John Reckless

Efficacy and tolerability of fluvastatin extended-release delivery system: a pooled analysis.

BACKGROUND At high doses, the pharmacokinetics of fluvastatin immediate-release (IR) are nonlinear, possibly due to saturation of hepatic uptake. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation without elevating systemic drug levels. OBJECTIVE This pooled analysis compared the efficacy and tolerability of extended-release (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising high-density lipoprotein cholesterol (HDL-C) levels in patients with hypercholesterolemia. METHODS Data were pooled from 3 double-blind, randomized, active-controlled, multicenter, parallel-group studies that compared changes in lipid and apolipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged > or =18 years with primary hypercholesterolemia (consistently elevated LDL-C level [> or =160 mg/dL] and plasma TG levels < or =400 mg/dL). The primary efficacy variable was percent change in LDL-C from baseline. RESULTS The pooled analysis provided an intent-to-treat efficacy study population of 1674 patients. At 4 weeks, fluvastatin XL 80 mg HS reduced LDL-C levels by a mean of 36.3% (median 38%), significantly greater than a mean reduction of 25.9% (median 27%) seen with fluvastatin IR 40 mg HS, and an incremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 and 24 weeks, fluvastatin XL 80 mg HS provided an LDL-C reduction equivalent to fluvastatin IR 40 mg BID (P < 0.001 for noninferiority). Significant, dose-related changes in HDL-C, LDL-C:HDL-C ratio, total cholesterol, TG, and apolipoprotein A-I and apolipoprotein B levels also occurred. Mean HDL-C level increased by 8.7% and median TG level decreased by 19% with fluvastatin XL 80 mg HS (P < 0.001 and P < 0.05 vs fluvastatin IR 40 mg HS, respectively). Maximum mean increases in HDL-C level (21%) and median decreases in TG level (31%) with fluvastatin XL 80 mg HS occurred in patients with type IIb dyslipidemia and the highest baseline TG. Adverse events were mild, with similar frequency in all treatment groups. CONCLUSIONS Once-daily administration of fluvastatin XL 80 mg provides enhanced efficacy with an additional 10.4% reduction in LDL-C levels compared with fluvastatin IR 40 mg HS, and superior increases in HDL-C levels, particularly in patients with elevated TG levels (P < 0.05 vs fluvastatin IR 40 mg HS). Fluvastatin XL 80 mg HS has a good tolerability profile and is effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.

Long‐term cost‐effectiveness of weight management in primary care

Background:  As obesity prevalence and health‐care costs increase, Health Care providers must prevent and manage obesity cost‐effectively.

Lipid-altering efficacy of ezetimibe⁄simvastatin 10⁄40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study

Background:  The aim of this study was to investigate the efficacy and safety profile of switching to ezetimibe/simvastatin (Eze/Simva) 10/40 mg compared with doubling the statin dose upon discharge in patients taking a statin and admitted to the hospital for the investigation of a coronary event.

The effects of insulin on the level and activity of the GLUT4 present in human adipose cells

SummaryHuman adipose cells are much less responsive to insulin stimulation of glucose transport activity than are rat adipocytes. To assess and characterize this difference, we have determined the rates of 3-O-methyl-D-glucose transport in human adipose cells and have compared these with the levels of glucose transporter 4 (GLUT4) assessed by using the bis-mannose photolabel, 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-(D-mannos-4-yloxy)-2-propylamine, ATB-BMFA. The rates of 3-O-methyl-D-glucose transport and the cell-surface level of GLUT4 are very similar in the human and rat adipocyte in the basal state. The Vmax for 3-O-methyl-D-glucose transport in fully insulin-stimulated human adipose cells is 15-fold lower than in rat adipose cells. Photolabelling of GLUT4 suggests that this low transport activity is associated with a low GLUT4 abundance (39·104 sites/cell; 19.9·104 sites at the cell surface). The turnover number for human adipose cell GLUT4 (5.8·104 min−1) is similar to that observed for GLUT4 in rat adipose cells and the mouse cell line, 3T3L1. Since 50% of the GLUT4 is at the cell surface of both human and rat adipose cells in the fully insulin-stimulated state, an inefficient GLUT4 exocytosis process cannot account for the low transport activity. The intracellular retention process appears to have adapted to release, in the basal state, a greater proportion of the total-cellular pool of GLUT4 to the cell surface of the larger human adipocytes. These cell-surface transporters are presumably necessary to provide the basal metabolic needs of the adipocyte. As a consequence of this adaptation to cell size and surface area, the residual intracellular-reserve pool of GLUT4 that is available to respond to insulin is lower in the human than in the rat adipocyte.

Projected cost-effectiveness of ezetimibe/simvastatin compared with doubling the statin dose in the United Kingdom: findings from the INFORCE study.

OBJECTIVE To evaluate the incremental cost-effectiveness ratio (ICER) of switching to ezetimibe/simvastatin (Eze/Simva) compared with doubling the submaximal statin doses, in patients with acute coronary syndrome (ACS) events in the INFORCE study. METHODS Lifetime treatment costs and benefits were computed using a Markov model. Model inputs included each patients cardiovascular risk factor profile and actual lipid values at baseline and 12 weeks (endpoint). Cardiovascular event and drug costs were discounted at 3.5%. Age-specific utilities were based on UK literature values and non-coronary heart disease mortality rates on the Office of National Statistics data. In the INFORCE study, 384 patients taking statins at stable doses for ≥6 weeks before hospital admission were stratified by statin dose/potency (low, medium, and high) and then randomized to doubling the statin dose or switching to Eze/Simva 10/40mg for 12 weeks. RESULTS The Eze/Simva group (n=195) had a higher mean baseline total cholesterol than the double-statin group (n=189). Analyses were adjusted for baseline characteristics. In the INFORCE study, Eze/Simva reduced low-density lipoprotein cholesterol (LDL-C) by ∼30% (vs. 4% with doubling statin doses) and significantly enhanced LDL-C goal attainment. In the cost-effectiveness analysis, Eze/Simva conferred 0.218 incremental discounted quality-adjusted life year (QALY) at a discounted incremental cost of £2524, for an ICER of £11,571/QALY (95% confidence interval=£8181-£18,600/QALY). The ICER was £13,552/QALY, £11,930/QALY, and £10,148/QALY in the low-, medium-, and high-potency strata, respectively. CONCLUSIONS Switching to Eze/Simva 10/40 mg is projected to be a cost-effective treatment (vs. double-statin) in UK patients with ACS.

Intensive versus guideline blood pressure and lipid lowering in patients with previous stroke: main results from the pilot ‘Prevention Of Decline in Cognition After Stroke Trial’ (PODCAST) randomised controlled trial

Background Stroke is associated with the development of cognitive impairment and dementia. We assessed the effect of intensive blood pressure (BP) and/or lipid lowering on cognitive outcomes in patients with recent stroke in a pilot trial. Methods In a multicentre, partial-factorial trial, patients with recent stroke, absence of dementia, and systolic BP (SBP) 125–170 mmHg were assigned randomly to at least 6 months of intensive (target SBP <125 mmHg) or guideline (target SBP <140 mmHg) BP lowering. The subset of patients with ischaemic stroke and total cholesterol 3.0–8.0 mmol/l were also assigned randomly to intensive (target LDL-cholesterol <1.3 mmol/l) or guideline (target LDL-c <3.0 mmol/l) lipid lowering. The primary outcome was the Addenbrooke’s Cognitive Examination-Revised (ACE-R). Results We enrolled 83 patients, mean age 74.0 (6.8) years, and median 4.5 months after stroke. The median follow-up was 24 months (range 1–48). Mean BP was significantly reduced with intensive compared to guideline treatment (difference –10·6/–5·5 mmHg; p<0·01), as was total/LDL-cholesterol with intensive lipid lowering compared to guideline (difference –0·54/–0·44 mmol/l; p<0·01). The ACE-R score during treatment did not differ for either treatment comparison; mean difference for BP lowering -3.6 (95% CI -9.7 to 2.4), and lipid lowering 4.4 (95% CI -2.1 to 10.9). However, intensive lipid lowering therapy was significantly associated with improved scores for ACE-R at 6 months, trail making A, modified Rankin Scale and Euro-Qol Visual Analogue Scale. There was no difference in rates of dementia or serious adverse events for either comparison. Conclusion In patients with recent stroke and normal cognition, intensive BP and lipid lowering were feasible and safe, but did not alter cognition over two years. The association between intensive lipid lowering and improved scores for some secondary outcomes suggests further trials are warranted. Trial Registration ISRCTN ISRCTN85562386

Efficacy of Ezetimibe/Simvastatin 10/40 mg Compared to Doubling the Dose of Low-, Medium- and High-Potency Statin Monotherapy in Patients with a Recent Coronary Event

Objective: The aim of the study was to compare the efficacy/safety of doubling the dose of low-, medium- and high-potency statins on lipids/lipoproteins versus ezetimibe/simvastatin (EZE/SIMVA) 10/40 mg in patients with a recent coronary event. Methods: In this open-label study, patients were stratified by baseline statin therapy (low, medium and high potency) and randomized equally to statin dose doubling or EZE/SIMVA 10/40 mg for 12 weeks. Primary analysis concerned change in low-density lipoprotein cholesterol for the whole population. Treatment-by-stratum interaction evaluated the consistency of treatment effect across statin potency strata. Post hoc analysis of between-group efficacy within strata was performed using ANCOVA. Results: Within each stratum, EZE/SIMVA produced significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, apolipoprotein B and non-high-density lipoprotein cholesterol (HDL-C) compared to statin doubling. Numerical trends toward smaller between-group reductions were observed with higher-potency statins and reached statistical significance for apolipoprotein B and non-HDL-C. No significant between-group differences in HDL-C and C-reactive protein were observed within each stratum. EZE/SIMVA produced larger reductions in triglycerides versus low-potency statin, whereas it was similarly effective compared with intermediate-/high-potency statins. The safety/tolerability profiles of the treatments were similar across the strata. Conclusions: EZE/SIMVA 10/40 mg produced greater improvements in lipids with a similar safety profile compared to doubling the dose of low-, medium- and high-potency statins.

Association of a reduction in low-density lipoprotein cholesterol with incident cardiovascular and cerebrovascular events among people with type 2 diabetes mellitus.

Background Although there is overwhelming evidence that reducing low-density lipoprotein cholesterol (LDL-C) with statins leads to reductions in cardiovascular disease, less is known about the effects in persons with type 2 diabetes mellitus (T2DM) without pre-existing vascular events. Methods and results Using the UK-based General Practice Research Database we conducted a retrospective cohort study of 21,998 T2DM patients aged 35–69 with ≥2 prescriptions for lipid-modifying therapy (2000–2009). We categorized LDL-C change (mmol/l) between last available and baseline lipid values as reduction (≥3.0, 2.0–2.9, 1.0–1.9, 0.3–0.9), no-change (±0.2 of baseline), or increase (>0.2). Outcomes were incident composite cardiovascular (n = 621) and cerebrovascular events (n = 274). We estimated hazard ratios (HRs) of study outcomes and 95% confidence intervals (CIs) for LDL-C change compared with the no-change group. Compared to no changes, adjusted HRs of cardiovascular events for a reduction ≥3.0 and a reduction between 2.0–2.9 were 0.41 (95% CI: 0.23–0.71) and 0.51 (95% CI: 0.34–0.76) (p for linear trend <0.001). LDL-C reduction yielded a decreased cerebrovascular event risk compared to no change, even with the smallest reduction (adjusted HR = 0.59, 95% CI: 0.36–0.98). Conclusions Decreasing LDL-C is associated with a reduced risk of cardiovascular and cerebrovascular events among T2DM patients without such pre-existing events. The magnitude of the protective effect on cerebrovascular events is less certain, and further studies are warranted.

Baseline characteristics, analysis plan and report on feasibility for the Prevention Of Decline in Cognition After Stroke Trial (PODCAST)

BackgroundA common complication after stroke is development of cognitive impairment and dementia. However, effective strategies for reducing the risk of developing these problems remain undefined. Potential strategies include intensive lowering of blood pressure (BP) and/or lipids. This paper summarises the baseline characteristics, statistical analysis plan and feasibility of a randomised control trial of blood pressure and lipid lowering in patients post-stroke with the primary objective of reducing cognitive impairment and dementia.MethodsThe Prevention Of Decline in Cognition After Stroke Trial (PODCAST) was a multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial internal pilot trial running in secondary and primary care. Participants without dementia were enrolled 3–7 months post ischaemic stroke or spontaneous intracerebral haemorrhage, and randomised to intensive versus guideline BP lowering (target systolic BP <125 mmHg versus <140 mmHg); patients with ischaemic stroke were also randomised to intensive or guideline lipid lowering (target LDL cholesterol <1.4 mmol/L versus <3 mmol/L). The primary outcome was the Addenbrooke’s Cognitive Examination-Revised; a key secondary outcome was to assess feasibility of performing a large trial of one or both interventions. Data are number (%) or mean (standard deviation). The trial was planned to last for 8 years with follow-up between 1 and 8 years. The plan for reporting the main results is included as Additional file 2.Results83 patients (of a planned 600) were recruited from 19 UK sites between 7 October 2010 and 31 January 2014. Delays, due to difficulties in the provision of excess treatment costs and to complexity of follow-up, led to few centres taking part and a much lower recruitment rate than planned. Patient characteristics at baseline were: age 74 (SD 7) years, male 64 (77 %), index stroke ischaemic 77 (93 %), stroke onset to randomisation 4.5 [SD 1.3] months, Addenbrooke’s Cognitive Examination-Revised 86 (of 100, SD 8), Montreal Cognitive Assessment 24 (of 30, SD 3), BP 147/82 (SD 19/11) mmHg, total cholesterol 4.0 (SD 0.8) mmol/L and LDL cholesterol 2.0 (SD 0.7) mmol/L, modified Rankin Scale 1.1 (SD 0.8).ConclusionLimited recruitment suggests that a large trial is not feasible using the current protocol. The effects of the interventions on BP, lipids, and cognition will be reported in the main publication.Trial registrationISRCTN85562386 registered on 23 September 2009

Diet and Type I (insulin-dependent) diabetes

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