Reduction in Arterial Stiffness Index (SI) in Response to Combination Antioxidant Therapy.

Antioxidants reduce arterial stiffness, but the effects previously reported are weak. A systematic review of the antioxidants vitamin E, vitamin C, vitamin A, and beta-carotenes (the most commonly studied antioxidants) on pulse wave velocity (PWV) found an effect size of only -0.20 (approximately -16 m/s or -2.5%). Studies in rats of the potent pro-oxidant substance acetaldehyde have shown that combinations of sulfur-containing antioxidants, including thiamine and l-cysteine, with ascorbic acid potently protect against oxidative-stress-mediated mortality. The effects of these combinations of oxidants on PWV have not been studied. The present study evaluated the effects of 2 weeks of therapy with a combination of sulfur-containing antioxidants (cysteine, thiamine, and pyridoxine) in combination with ascorbic acid on stiffness index (SI), a measure of arterial stiffness that is strongly correlated with PWV, using a Pulse Trace recorder in a diverse group of 78 volunteers. SI fell by -1.7 m/s relative to placebo (95% confidence intervals -0.6 to -2.7 m/s), a reduction of -19% (95% confidence intervals -9% to -31%). The Glass effect size was 1.4, indicating a very strong treatment effect which was substantially greater than the effect size found in previous studies of antioxidants. PWV reduction was correlated significantly with increasing age. Further studies of similar antioxidant combinations are required to determine whether they are of value in the treatment or prevention of cardiovascular disease.

Systematic review and meta-analysis of the association between all-cause mortality and statin therapy in patients with preserved ejection fraction heart failure (HFpEF).

BACKGROUND: Heart failure (HF) is a growing global health burden increasing in prevalence as the average age of the population rises. HF with preserved ejection fraction (HFpEF) is defined as EF that is ≥50% and represents almost half of the population with HF. METHODS: We conducted a systematic review and meta-analysis exploring an association between HFpEF and statin use on all-cause mortality and cardiovascular rehospitalisation. Searches were conducted in MEDLINE via Ovid, The Cochrane Library for clinical trials in CENTRAL and Embase via Ovid for articles published between 1 January 2000 and 2 July 2021. Risk of bias was assessed using the Newcastle-Ottawa Scale and evidence rated for quality using the GRADE approach. RESULTS: A total of 19 studies were included in the review. The analysis suggests a risk reduction of 27% for the statin exposed participants compared to the statin non-exposed participants (HR 0.73, 95% CI: 0.68-0.79) with regard to all-cause mortality. There is a low level of heterogeneity (I2 = 38%) associated with this result that has been accounted for by using a random effects model, however given the included studies are observational, the quality of the evidence is rated as low. Information on rehospitalisation was insufficient for determining the impact of statin use on rehospitalisations. CONCLUSION: Our meta-analysis revealed a reduction in all-cause mortality in patients with HFpEF on statin therapy. Considering the outcomes from this meta-analysis there is a need for high level studies to provide quality evidence on the use of statins in patients with HFpEF.

Drug Interactions of Direct-Acting Oral Anticoagulants.

In recent years, new direct-acting oral anticoagulants (DOACs) have been introduced into clinical practice that specifically inhibit either factor Ia or Xa. These drugs have, to a large extent, replaced warfarin for the treatment of venous thrombosis, pulmonary embolism, and non-valvular atrial fibrillation. They have potential advantages over warfarin in providing more stable anticoagulation and the lack of a need for regular venesection to monitor activity. They also have the promise of less drug and food interactions. All of these drugs are substrates for the permeability glycoprotein (P-gp) excretion system, and several are metabolised, in part, by cytochrome P450 (CYP) 3A4. This current article assesses the interactions that do or may occur with the DOACs, particularly with respect to the P-gp and CYP3A4 systems.

Cardiovascular effects of drugs used to treat Alzheimer's disease.

Drugs that are used to treat Alzheimer's disease include the acetyl cholinesterase inhibitors (ACHIs) donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine. Adverse cardiovascular events with these drugs are very uncommon. However, there is evidence that ACHI therapy is associated with a small but significant increase in the risk of syncope and bradycardia. There are also a few reports that these drugs may occasionally be associated with QT prolongation and torsades de pointes ventricular tachycardia. Adverse cardiovascular effects of ACHIs including syncope and bradycardia are less common than their adverse gastrointestinal effects, but they remain important considerations in susceptible individuals. In contrast, animal studies and some observational studies suggest that ACHIs may reduce myocardial infarction and cardiovascular mortality and have favourable effects on hemodynamics and survival in heart failure. Further research is required to confirm these potential beneficial effects. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use.

Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer.

BACKGROUND: Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer. METHODS: The pharmacokinetics of phenoxodiol was studied following a single intravenous (iv) bolus dose and during a continuous intravenous infusion. Three men with prostate cancer and 3 women with breast cancer received IV bolus phenoxodiol (5 mg/kg) and plasma was sampled for free and total phenoxodiol levels. On a separate occasion 5 of the same patients received a continuous intravenous infusion of phenoxodiol (2 mg/kg/h) and plasma was again sampled for free and total phenoxodiol levels. Phenoxodiol was measured using gradient HPLC with ultraviolet detection. RESULTS: Following bolus injection, free and total phenoxodiol appeared to follow first order pharmacokinetics. The elimination half-lives for free and total phenoxodiol were 0.67 ± 0.53 h and 3.19 ± 1.93 h, respectively, while the total plasma clearance rates were 2.48 ± 2.33 L/h and 0.15 ± 0.08 L/h, respectively. The respective apparent volumes of distribution were 1.55 ± 0.69 L/kg and 0.64 ± 0.51 L/kg. During continuous intravenous infusion, free phenoxodiol accumulated rapidly to reach a mean concentration at steady state of 0.79 ± 0.14 µg/ml after 0.87 ± 0.18 h. The apparent accumulation half-life of free phenoxodiol was 0.17 ± 0.04 h while the plasma clearance during continuous infusion was 1.29 ± 0.23 L/h. CONCLUSIONS: Phenoxodiol has a short plasma half-life, particularly in the free form, leading to a rapid attainment of steady state levels during continuous intravenous infusion. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000334000.

Clinical pharmacology of isoflavones and its relevance for potential prevention of prostate cancer.

Isoflavones are phytoestrogens that have pleiotropic effects in a wide variety of cancer cell lines. Many of these biological effects involve key components of signal transduction pathways within cancer cells, including prostate cancer cells. Epidemiological studies have raised the hypothesis that isoflavones may play an important role in the prevention and modulation of prostate cancer growth. Since randomized phase III trials of isoflavones in prostate cancer prevention are currently lacking, the best evidence for this concept is presently provided by case control studies. However, in vitro data are much more convincing in regard to the activity of a number of isoflavones, and have led to the development of genistein and phenoxodiol in the clinic as potential treatments for cancer. In addition, the potential activity of isoflavones in combination with cytotoxics or radiotherapy warrants further investigation. This review focuses on the clinical pharmacology of isoflavones and its relevance to their development for use in the prevention of prostate cancer, and it evaluates some of the conflicting data in the literature.

Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors.

The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. Increased arterial stiffness has been proposed as a common pathway by which INSR leads to increased cardiovascular risk. We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. There is emerging evidence that early stages of INSR may be characterized by increased basal nitric oxide activity and increased activity of non-NO vasodilators such as endothelial derived hyperpolarization factor (EDHF) which is manifest by reduced arterial stiffness. Depletion of NO or ineffectiveness of NO mediated vasodilator mechanisms associated with the progression of INSR to type 2 diabetes may result in increased arterial stiffness, which predicts the development of cardiovascular disease. Thus in the early stages of INSR, increased NO and EDHF activity may represent compensatory mechanisms to early vascular damage. The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. AT2R activity is increased in early in INSR and may contribute to the apparent increase in basal NO activity. AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors.

Effects of cardiovascular angiotensin II type 1 receptor blockade on nitric oxide synthase inhibition in patients with insulin resistance syndrome.

BACKGROUND: There is evidence that in the early stages of type II diabetes, the cardiovascular system compensates by increasing endothelial nitric oxide synthase (e-NOS) expression. In the advanced stages of disease, e-NOS is diminished, and is associated with endothelial dysfunction. Angiotensin II, acting via the angiotensin II type 1 (AT(1)) receptor, is central to the development of endothelial dysfunction. The effect of AT(1) receptor blockade on NOS expression and activity in humans with early insulin resistance syndrome (INSR) has not been previously investigated. Eight subjects with INSR participated in a randomized, double-blind, placebo-controlled, crossover study. Subjects were randomized to receive telmisartan or placebo (1 month of each) in a two-period crossover study with a 1-week washout period in between. The arterial stiffness and haemodynamic response to intravenous L-nitro-monomethyl arginine (L-NMMA 3mg/kg) was assessed at baseline and at the end of each treatment phase. SI (Stiffness index, a measure of large artery stiffness) and RI (Reflection index, small- to medium-sized arterial stiffness) were measured using digital photoplethysmography. Haemodynamic parameters [Heart rate (HR), Systolic blood pressure (SBP), Diastolic BP (DBP) and systemic vascular resistance index (SVRI)] were measured non-invasively using trans-thoracic bioimpedance. RESULTS: Telmisartan significantly reduced baseline SI, SBP, DBP and SVRI. Infusion of L-NMMA produced a significant increase in RI and a significant reduction in HR during placebo therapy. Telmisartan therapy attenuated these responses. CONCLUSION: Telmisartan therapy reduced NOS activity and/or expression in these subjects, possibly because of improved vascular function arising from AT(1) receptor blockade.

Complex valve disease: pre-surgical functional capacity evaluation using peak oxygen consumption.

BACKGROUND AND AIM OF THE STUDY: Complex heart valve disease constitutes both mixed and multiple valve pathologies that coexist in a single heart. The chronicity of complex valve disease results in a slow decline in functional capacity. Currently, very few data exist relating to chronic complex valve disease. The clinical assessment of exertional dyspnea (NYHA class) is central to the decision to operate and predict a prognosis. Dyspnea causes significant functional limitations. Peak oxygen consumption (peak VO2) is the 'gold standard' of objectively measuring functional aerobic capacity, and is an important predictor of prognosis. The onset of dyspnea is the most common indication for valve surgery. The study aim, in patients with complex valve disease, was to: (i) objectively assess functional aerobic capacity using peak VO2; and (ii) compare the differences between NYHA classes I and II in relation to body composition, echocardiographic severity, and functional capacity METHODS: A total of 45 patients with complex valve disease, who had been referred for the timing of surgery, was evaluated. The control group comprised 15 healthy subjects. All patients underwent a clinical assessment (to determine NYHA class), echocardiography and cardiopulmonary testing (peak VO2). RESULTS: Patients with complex valve disease achieved significantly lower peak VO2 values than controls (16 +/- 5.9 versus 31.4 +/- 5.9 ml/kg/min; p = 0.0001). The peak VO2 (percentage predicted) was significantly different between asymptomatic (NYHA class I) patients (70.9 +/- 20%) and symptomatic (NYHA class II) patients (55.1 +/- 21%; p = 0.003), with an overlap between classes. There was no significant difference in the echocardiographic severity of the valve lesions between NYHA classes. In a multivariable regression analysis, the peak VO2 and VEN/VCO2 slope were powerful predictors of poor outcome (Hazards ratio 2.15, 5.62; p <0.05). CONCLUSION: Patients with complex valve disease show significant functional capacity impairment, which may be difficult to detect from their clinical presentation. Consequently, peak VO2 measurements are required for the objective evaluation of functional capacity. The detection of a decline in peak VO2 will improve the timing of valve replacement and repair, and avoid adverse outcomes.

Expert opinion on tilarginine in the treatment of shock.

Tilarginine is L-N-monomethyl arginine (L-NMMA) or N(G)-monomethyl-L-arginine HCL, a non-selective inhibitor of nitric oxide synthase (NOS), which has been studied in the treatment of septic shock and cardiogenic shock complicating myocardial infarction. Despite strong evidence that excessive nitric oxide (NO) production plays a pivotal role in the pathogenesis of septic shock and may contribute to the pathogenesis of cardiogenic shock complicating myocardial infarction, outcome studies in these two disorders have proved disappointing. L-NMMA therapy was associated with an excess mortality, particularly at doses > 5 mg/(kg h), in septic shock whereas the effects of a lower dose (1 mg/(kg h)) in cardiogenic shock complicating myocardial infarction were neutral. The excess mortality in patients with septic shock was almost certainly the result of unfavourable haemodynamic changes induced by L-NMMA (decreased cardiac output, increased pulmonary vascular resistance and reduced tissue oxygen delivery) whereas the lack of benefit in patients with cardiogenic shock complicating myocardial infarction may have been because the dose of L-NMMA was too low. Further studies of L-NMMA at doses < 5 mg/(kg h) in conjunction with inotrope support may produce more beneficial results. Conversely, the use of a selective inducible NOS inhibitor to reduce the pathological effects of excessive NO production although leaving the beneficial effects of vascular NO production by endothelial NOS unaltered may prove to be of value.

Arterial stiffness indices in healthy volunteers using non-invasive digital photoplethysmography.

BACKGROUND: Increased arterial stiffness is a marker of cardiovascular damage, even in the absence of clinically apparent disease. It is likely to become an important clinical tool in cardiovascular risk assessment. AIMS AND METHODS: We studied a group of healthy subjects and measured their arterial stiffness by digital photoplethysmography. We aimed to obtain a range of arterial stiffness values, and investigated the influence of age, gender, race, body mass index, fasting lipids and haemodynamic factors. RESULTS: One hundred and fifty-two healthy subjects, aged between 18 and 67 years, on no medications and with no significant medical illnesses were recruited. The population was predominantly Caucasian (n = 112). Two measures of arterial stiffness were obtained: stiffness index (SI), a measure of large arterial stiffness, and reflection index (RI), a measure of small to medium-sized arterial stiffness. SI and RI were significantly correlated with age, total cholesterol, low-density lipoprotein-cholesterol, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP). Race was a significant independent predictor of SI. CONCLUSION: Digital photoplethysmography is a portable, operator-independent, reproducible and simple method of measuring arterial stiffness. Ranges of normality of arterial stiffness will depend on the individual's age, race, lipid levels, HR and blood pressure.

Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers.

BACKGROUND AND OBJECTIVE: NV-52 is a novel synthetic flavonoid thromboxane synthase (TXS) inhibitor that may be useful for the maintenance of remission in inflammatory bowel disease (IBD). This study was conducted to determine the single- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers (five men, four women; mean [+/- SD] age 23 +/- 2 years). METHODS: NV-52 400 mg was administered once daily for 10 days (excluding day 2) in an open-label study. Plasma was sampled and urine was collected for 48 hours after the first and last doses. Plasma and urine unconjugated and total (unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrations were measured using liquid chromatography-mass spectrometry. RESULTS: No adverse events were observed. Unconjugated and total NV-52 appeared and rose rapidly in plasma following the first dose. Time to maximum concentration values were 1.92 +/- 1.17 and 2.72 +/- 1.52 hours for unconjugated and total NV-52, respectively. Unconjugated and total NV-52 were eliminated with plasma half-lives of 13.12 +/- 17.31 and 18.03 +/- 19.06 hours, respectively, following the first dose. Pre-dose levels following multiple-dose administration were 135.17 +/- 120.03 and 751.9 +/- 679.74 ng/mL for unconjugated and total NV-52, respectively. Multiple-dose administration did not significantly alter the pharmacokinetics of NV-52. Renal elimination accounted for about 20-35% of the total (largely conjugated) drug but only 1% of unconjugated NV-52. CONCLUSIONS: Plasma concentrations of unconjugated NV-52 following single- and multiple-dose administration were well above the range found to be associated with suppression of colitis in a murine model of IBD.

Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome.

INSR (insulin-resistance syndrome) affects 25% of the Australian population and is associated with increased cardiovascular risk. In the present study, we postulated that early cardiovascular changes in these individuals may be associated with an activated RAS (renin-angiotensin system). We studied 26 subjects: 13 with INSR [waist circumference, 99+/-6 cm; HOMA (homoeostasis model assessment) score, 2.5+/-0.3] and 13 NCs (normals controls; waist circumference, 77+/-2 cm; HOMA score, 1.4+/-0.2). All received intravenous GTN (glyceryl trinitrate; 10, 20 and 40 microg/min), L-NMMA (N(G)-monomethyl-L-arginine; 3 mg/kg of body weight), AngII (angiotensin II; 8 and 16 ng/min), the selective AT(2)R (AngII type 2 receptor) inhibitor PD123319 (10 and 20 microg/min) and AngII (16 ng/min)+PD123319 (20 microg/min). At the end of each infusion, arterial stiffness indices [SI (stiffness index) and RI (reflection index)] and haemodynamic parameters were measured. There was a significantly higher RI response to AngII (P=0.0004 for both 8 and 16 ng/min doses) and to PD123319 (P=0.004 and P=0.03 for 10 and 20 microg/min doses respectively) in subjects with INSR compared with NCs. Co-infusion of AngII and PD123319 did not lead to additive changes in RI. RI responses to L-NMMA and GTN were not significantly different in both groups. No significant differences in SI and haemodynamic responses were detected. In conclusion, AT(1)R (AngII type 1 receptor) and AT(2)R activity produce arterial stiffness changes in subjects with INSR. Evidence of increased AT(1)R- and AT(2)R-mediated responses in small-to-medium-sized arteries in INSR was found, and may play an early role in the pathogenesis of vascular changes in INSR before haemodynamic changes become apparent.

The withdrawal of torcetrapib from drug development: implications for the future of drugs that alter HDL metabolism.

In December 2006, Pfizer withdrew torcetrapib, a cholesterol ester transferase protein (CETP) that elevates plasma HDL levels, from further development following an excess in mortality in the active treatment arm of the study. Although torcetrapib successfully elevated HDL levels, significant increases in blood pressure were observed in three surrogate outcome studies that were conducted over the approximate same time period. Two of these studies examined carotid intima-medial thickness and one examined coronary artery atheroma load and none of the studies found a significant benefit in favour of torcetrapib therapy. It is likely that the torcetrapib-induced increase in blood pressure contributed to the apparent adverse effect of the drug on mortality and further studies are needed to determine why this occurred and whether it is a class effect of CETP inhibitors. In addition, further research is needed to determine whether the manner which CETP alters vascular biology and, in particular, the effect that it has on vascular inflammation associated with denuded endothelium. Despite disappointing results so far, CETP inhibitors should not be abandoned as much remains to be learnt from them and they may yet prove to be a valuable class of lipid-modifying drug.

Nv-52: a novel thromboxane synthase inhibitor for the treatment of inflammatory bowel disease.

NV-52, a synthetic flavonoid derivative, is a selective thromboxane synthase (TXS) inhibitor that is being developed as a treatment for inflammatory bowel disease. NV-52 selectively inhibits TXS in vitro in physiological relevant concentrations, causing a reduction in thromboxane B(2) of

Selective COX-2 inhibitors, NSAIDs and cardiovascular events - is celecoxib the safest choice?

Inhibitors of cyclo-oxogenase (COX) are widely used anti-inflammatory drugs. In recent years concerns have arisen about the cardiovascular safety of these drugs, initially because of reported associations between therapy with the COX-2 selective inhibitor rofecoxib and myocardial infarction. However, subsequent data have suggested an association between therapy with non-selective COX inhibitors (NSAIDs) and serious cardiovascular events. This article reviews the clinical trial and population data linking COX inhibition to cardiovascular events. The data currently available suggests that both specific and non-specific COX inhibitors may increase the risk of serious cardiovascular events, but that the effect varies between the individual drugs. The strongest evidence for an increased risk of serious cardiovascular events is with rofecoxib therapy. Celecoxib therapy may be associated with an increased risk of cardiovascular events, but only when used at doses substantially higher than those recommended for the treatment of arthritis. There is a greater body of evidence supporting the relative cardiovascular safety of celecoxib when used at the doses recommended for the treatment of arthritis than for any of the other selective COX-2 inhibitors or NSAIDs.

Isoflavone therapy for menopausal flushes: a systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of all randomized, controlled trials of isoflavone supplementation to determine the efficacy of isoflavone therapy in reducing the number of daily menopausal flushes. METHODS: A comprehensive search of published studies of isoflavone treatment and menopausal flushing was undertaken. Studies were selected if they were randomized, were placebo controlled, provided the number of baseline flushes, the variance in flushes and the reduction in flushes. Effects for isoflavone treatment compared to control were calculated and a meta-analysis was performed. Regression analysis, weighted for the size of the study was performed to investigate the relationship between the dose of isoflavone, or number of baseline flushes and the reduction in flushes achieved compared to control. RESULTS: Isoflavone supplementation was found to be associated with a significant reduction in flushes (effect size -0.28, 95% confidence intervals -0.39 to -0.18, P < 0.0001). Marked heterogeneity was found between the studies, but the effect remained significant when analyzed using a random effects model (delta = -0.49, 95% confidence intervals -0.81 to -0.17, P = 0.001). The percentage reduction in flushes was significantly related to the number of baseline flushes per day and the dose of isoflavone studied (beta = -0.49 and -0.26, respectively, both P < 0.0001). CONCLUSIONS: These results suggest that isoflavone supplementation may produce a slight to modest reduction the number of daily flushes in menopausal women and that the benefit may be more apparent in women experiencing a high number of flushes per day.

Phase I and pharmacokinetic study of weekly NV06 (Phenoxodiol), a novel isoflav-3-ene, in patients with advanced cancer.

BACKGROUND: We wished to define the maximum tolerated dose (MTD), toxicity, and pharmacokinetics of the novel isoflav-3-ene, NV06 (Phenoxodioltrade mark), a compound with a diphenolic structure related chemically and biologically to genistein and flavopiridol. PATIENTS AND METHODS: Twenty-one patients with advanced cancers were treated with weekly intravenous administration of NV06 at escalating dose levels with 1-4 patients at each dose cohort. Plasma sampling was undertaken to characterize the pharmacokinetic (PK) profile of the compound. RESULTS: Toxicity was minimal, with asymptomatic Grade 3 lymphocytopenia occurring in nine patients. Nine patients developed Grade 1 nausea, six patients developed Grade 1 increases in alkaline phosphatase, and six patients developed Grade 1 increases in transaminases. Two patients experienced hypersensitivity reactions. The MTD was not reached. Most patients had progressive disease on treatment but eight completed 12 weeks and two completed 24 weeks of treatment. The best response was stable disease of 6 months duration. The plasma half-life (T1/2), clearance (Cl), and volume of distribution (VD) were 304 (+/-91) min, 82 (+/-19) ml/min and 32,663 (+/-7,199) ml, respectively, for total NV06. CONCLUSIONS: NV06 is well tolerated and can be given safely as an intravenous infusion over 1-2 h at a dose of at least 30 mg/kg.

The effects of lipid-lowering drug therapy on cardiovascular responsiveness in type 2 diabetic patients.

Type 2 diabetes is associated with a high prevalence of dyslipidaemia and a high incidence of cardiovascular disease. Lipid lowering therapy with HMG Co-A reductase inhibitors (statins) reduce the risk of cardiovascular events in type 2 diabetic and non-diabetic patients, effects which are believed to be partly due to improvements in vascular function. The aetiology of abnormal vascular function in type 2 diabetics is likely to be multifactorial and the pattern of vascular dysfunction in type 2 diabetes may differ from that which occurs in non-diabetic patients with dyslipidaemia. Abnormalities in endothelium derived hyperpolarising factor (EDHF) mediated vasodilation in resistance vessels may be more prominent in both type 1 and type 2 diabetes than in non-diabetic patients with endothelial dysfunction. The effects of lipid lowering therapy on vascular responsiveness may differ in type 2 diabetic patients from those found in non-diabetic patients. Statin therapy does not appear to improve responses to endothelial dependent vasodilators in type 2 diabetics, but may alter the ratio between nitric oxide (NO) and EDHF mediated responses. Fibrate therapy improves flow mediated dilation of brachial arteries in type 2 diabetic patients, but only appears to improve endothelium dependant vasodilator responses in resistance vessels when given in conjunction with co-enzyme Q.