observed in these patients because they were glycemically stable and their glucose and HbA(1) levels were close to normal values. In conclusion, daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.     

Escape phenomenon occurs by lowering cholesterol with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor in patients with familial hypercholesterolemia

3 beta-Hydroxycompactin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is a useful drug as an anticholesterolemic agent. However, in some patients with familial hypercholesterolemia, treatment was associated with a rebound in serum cholesterol concentration when the dose was increased from 10 to 40 mg/day. The rebound was more remarkable when the basal cholesterol level was lowered by cholestyramine and/or probucol. The phenomenon seems to be due to an induction of HMG-CoA reductase as seen in some animals and cultured cells.     

HMG-CoA reductase inhibitors suppress the development and progression of carotid artery intimal-medial thickening in hypercholesterolemic type 2 diabetic patients

We reported previously that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (RIs) suppressed in vitro oxidized-low density lipoprotein-induced macrophage growth. To elucidate whether HMG-CoA RIs have anti-atherogenic effects separate from their cholesterol-lowering effect, total plasma levels of cholesterol in patients with type 2 diabetes mellitus (type 2 DM) and hypercholesterolemia were reduced to normal by one-year treatment with HMG-CoA RIs and intimal-medial thickness (IMT) of the common carotid arteries (CCA) was measured. Patients with type 2 DM and hypercholesterolemia received either pravastatin (n = 15) or simvastatin (n = 15), while another group of type 2 DM patients with normocholesterolemia did not receive these agents. IMT of the CCA was measured using Powervision SSA-370A, probe 7.5 Mhz. The mean IMT and the rate of increase of IMT were relatively elevated in the order of the simvastatin-treatment group, pravastatin-treatment group, and control group. Our results suggested that HMG-CoA RIs might have anti-atherogenic effects in addition to their cholesterol-lowering effect.     

Acute hepatitis induced by HMG-CoA reductase inhibitor,lovastatin

Summary The HMG-CoA reductase inhibitor, lovastatin, is known to induce asymptomatic liver dysfunction in a few patients. We report the case of an adult who suffered from clinical hepatitis three months after the onset of lovastatin administration. Manifestations included asthenia, jaundice, and increased aminotransferase and alkaline phosphatase activities. Histologic examination showed centrilobular necrosis, centrilobular cholestasis, and infiltrates with mononuclear and polymorphonuclear cells, including eosinophils. Withdrawal of lovastatin was followed by complete normalization of liver tests within two months.     

Treatment with a proton pump inhibitor improves glycaemic control in type 2 diabetic patients - a retrospective analysis

We retrospectively studied whether treatment with esomeprazole improved HbA?(c) levels in type 2 diabetic patients. We selected 21 patients who had been treated with esomeprazole for 11 ± 3 months and 21 controls. HbA?(c) levels decreased in the esomeprazole-treated group. Our data indicate that proton pump inhibitors may improve glycaemic control in type 2 diabetic patients.     

A new HMG-CoA reductase inhibitor, pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits

BACKGROUND: The remarkable anti-atherosclerotic effects of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model. OBJECTIVE: We have investigated the effect of pitavastatin, a newly developed statin, on atherosclerosis in rabbits. METHODS AND RESULTS: Oophorectomized female NZW rabbits were fed 0.3% cholesterol chow for 12 weeks with or without pitavastatin (0.1mg/kg per day) (Gp.NK and HCD). The level of serum cholesterol was decreased in Gp.NK compared with Gp.HCD (772.8 +/- 70.2 versus 1056.9 +/- 108.3 mg/d), whereas no significant alterations were observed in triglyceride and HDL-cholesterol. NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N(G)-monomethyl-l-arginine acetate were all improved by pitavastatin treatment. Pitavastatin treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits. In the aorta, the expression of eNOS mRNA was significantly up regulated and O(2)(-) production was slightly reduced in Gp.NK animals. Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp.NK compared with those from Gp.HCD ( 15.1 +/- 5.3 versus 41.9 +/- 10.2%, 3.1 +/- 1.1versus 7.9 +/- 1.2% in Gp.NK and Gp.HCD aortic arch and thoracic aorta). Anti-macrophage staining area, the MMP1 or 2 and the nitrotyrosine positive area were decreased in Gp.NK. CONCLUSION: Pitavastatin retards the progression of atherosclerosis formation and it improves NO bioavailability by eNOS up-regulation and decrease of O(2)(-).