The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study

ABSTRACT

Objective: To assess the incremental low-density lipoprotein-cholesterol (LDL-C) lowering efficacy of doubling the statin dose or switching to the ezetimibe/simvastatin 10/20?mg combination tablet (EZE/SIMVA) in patients on simvastatin 20?mg or atorvastatin 10?mg not at LDL-C target < 2.5?mmol/L.

Study design and methods: Patients with documented coronary heart disease (CHD) and/or type 2 diabetes (DM2) with LDL-C ≥ 2.5 and < 5.0?mmol/L despite treatment with atorvastatin 10?mg or simvastatin 20?mg were randomized to (1) double statin dose or (2) switch to ezetimibe/simvastatin 10/20, according to a PROBE study design. LDL-C, lipoprotein subfractions and safety data were assessed during the study.

Results: 119 of 178 (67%) patients in the EZE/SIMVA group and 49 of 189 (26%) in the doubling statin group reached target LDL-C < 2.5?mmol/L. The odds ratio of success for EZE/SIMVA versus doubling statin treatment in reaching the LDL-C target of < 2.5?mmol/L was 5.7 (95% CI: 3.7–9.0, p < 0.0001). A reduction in total cholesterol (TC), total/high density lipoprotein (HDL) cholesterol ratio and apolipoprotein B was observed in both groups, but this reduction was significantly more pronounced in the EZE/SIMVA group as compared with the doubling statin dose group. Treatment was well tolerated and no difference was observed between the two groups with regard to adverse effects.

Conclusions: In CHD/DM2 patients treated with simvastatin or atorvastatin with LDL-C persistently ≥ 2.5?mmol/L, switching to the EZE/SIMVA was more effective in attaining the LDL-C target of < 2.5?mmol/L than doubling the statin dose.     

Efficacy and safety of ezetimibe co-administered with atorvastatin in untreated patients with primary hypercholesterolaemia and coronary heart disease

ABSTRACT

Objective: Combination of ezetimibe (EZE) with a statin represents an attractive strategy for cholesterol-lowering treatment, as it inhibits the two main sources of cholesterol: absorption from the intestine (inhibited by EZE) and endogenous biosynthesis (inhibited by statins).

Research design and methods: This multicentre, double-blind, placebo-controlled study randomised a total of 148 men and women with primary hypercholesterol­aemia and coronary heart disease (CHD) to receive treatment for 6 weeks with either EZE 10?mg + atorvastatin 10?mg (EZE + ATV; n = 72) or placebo/atorvastatin 10?mg (ATV; n = 76). The primary efficacy variable was the mean percentage change in low-density lipoprotein cholesterol (LDL?C) from baseline to study endpoint.

Results: At 6 weeks, EZE + ATV provided a significantly greater adjusted mean change from baseline in LDL?C compared with ATV monotherapy (–50.5% vs. –36.5%; p < 0.0001), equating to an additional 14.1% reduction (95% CI –17.90, –10.19) in LDL?C. A significantly higher proportion of patients on EZE + ATV achieved the new Joint British Societies (JBS 2) recommended LDL?C goal of < 2?mmol/L (62% vs. 12% with ATV alone; p < 0.0001) and the JBS 2 minimum treatment standard of < 3?mmol/L (93% vs. 79% with ATV alone). Patients receiving EZE + ATV were 12 times more likely to reach LDL?C targets (odds ratio 12.1; 95% CI 5.8, 25.1; p < 0.0001) compared with patients receiving ATV monotherapy. Clinical chemistry profiles and the incidence of adverse events were similar in both groups.

Conclusions: Adding EZE to ATV monotherapy represents an attractive and well-tolerated treatment option to bring patients at high risk of CHD to the aggressive LDL?C goals recommended by recent treatment guidelines.     

Clinical experience with ezetimibe/simvastatin in a Mediterranean population

ABSTRACT

Objectives: This study aimed to describe the clinical experience of the ezetimibe (EZE)/simvastatin (SIMVA) combination in a hypercholesterolaemic Greek population who did not attain the cholesterol goals on statin treatment alone.

Methods: Patients already treated with a statin, at any dose, for at least 8 weeks, with LDL-C levels above the goal, (>100, >130 or >160?mg/dl according to their risk category), where the physician chose EZE/SIMVA as appropriate treatment, entered the study. Medical history, demographics and laboratory values were recorded at baseline and 2 months later.

Results: The study included 1514 patients (male 53.4%) of mean age 60.1?±?10.5 years. Diabetes mellitus was reported in 29.9% of the patients, 61.2% had hypertension, 39% were obese, 10.5% had a history of myocardial infarction and 6.8% had a history of stroke or peripheral arterial disease. Current and ex-smoking was reported in 46.8%. Atorvastatin (33%) and SIMVA (27.2%) were the most frequently used statins prior to using the EZE/SIMVA regimen. After 2 months of EZE/SIMVA therapy mean LDL-C was reduced by 33%, mean total cholesterol by 26%, mean triglycerides by 15%, while HDL-C was increased by 10%. The percentage of patients who achieved the LDL-C goal with EZE/SIMVA was 73.8%. One serious adverse event, not related to study treatment and 23 adverse events in total were recorded. There was a significant decrease in serum creatinine levels in patients with baseline values greater than 1.0?mg/dl (88?μmol/L).

Conclusions: Treatment with the EZE/SIMVA combination appears an effective and safe therapeutic option for patients who do not achieve the LDL-C goals on statin therapy alone.     

Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with diabetes mellitus or metabolic syndrome

SUMMARY

Objective: To conduct a post-hoc assessment of the lipid-modifying effects of adding the cholesterol absorption inhibitor, ezetimibe, to on-going statin therapy in patients with diabetes mellitus (DM) or metabolic syndrome (MetS).

Research design and methods: This was a post-hoc analysis of data from a randomized, double-blind, placebo-controlled trial designed to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy and safety of adding ezetimibe 10?mg/day versus placebo to ongoing, open-label statin treatment for 8 weeks in hypercholesterolemic patients. Qualifying LDL-C levels and target LDL-C goals were based on National Cholesterol Education Program risk categories. The DM subgroup were patients who entered the study with a prior diagnosis of DM. Patients were classified as having MetS if they met 3 or more of the following criteria at baseline: triglycerides (TG) ≥ 150?mg/dL (1.69 mmol/L); high-density lipoprotein cholesterol (HDL-C) < 40?mg/dL (1.04 mmol/L) for men or < 50?mg/dL (1.29 mmol/L) for women; fasting serum glucose (FSG) ≥ 110?mg/dL (≥ 6.1 mmol/L); a diagnosis of hypertension or taking hypertension medication or blood pressure ≥ 130/ ≥ 85 mmHg; waist circumference > 88?cm (women) or > 102?cm (men). DM patients were excluded from the MetS subgroup analysis.

Main outcome measures: The objectives were to assess the effects of treatment on plasma concentrations of LDL-C and other lipid variables, and on the percentage of patients achieving LDL-C target levels at the end of the study.

Results: Of 769 patients enrolled in the original study, there were 191 (24.8%) with DM and 195 (25.4%) with MetS. Regardless of subgroup, ezetimibe + statin was significantly more effective than statin alone at lowering plasma levels of LDL-C, non-HDL-C, total cholesterol, apolipoprotein B, and triglycerides (between-group p < 0.001 for all). For all lipid parameters, the relative treatment effects were generally consistent regardless of DM or MetS status. Significantly more ezetimibe than placebo patients in all subgroups achieved prespecified LDL-C goals (?p < 0.001 for all), and although more patients in the DM and MetS groups, respectively, achieved the goal compared with their non-DM and non-MetS counterparts [83.6% (DM) versus 67.2 (non-DM) and 71.8% (MetS) versus 65.6% (non-MetS)], these differences were not significant after adjusting for differences in baseline LDL-C levels. Ezetimibe was well-tolerated and had a favorable safety profile in all subgroups.

Conclusions: The co-administration of ezetimibe with statins, a therapeutic regimen that inhibits both the absorption and synthesis of cholesterol, offers a well-tolerated and efficacious treatment to lower LDL-C in patients with DM and MetS.     

Abnormal lipids in high-risk patients achieving cholesterol targets: a cross-sectional study of routinely collected UK general practice data

ABSTRACT

Background and objectives: Lipid management in UK general practice targets the achievement of total cholesterol (TC) targets in high-risk individuals. Statins alone have a modest effect on non-LDL-C components of the lipid profile, leaving these patients at significant residual cardiovascular (CV) risk. Improving risk further would require the addition of non-statin therapies. This analysis explores what proportion of the UK population with cardiovascular disease (CVD) and TC levels at or below target may still be at risk because of residual dyslipidaemia.

Methods: CV risk profiles were extracted from a research database of 602?222 patients from 98 UK general practices. Patients were categorised according to their prior CV history and use of statins. Mean values and proportions achieving treatment targets were assessed for TC, low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and triglycerides (TG).

Results: In all, 48?499 patients with pre-existing CVD or diabetes were identified. 73% of statin-treated patients and 63% of untreated patients had a TC ≤?5?mmol/L. 28.6% of patients treated to a TC target had LDL-C?> 3?mmol/L. Amongst those with both TC and LDL-C treated to target, 22.5% had low HDL-C and 37.2% had high triglyceride (TG). Within this group, more women than men had abnormal HDL-C (25.4?vs. 20.7% p?< 0.0001). Patients with diabetes were more likely than non-diabetics to have abnormalities of both HDL-C (28.9?vs. 16.4% p?< 0.0001) and triglyceride (44.9?vs. 29.5% p?< 0.0001) despite normal TC and LDL-C.

Conclusions: Around 60% of high-risk patients have residual dyslipidaemias despite achieving the Quality and Outcomes Framework (QOF) TC target. New patterns of treatment are required in order to extend lipid management beyond simple total cholesterol lowering.     

Consistency of lipid-altering effects of ezetimibe/simvastatin across gender,race, age,baseline low density lipoprotein cholesterol levels,and coronary heart disease status: results of a pooled retrospective analysis

ABSTRACT

Background: The combination tablet containing ezetimibe and simvastatin (EZE/SIMVA), inhibits both the intestinal absorption and endogenous production of cholesterol, providing significantly greater low-density lipoprotein cholesterol (LDL-C) lowering than EZE or SIMVA alone. The purpose of this pooled analysis was to evaluate the consistency of efficacy (i.e., between-treatment difference) of EZE/SIMVA versus SIMVA within several selected subgroups of patients with primary hypercholesterolemia.

Methods: For the present analysis, data were pooled from three similarly designed, 12‐week, randomized, double-blind, placebo-controlled factorial studies consisting of 3083 patients with primary hypercholesterolemia (?n = 311 in placebo group; n = 302 in EZE group; n = 1234 in pooled SIMVA group; n = 1236 in pooled EZE/SIMVA group). In these clinical studies, primary hypercholesterolemia was defined as an LDL‐C value between 145 and 250?mg/dL inclusive and a triglyceride (TG) level of less than 350?mg/dL. The results for the pooled SIMVA and pooled EZE/SIMVA groups were used for the present analyses. The pooled analyses focused on the consistency of the between-treatment differences (i.e., incremental effect) for EZE/SIMVA (pooled across doses) versus SIMVA (pooled across doses) on various lipid and non-lipid parameters within different patient subgroups defined according to gender, race (Caucasian, Non-Caucasian), baseline age (< 65, ≥ 65 years), baseline LDL‐C (< 160, ≥ 160?mg/dL), and coronary heart disease (CHD) history. Tolerability was also examined for pooled EZE/SIMVA and pooled SIMVA within these selected subgroups. In a modified intention-to-treat analysis, an ANOVA model was used for testing the consistency of pooled treatment effects on lipid and non-lipid parameters within each selected subgroup.

Results: For the entire cohort, baseline lipid profiles were similar for the patients in the pooled EZE/SIMVA group compared with those in the pooled SIMVA group. Treatment with EZE/SIMVA led to significant (?p < 0.001) incremental improvements in LDL‐C, non-high density lipoprotein cholesterol (non-HDL‐C), apolipoprotein B, TG and high sensitivity C‐reactive protein compared to SIMVA, across the entire cohort. These changes were consistent within each of the selected subgroups. Moreover, more patients attained LDL‐C goal levels < 100?mg/dL with EZE/SIMVA than with SIMVA in the entire cohort and this was consistent across all subgroups, except baseline LDL‐C. In this pooled retrospective analysis, treatment with EZE/SIMVA was generally well tolerated across subgroups, with a safety profile similar to SIMVA monotherapy. Although this pooled analysis was performed on a large cohort of patients with primary hypercholesterolemia, the results of this analysis were specific for this select patient population and generalizations to other populations should be applied with caution.

Conclusion: The enhanced lipid-altering effects of EZE/SIMVA versus those of SIMVA observed in the entire cohort were consistent within all subgroups examined. EZE/SIMVA represents an effective and well-tolerated therapeutic option for the treatment of a wide range of patient subgroups with primary hypercholesterolemia.     

Efficacy and safety of coenzyme A versus fenofibrate in patients with hyperlipidemia: a multicenter,double-blind,double-mimic,randomized clinical trial

Abstract

Background: We investigated the lipid-lowering efficacy and safety of coenzyme A (CoA) versus fenofibrate in Chinese patients with moderate dyslipidemia.

Methods: A total of 417 subjects (aged 18–75?years) diagnosed with moderate dyslipidemia (triglyceride 2.3–6.5?mmol/L) from 13 large cardiovascular centers in China were recruited and randomly divided into a fenofibrate group (n?=?207), which received 200?mg of fenofibrate orally once daily, and a CoA group (n?=?210), which received 400?mg of CoA orally once a day. Blood lipoproteins, liver and renal function, creatine kinase, and blood glucose were measured at baseline, and after 4 and 8?weeks of treatment.

Results: The baseline triglyceride (TG) level in the fenofibrate group and the CoA group was 3.39?±?0.99?mmol/L and 3.60?±?1.11?mmol/L, respectively. After treatment for 4 and 8?weeks with fenofibrate, TG was reduced by 31.62% and 33.13%. In the CoA group, TG was reduced by 17.29% and 23.80%. Compared with baseline, total cholesterol (TC) was significantly decreased in both groups after either 4 or 8?weeks of treatment (p?<?.05). CoA increased high-density lipoprotein cholesterol (HDL-C) after 4?weeks of treatment, whereas it had no significant effect on HDL-C after 8?weeks of treatment. Low-density lipoprotein cholesterol (LDL-C) was not modified in either group. The incidence of side effects was significantly lower in the CoA group compared with the fenofibrate group (p?<?.05).

Conclusions: Compared with fenofibrate, CoA has less effect on reducing plasma TG levels in subjects with moderate dyslipidemia. However, it has fewer adverse effects.     

Efficacy and Safety of Fenofibric Acid Co-Administered with Low- or Moderate-Dose Statin in Patients with Mixed Dyslipidemia and Type 2 Diabetes Mellitus

Background

Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus.

Objective

To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population.

Study Design

A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials.

Setting

Multiple clinical research facilities in the US and Canada.

Patients

Patients with mixed dyslipidemia and type 2 diabetes (n= 586).

Intervention

Fenofibric acid (Trilipix®) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor®] 10, 20, or 40 mg; simvastatin [Zocor®] 20, 40, or 80 mg; or atorvastatin [Lipitor®] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin.

Main Outcome Measure

Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events.

Results

Fenofibric acid + low-dose statin resulted in significantly (p<0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (?43.9%) than low-dose statin monotherapy (4.7% and ?18.1%, respectively) and significantly (p<0.001) greater reductions in lowdensity lipoprotein cholesterol (LDL-C) [?34.0%] than fenofibric acid monotherapy (?5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p≤0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (?43.4%) than moderate-dose statin monotherapy (8.7% and ?24.2%, respectively) and significantly (p<0.001) greater reductions in LDL-C (?32.6%) than fenofibric acid monotherapy (?5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments.

Conclusion

Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy.     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

A multicentre,open study to assess the effect of individualizing starting doses of atorvastatin according to baseline LDL-C levels on achieving cholesterol targets: the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST-2) study

ABSTRACT

Objectives: ACTFAST-2 was designed to match the starting dose of a statin to the baseline low density lipoprotein-cholesterol (LDL-C) value, to allow high-risk European subjects to achieve LDL-C targets within 12 weeks with the initial dose or one up-titration.

Research design and methods: This was a 12-week, prospective, open-label trial that enrolled 610 high-risk subjects from 8 European countries. Subjects with LDL-C > 2.6?mmol/L (> 100?mg/dL),but ≤ 5.7?mmol/L (≤ 220?mg/dL) were assigned a starting dose of atorvastatin (10, 20, 40, 80?mg/day) according to LDL-C level and status of statin use at baseline (either statin-free or statin-treated), with a single up-titration at 6 weeks if needed.

Results: At 12 weeks, 68.0% of subjects overall, including 73.5% of statin-free and 60.5% of statin-treated subjects, achieved LDL-C target (< 2.6?mmol/L (< 100?mg/dL). The total cholesterol/high density lipoprotein-cholesterol (TC/HDL-C) ratio target was achieved by 75.2% of subjects overall, including 78.1% of statin-free and 71.2% of statin-treated subjects. In the statin-free group, LDL-C decreased by a mean of 42%. In the statin-treated group, atorvastatin led to an additional 31% reduction in LDL-C over the statin used at baseline. Mean decreases in TC/HDL-C ratio were 30% and 20% in the statin-free and statin-treated groups, respectively. The incidence of AST/ALT greater than 3 times of upper limit of normal range in all patients was 0.8% and no rhabdomyolysis was reported.

Conclusion: This study confirms that use of a flexible starting dose of atorvastatin allows the large majority of high-risk subjects to achieve their LDL-C target safely within 12 weeks with an initial dose or just a single up-titration.     

Efficacy and safety of extended-release fluvastatin in Turkish patients with hypercholesterol­aemia: TULiPS (Turkish Lipid Study)

ABSTRACT

Objective: The efficacy and safety of extended-release fluvastatin (fluvastatin XL), 80?mg once daily, was assessed in Turkish patients with primary hypercholesterolaemia (low-density lipoprotein cholesterol (LDL?C) 3.37–5.70?mmol/l and triglyceride (TG) <?4.52?mmol/l).

Research design: in this open-label, prospective, multi-centre study, 154 patients were given fluvastatin XL 80?mg once daily and lipid levels were assessed after 2 and 12 weeks.

Results: Fluvastatin XL 80?mg once daily significantly reduced LDL?C levels by 38.8 and 38.1% at weeks 2 (n = 140) and 12 (n = 116), respectively (?p < 0.001 vs. baseline). Treatment with fluvastatin XL for 2 and 12 weeks significantly reduced total cholesterol levels by 30.2 and 27.4%, respectively (?p < 0.001 vs. baseline) and reduced TG levels by 14.9 and 7.5%, respectively (?p < 0.001 vs. baseline). Following stratification by risk factors for coronary heart disease (CHD) according to the National Cholesterol Education Program Adult Treatment Panel iii guidelines, 87.3% of patients with ≥?2 risk factors, and 67.4% of patients with existing CHD or CHD risk equivalents achieved target LDL?C levels (<?3.37?mmol/l and <?2.59?mmol/l, respectively) with fluvastatin XL. Fluvastatin XL reduced high-density lipoprotein cholesterol by 8.9 and 4.7% at weeks 2 and 12 weeks, respectively. fluvastatin XL 80?mg once daily was generally well-tolerated.

Conclusions: This open-label study indicates fluvastatin XL 80?mg once daily is an effective and well-tolerated lipid-lowering therapy for the reduction of CHD risk in Turkish patients.     

Antihyperlipidemic activity of adenosine triphosphate in rabbits fed a high-fat diet and hyperlipidemic patients

Context Recently, adenosine triphosphate (ATP) was occasionally found to decrease the triglyceride (TG) levels in several hyperlipidemic patients in our clinical practice.

Objective The study investigates the anti-hyperlipidemic effects of ATP in a high-fat fed rabbit model and hyperlipidemic patients.

Materials and methods Twenty-four rabbits were randomly divided into three groups of eight animals each as follows: normal diet, high-fat diet and high-fat diet?+?ATP group. ATP supplementation (40?mg/day) was started at the 20th day and lasted for 10 days. Serum concentrations of total cholesterol (TC), TG, LDL-C, HDL-C were measured on the 20th day and 30th day. Heart, liver and aorta were subjected histopathological examination. Twenty outpatients diagnosed primary hyperlipidemia took ATP at a dose of 60?mg twice a day for 1 week.

Results Feeding rabbits with a high-fat diet resulted in a significant elevation of lipid parameters including TC, TG, LDL-C, VLDL-C compared to the normal diet group (p?<?0.01). ATP treatment significantly decreased serum TG level (p?<?0.01), whilst other parameters remained statistically unaltered. Meanwhile, ATP significantly reduced the thickness of fat layer in cardiac epicardium (p?<?0.05) and pathological gradation of ballooning degeneration in hepatocytes (p?<?0.05). After taking ATP for 1 week, hyperlipidemia patients exhibited a significant decrease of TG (p?<?0.01), but other lipid parameters had no significant change.

Discussion and conclusion The study indicates that ATP selectively decreases serum TG levels in high-fat diet rabbits and hyperlipidemic patients. Therefore, ATP supplementation may provide an effective approach to control TG level.     

Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes

ABSTRACT

Objective: To evaluate the efficacy and safety of once-daily saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes (T2D) and inadequate glycemic control.

Research design and methods: This study included a main treatment cohort (MTC) with 401 patients (HbA_1c?≥?7% and ≤10%) randomized and treated with oral saxagliptin 2.5, 5, or 10?mg once daily or placebo for 24 weeks and a separate open-label cohort (OLC) with 66 patients (HbA_1c?>?10% and ≤12%) who received saxagliptin 10?mg once daily for 24 weeks. Primary endpoint was HbA_1c change from baseline to week 24. Secondary endpoints included change from baseline to week 24?in fasting plasma glucose (FPG), proportion of patients achieving HbA_1c?<?7%, and changes in postprandial glucose area-under-the-curve (PPG-AUC). Efficacy analyses for continuous variables were performed using an ANCOVA model with last-observation-carried-forward methodology.

Results: In the MTC, saxagliptin demonstrated statistically significant decreases in adjusted mean HbA_1c changes from baseline (mean, 7.9%) to week 24 (?0.43%, ?0.46%, ?0.54%) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +0.19% for placebo (all p?<?0.0001). Adjusted mean FPG was significantly reduced from baseline (?15, ?9, ?17?mg/dL) for saxagliptin 2.5, 5, and 10?mg, respectively, vs. +6?mg/dL for placebo (p?=?0.0002, p?=?0.0074, p?<?0.0001, respectively). More saxagliptin-treated patients achieved HbA_1c?<?7% at week 24 (35% [p?=?NS], 38% [p?=?0.0443], 41% [p?=?0.0133]) for saxagliptin 2.5, 5, and 10?mg, respectively, than placebo (24%). PPG-AUC was reduced for saxagliptin 2.5, 5, and 10?mg (?6868, ?6896, ?8084?mg·min/dL, respectively) vs. placebo (?647?mg·min/dL) with statistical significance demonstrated for saxagliptin 5?mg (p?=?0.0002) and 10?mg (p?<?0.0001). HbA_1c, FPG, and PPG-AUC reductions were also observed in the OLC at 24 weeks. In the MTC, adverse event frequency was similar across all study arms. No cases of confirmed hypoglycemia (symptoms, with fingerstick glucose ≤50?mg/dL) were observed in either cohort. Saxagliptin was not associated with weight gain. Study limitations included the lack of a control group for the OLC and the use of prespecified rescue criteria, which limited the exposure time during which patients could remain on their originally randomized medication without the introduction of additional antihyperglycemic rescue treatment.

Conclusions: Once-daily saxagliptin monotherapy for 24 weeks was generally well tolerated and demonstrated clinically meaningful reductions in key parameters of glycemic control vs. placebo.

Trial Registration: Clinical Trials NCT00121641     

Secondary prevention of diabetic patients with coronary artery disease in cardiac rehabilitation: risk factors,treatment and target level attainment*

ABSTRACT

Introduction: Diabetic patients who have suffered from an acute coronary syndrome (ACS) or have had coronary artery bypass graft (CABG) surgery are at very high risk of recurrent cardiovascular events. Their prognosis, however, can be improved if the target values for blood pressure (BP?<?130/80?mmHg) or low density lipoprotein cholesterol [LDL-C?<?2.6?mmol/L (100?mg/dl), optionally?<?1.8?mmol/L (70?mg/dl)] are achieved. It is not known what proportion of diabetic patients receives such stringent secondary prevention measures and achieves target level attainment for BP, lipids and glucose in cardiac rehabilitation (CR).

Methods: During 2003 to 2005, 11?973 diabetic (29.7%) and 28?370 non-diabetic patients (70.3%), predominantly after ACS (74 and 80%), were included in a nationwide registry. At entry and at discharge, patient characteristics, pharmacotherapy and blood pressure, lipids and blood glucose were recorded. In a mixed model approach, temporal changes between centres and within centres, respectively, were analysed.

Results: At discharge, a lower proportion of diabetic patients achieved normalisation of BP (in 2005: <140/90?mmHg: 78.4 vs. 82.9% in non-diabetic patients, p?<?0.001) or <130/80?mmHg (45.5 vs. 49.8%), respectively. LDL-C?<?2.6?mmol/L was more frequently attained in diabetic patients (68.2 vs. 66.5%), as was LDL-C?<?1.8?mmol/L (28.8 vs. 23.0%). Fasting blood glucose was not changed during the observation period, as at discharge almost a quarter of all diabetic patients exceeded the threshold value of 7.0?mmol/L (126?mg/dl). In 2005 at discharge, statin therapy was administered in 93% in both diabetics and non-diabetics, acetylic salicylic acid in 79% in diabetics vs. 80% in non-diabetic patients (clopidogrel: 41 vs. 45%).

Conclusion: Generally there is room for improvement in the management of cardiac risk factors for both patients groups. In diabetic patients in CR at high risk for recurrent cardiac events, in recent years an improvement of the lipid profile has been observed. Hypertension and glycaemia are still not optimally addressed.     

Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind,placebo-controlled,clinical trial

ABSTRACT

Objective: To assess the efficacy and safety of combination therapy with pioglitazone and metformin in Japanese patients with type 2 diabetes.

Research design and methods: During a 12-week observation period 236 patients were treated with metformin 500 or 750?mg/day. 169 patients with a confirmed HbA_1c level ≥ 6.5% were randomized (stratified according to metformin dosage) to receive pioglitazone 15?mg/day for 12 weeks then increased to 30?mg/day for a further 16 weeks (n?=?83), or placebo (n?=?86). Outcome measures included HbA_1c, fasting blood glucose (FBG), percentage of patients achieving HbA_1c?<?6.5%, lipid profile, and other metabolic parameters.

Results: Mean HbA_1c was reduced by 0.67% in patients receiving pioglitazone plus metformin versus an increase of 0.25% in those receiving metformin alone (p?<?0.0001). After 8 weeks’ treatment and until the end of the study, HbA_1c was significantly lower with pioglitazone plus metformin and more patients in this group achieved an HbA_1c?<?6.5% (38.6% vs. 8.1%; p?<?0.0001). FBG was also reduced by a significantly greater amount in patients receiving pioglitazone plus metformin compared with metformin monotherapy (?20.5 vs. 1.9?mg/dl; p?<?0.0001). Combination therapy was associated with significantly increased HDL-cholesterol, total cholesterol, and adiponectin, and significantly decreased levels of fasting insulin, free fatty acids, and homeostasis model assessment insulin resistance (HOMA-R) compared with metformin monotherapy. Overall, combination therapy and monotherapy were equally well tolerated and the incidence of adverse effects ‘possibly’ related to therapy was 15.7% and 11.6% (p?=?0.505), respectively. Edema occurred slightly more often in the combination group (6.0 vs. 1.2%).

Conclusion: Pioglitazone plus metformin significantly improved glycemic control (HbA_1c and FBG), and markers associated with increased insulin resistance and cardiovascular risk compared with metformin monotherapy.

Clinical trial registration number: UMIN 000001110.     

Impact of adjunctive thiazolidinedione therapy on blood lipid levels and glycemic control in patients with type 2 diabetes

SUMMARY

Objective: This study was undertaken to assess the effect of pioglitazone hydrochloride and rosiglitazone maleate on blood lipid levels and glycemic control when these drugs are used as adjunctive therapy in type 2 diabetes.

Research design and methods: Patients with type 2 diabetes receiving metformin and/or sulfonylurea (n?=?829) were evaluated in this national, multicenter, retrospective study. Medical records from 318 endocrinology practices in the USA were randomly selected and screened for study inclusion. Data related to patient demographics and laboratory data were extracted from medical records and analyzed for primary and secondary outcomes.

Main outcome measures: The primary study outcome was the mean change in plasma triglyceride (TG) levels. Secondary outcome measures included mean changes in total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations and hemoglobin A1C levels.

Results:With pioglitazone, TG levels declined by a mean of 51.5?mg/dl (P?<?0.001), HDL-C levels rose by 3.3?mg/dl (P?<?0.001), and no change was seen in LDL-C or TChol. Treatment with rosiglitazone was associated with no significant change in TG levels and a 1.5?mg/dl mean increase in HDL-C (P?<?0.001). Furthermore, rosiglitazone therapy was associated with an 8?mg/dl mean increase in TChol (P?<?0.001), and a 5.8?mg/dl mean increase in LDL-C (P?<?0.001). Hemoglobin A1C levels were significantly reduced by approximately 1% within thiazolidinedione (TZD) cohorts (P?<?0.001), but were not significantly different between study groups (P?=?0.257).

Conclusions: Results from this study suggest that pioglitazone has a more favorable effect on lipid profiles of patients with type 2 diabetes compared with rosiglitazone. In particular, differences were observed in TG and LDL-C levels. Both TZDs were equivalent at reducing hemoglobin A1C levels. These differences in lipid effects may have an impact on cardiovascular outcomes. The full clinical importance of these lipid alterations must be further assessed in prospective trials.     

Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study

ABSTRACT

Background: Reducing low-density lipoprotein cholesterol (LDL-C) levels to National Cholesterol Expert Panel (NCEP) goal is recommended. However, sex-specific effects may influence benefit.

Methods and results: In this post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD) Evaluation [GREACE] study we investigated the extent in vascular event reduction by statin treatment according to sex. From a total of 1600 patients with stable CHD, 624/176 and 632/168 were men/women on atorvastatin or on usual care, respectively. During 3-year follow-up, comparison of atorvastatin treatment with usual care demonstrated a relative risk reduction (RRR) of the primary end point (all vascular events) of 54?%?in women (hazard ratio [HR] 0.46, 95?%?confidence interval [CI] 0.24–0.87, p?=?0.003) and of 50?%?in men (HR 0.50, 95?%?CI 0.32–0.70, p?<?0.001). The fall in LDL-C levels played the key role in end point reduction in both sexes. However, in men there was an additional benefit related to the atorvastatin-induced increase in high density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR), while in women end points were related to a substantial triglycerides (TG) reduction.

Conclusions: Treatment with atorvastatin to the NCEP LDL-C goal compared with “usual care” significantly reduced CHD morbidity and mortality in both men and women. Both men and women benefited from statin treatment possibly with different mechanisms making a contribution over and above LDL-C reduction.