D. P. Mikhailidis

The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study

Background: Little is known about statins in the prevention of dyslipidaemia induced renal function decline. The secondary coronary heart disease (CHD) prevention GREACE study suggested that dose titration with atorvastatin (10–80 mg/day, mean dose 24 mg/day) achieves the national cholesterol educational programme treatment goals and significantly reduces morbidity and mortality, compared with usual care. Aims: To report the effect of statin on renal function compared with untreated dyslipidaemia in both treatment groups. Methods/Results: All patients had plasma creatinine values within the reference range < 115 µmol/litre (13 mg/litre). The on study creatinine clearance (CrCl), as estimated (for up to 48 months) by the Cockroft-Gault formula, was compared within and between treatment groups using analysis of variance to assess differences over time. Patients from both groups not treated with statins (704) showed a 5.2% decrease in CrCl (p < 0.0001). Usual care patients on various statins (97) had a 4.9% increase in CrCl (p  =  0.003). Structured care patients on atorvastatin (783) had a 12% increase in CrCl (p < 0.0001). This effect was more prominent in the lower two quartiles of baseline CrCl and with higher atorvastatin doses. After adjustment for 25 predictors of all CHD related events, multivariate analysis revealed a hazards ratio of 0.84 (confidence interval 0.73 to 0.95; p  =  0.003) with every 5% increase in CrCl. Conclusions: In untreated dyslipidaemic patients with CHD and normal renal function at baseline, CrCl declines over a period of three years. Statin treatment prevents this decline and significantly improves renal function, potentially offsetting an additional factor associated with CHD risk.

Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia.

Beyond allopurinol and the well-established uricosuric drugs, several other agents can decrease serum uric acid (SUA) levels, such as losartan, fenofibrate and some non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs increase renal urate excretion. Hyperuricaemia and gout are common problems (at least 1% of Western men are affected by gout). Raised SUA levels increase the incidence of acute gout and renal calculi. Hyperuricaemia may also predict an increased risk of vascular events. Therefore, lowering SUA levels is of clinical relevance. In this review we consider the effect on SUA levels of drugs that are prescribed for indications other than treating hyperuricaemia. These drugs may obviate the need for specific treatment (e.g. allopurinol) aimed at lowering SUA levels. Furthermore, because hyperuricaemic patients may already be on several drugs (e.g. due to associated dyslipidaemia, hypertension and/or arthritis) compliance may be improved by avoiding additional medication. The potential for adverse effects associated with polypharmacy would also be decreased.

Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study

ABSTRACT Background: Obesity is becoming increasingly common worldwide and is strongly associated with the metabolic syndrome (MetS). MetS is considered to be a cluster of risk factors that increase the risk of vascular events. Objective: In an open-label randomised study (the FenOrli study) we assessed the effect of orlistat and fenofibrate treatment, alone or in combination on reversing the diagnosis of the MetS (primary end-point) as well as on anthropometric and metabolic parameters (secondary end-points) in overweight and obese patients with MetS but no diabetes. Methods: Overweight and obese patients (N = 89, body mass index (BMI) > 28 kg/m2) with MetS [as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria] participated in the study. Patients were prescribed a low-calorie low-fat diet and were randomly allocated to receive orlistat 120 mg three times a day (tid) (O group), micronised fenofibrate 200 mg/day (F group), or orlistat 120 mg tid plus micronised fenofibrate 200 mg/day (OF group). Body weight, BMI, waist circumference, blood pressure, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL‐C), high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, triglyceride, creatinine (SCr) and uric acid (SUA) levels, as well as homeostasis model assessment (HOMA) index and liver enzyme activities were measured at baseline and after 3 months of treatment. Results: Of the 89 patients enrolled, three (one in each group) dropped out during the study due to side effects. After the 3‐month treatment period, 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (primary end-point, p < 0.0001 vs. baseline in all treatment groups). No significant difference in the primary end-point was observed between the three treatment groups. Significant reductions in body weight, BMI, waist circumference, blood pressure, TC, LDL‐C, non-HDL‐C, triglyceride and SUA levels, as well as gamma-glutamyl transpeptidase activity and HOMA index were observed in all treatment groups. In the OF group a greater decrease in TC (–26%) and LDL‐C (–30%) was observed compared with that in the O and F groups ( p < 0.01) and a more pronounced reduction of triglycerides (–37%) compared with that in the O group ( p < 0.05). SUA levels and alkaline phosphatase activity decreased more in the F and OF groups compared with the O group ( p < 0.05). Moreover, SCr significantly increased and estimated creatinine clearance decreased in the F and OF groups but they were not significantly altered in the O group ( p < 0.01 for the comparison between O and either F or OF groups). Glucose (in groups O and OF), as well as insulin levels and HOMA index (in all groups), were significantly reduced after treatment ( p < 0.05 vs. baseline). Conclusion: The combination of orlistat and micronised fenofibrate appears to be safe and may further improve metabolic parameters in overweight and obese patients with MetS compared with each monotherapy.

Effect of statins and ACE inhibitors alone and in combination on clinical outcome in patients with coronary heart disease.

We assessed the ‘synergy’ of statins and angiotensin-converting enzyme inhibitors (ACEI) in reducing vascular events in patients with coronary heart disease (CHD). The GREek Atorvastatin and CHD Evaluation (GREACE) Study, suggested that aggressive reduction of low density lipoprotein cholesterol to 2.59 mmol/l (<100 mg/dl) significantly reduces morbidity and mortality in CHD patients, in comparison to undertreated patients. In this post hoc analysis of GREACE the patients (n=1600) were divided into four groups according to long-term treatment: Group A (n=460 statin+ACEI), B (n=420; statin, no ACEI), C (n=371;no statin, on ACEI), and D (n=349; no statin, no ACEI). Analysis of variance was used to assess differences in the relative risk reduction (RRR) in ‘all events’ (primary end point) between groups. During the 3-year follow-up there were 292 cardiovascular events; 45 (10% of patients) in group A, 61 (14.5%) in group B, 91 in group C (24.5%) and 95 events in group D (27%). The RRR (95% confidence interval (CI) in the primary end point in group A was 31%, (95% CI −48 to −6%, P=0.01) in comparison to group B, 59% (95% CI −72 to −48%, P<0.0001) to group C and 63% (95% CI −74 to −51%, P<0.0001) to group D. There was no significant difference in RRR between groups C and D (9%, CI −27–10%, P=0.1). Other factors (eg the blood pressure) that can influence clinical outcome did not differ significantly between the four treatment groups. In conclusion, the statin+ACEI combination reduces cardiovascular events more than a statin alone and considerably more than an ACEI alone. Aggressive statin use in the absence of an ACEI also substantially reduced cardiovascular events. Treatment with an ACEI in the absence of a statin use reduced clinical events in comparison to patients not treated with an ACEI but not significantly, at least in these small groups of patients.

Fibrinogen: a predictor of vascular disease.

Raised plasma fibrinogen levels are associated with an increased risk of vascular events. This may be mediated by adverse effects of fibrinogen on plasma viscosity, coagulation, platelet activity, inflammation and atherogenesis. However, there is as yet no drug that specifically lowers plasma fibrinogen levels on a long-term basis. Thus, we do not have intervention trials demonstrating that lowering plasma fibrinogen levels will result in a decreased risk of vascular events. However, such a trial may never happen unless a specific agent is discovered or designed. Several drugs that are used in vascular disease prevention (e.g. lipid lowering agents and antihypertensives) may influence plasma fibrinogen levels. Whether such an additional effect accounts for variations in the benefit resulting from the use of different drugs within the same class remains to be established. The debate continues as to whether fibrinogen is just a marker of vascular risk or whether lowering its circulating levels will result in a significant decrease in clinically relevant endpoints. Whatever the case, the measurement of plasma fibrinogen levels is likely to provide a more comprehensive estimation of risk.

Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia.

ABSTRACT Objective: Hypercholesterolaemia is a major risk factor for atherosclerosis and coronary heart disease. Treatment with lipid lowering agents reduces the risk of vascular events. Colesevelam is a novel bile acid sequestrant (BAS) indicated for the treatment of hypercholesterolaemia, either as monotherapy or in combination with statins. Scope: This article reviews the efficacy, tolerability and safety of colesevelam in clinical practice. The literature search was based on a PubMed search up to January 2008. Findings: Colesevelam, used alone or in combination with other hypolipidaemic agents (statins, ezetimibe and fenofibrate), has an overall favourable effect on lipid profile. Specifically, colesevelam reduces total and low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B levels and increases high-density lipoprotein cholesterol and apolipoprotein AI. However, colesevelam may slightly raise triglyceride levels. Colesevelam can improve glycaemic control in diabetic patients. Moreover, it may have anti-inflammatory properties, as it can reduce high sensitivity C-reactive protein concentration. Colesevelam almost lacks the intense side effects of previously used BASs, thus resulting in better patient compliance. However, the dose regimen consisting of up to 7 tablets/day and high cost may limit its use. Conclusions: Colesevelam is a safe alternative for those intolerant to other lipid lowering medication. This BAS also provides an option for patients who do not reach their LDL-C goal despite treatment with a statin.

Nitric oxide in the lower urinary tract: physiological and pathological implications: NITRIC OXIDE IN THE LOWER URINARY TRACT

The collection and storage of urine by the detrusor and its periodic expulsion through the bladder neck and urethra (bladder outlet) are dependent upon complex neural pathways [1]. The neurotransmitters and the mechanisms that regulate these pathways are not only of research interest but may also provide a basis for therapeutic intervention in patients with voiding dysfunction. A decade ago, the study of amine mediators such as noradrenaline and acetylcholine (ACh) released by the sympathetic and parasympathetic nervous systems, respectively, dominated pharmacological research in the lower urinary tract. Recently, several nonadrenergic, noncholinergic (NANC) mediators have been recognized to play a signi®cant role in the physiology of the lower urinary tract [2]. Over the last decade, nitric oxide (NO) has increasingly gained recognition as an important cell mediator with a broad range of functions in the lower urinary tract. It is considered to be an important inhibitory NANC neurotransmitter as well as a modulator of the cellular immune response to invading microorganisms and tumour cells in the lower urinary tract of different animal species, including humans. This review examines the possible mechanisms by which NO may in ̄uence the function of the lower urinary tract, emphasising the source and synthesis of NO, its mechanisms of action and its evolving role in the pathophysiology of lower urinary tract disorders.

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 hormonal treatment on lipids in patients with cancer

Patients with malignant disease may need hormonal therapy as primary or adjuvant treatment or for palliation. Oestrogens usually decrease serum levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), increase high density lipoprotein cholesterol (HDL-C) concentration, but induce an elevation in serum triglyceride (TG) levels. Progestogens in the short-term decrease TC, LDL-C and HDL-C concentrations, and increase TG levels. In long-term treatment, progestogens usually have a small impact on lipid profile. Tamoxifen induces a decrease in TC and LDL-C levels, an increase in TG concentration, whereas either an increase, decrease or no change has been reported for HDL-C levels. Aromatase inhibitors induce an elevation, reduction or no change in lipid variables. These results depend mainly on the trial design, i.e. whether patients received prior treatment with tamoxifen or not and the duration of therapy. Gonadorelin analogues increase all lipid variables, but LDL-C alterations are usually non-significant. Anti-androgens usually decrease TC, LDL-C and HDL-C levels, whereas TG alterations vary. Information regarding the effects on lipid profile of somatostatin analogues is available almost exclusively in patients with acromegaly. In these patients somatostatin analogues usually induce no change or a decrease in TC and LDL-C levels, whereas they increase HDL-C and decrease TG serum concentrations. Oncologists should consider the lifestyle changes, and if needed hypolipidemic treatment, used to lower cardiovascular risk in non-cancer patients. Tamoxifen may rarely cause serious TG-related side effects, like acute pancreatitis.

Fish oils and vascular disease prevention: an update.

Considerable epidemiological data confirmed the existence of favorable associations between fish consumption and mortality from cardiovascular disease. Accumulating evidence suggests that n-3 polyunsaturated fatty acids supplementation is an effective additive treatment for the primary and secondary prevention of cardiovascular disease. Another indication for the use of n-3 PUFA is the treatment of hypertriglyceridemia as monotherapy or in combination with other lipid lowering agents (e.g. statins or fibrates). However, high doses of n-3 PUFA are required for this effect (e.g. 3-4 g/day). Fish oils may be acting via several mechanisms that include antiarrhythmic, antithrombotic and anti-inflammatory effects as well as plaque stabilization. Despite the current evidence supporting a beneficial effect of fish oils on vascular disease, more definitive studies than the ones already performed are required. Some ongoing trials may provide further insight into the indications for fish oil supplementation. This review considers the mechanisms accounting for the cardioprotective properties of n-3 polyunsaturated fatty acids. We also discuss the epidemiological and interventional studies evaluating the relationship between n-3 polyunsaturated fatty acids consumption and cardiovascular disease.