Sandra J. Hamilton

Coenzyme Q10 Improves Endothelial Dysfunction in Statin-Treated Type 2 Diabetic Patients

OBJECTIVE The vascular benefits of statins might be attenuated by inhibition of coenzyme Q10 (CoQ10) synthesis. We investigated whether oral CoQ10 supplementation improves endothelial dysfunction in statin-treated type 2 diabetic patients. RESEARCH DESIGN AND METHODS In a double-blind crossover study, 23 statin-treated type 2 diabetic patients with LDL cholesterol <2.5mmol/l and endothelial dysfunction (brachial artery flow-mediated dilatation [FMD] <5.5%) were randomized to oral CoQ10 (200 mg/day) or placebo for 12 weeks. We measured brachial artery FMD and nitrate-mediated dilatation (NMD) by ultrasonography. Plasma F2-isoprostane and 24-h urinary 20-hydroxyeicosatetraenoic acid (HETE) levels were measured as systemic oxidative stress markers. RESULTS Compared with placebo, CoQ10 supplementation increased brachial artery FMD by 1.0 ± 0.5% (P = 0.04), but did not alter NMD (P = 0.66). CoQ10 supplementation also did not alter plasma F2-isoprostane (P = 0.58) or urinary 20-HETE levels (P = 0.28). CONCLUSIONS CoQ10 supplementation improved endothelial dysfunction in statin-treated type 2 diabetic patients, possibly by altering local vascular oxidative stress.

Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus

Endothelial dysfunction is universal in diabetes, being intimately involved with the development of cardiovascular disease. The pathogenesis of endothelial dysfunction in diabetes is complex. It is initially related to the effects of fatty acids and insulin resistance on ‘uncoupling’ of both endothelial nitric oxide synthase activity and mitochondrial function. Oxidative stress activates protein kinase C (PKC), polyol, hexosamine and nuclear factor kappa B pathways, thereby aggravating endothelial dysfunction. Improvements in endothelial function in the peripheral circulation in diabetes have been demonstrated with monotherapies, including statins, fibrates, angiotensin-converting enzyme (ACE) inhibitors, metformin and fish oils. These observations are supported by large clinical end point trials. Other studies show benefits with certain antioxidants, L-arginine, folate, PKC-inhibitors, peroxi-some proliferator activated receptor (PPAR)-α and -γ agonists and phosphodiesterase (PDE-5) inhibitors. However, the benefits of these agents remain to be shown in clinical end point trials. Combination treatments, for example, statins plus ACE inhibitors and statins plus fibrates, have also been demonstrated to have additive benefits on endothelial function in diabetes, but there are no clinical outcome data to date. Measurement of endothelial dysfunction in cardiovascular research can provide fresh opportunities for exploring the mechanism of benefit of new therapeutic regimens and for planning and designing large clinical trials.

Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment.

Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients

Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1+/-0.6 compared with -0.3+/-0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with -1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P < or = 0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=-0.61, P=0.02) and apoB-100 (r=-0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients

Aim: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very‐low‐density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy.

Effects of Extended-Release Niacin on the Postprandial Metabolism of Lp(a) and ApoB-100–Containing Lipoproteins in Statin-Treated Men With Type 2 Diabetes Mellitus

Objective—The effects of extended-release niacin (ERN; 1–2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100–containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. Approach and Results—The kinetics of Lp(a) and very low–density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography–mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (−26.5%) and the production rates of apo(a) (−41.5%) and Lp(a)-apoB-100 (−32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (−58.7%), intermediate-density lipoprotein (−33.6%), and LDL (−18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, −49.8%; intermediate-density lipoprotein, −44.7%; LDL, −46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (−21.9%). Conclusions—In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100–containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

Effect of Niacin on High-Density Lipoprotein Apolipoprotein A-I Kinetics in Statin-Treated Patients With Type 2 Diabetes Mellitus

Objective—To investigate the effect of extended-release (ER) niacin on the metabolism of high-density lipoprotein (HDL) apolipoprotein A-I (apoA-I) in men with type 2 diabetes mellitus on a background of optimal statin therapy. Approach and Results—Twelve men with type 2 diabetes mellitus were recruited for a randomized, crossover design trial. Patients were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed over to the alternate therapy after a 3-week washout period. Metabolic studies were performed at the end of each treatment period. HDL apoA-I kinetics were measured after a standardized liquid mixed meal and a bolus injection of d3-leucine for 96 hours. Compartmental analysis was used to model the data. ER niacin significantly decreased plasma triglyceride, plasma cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, and apoB (all P<0.05) and significantly increased HDL cholesterol and apoA-I concentrations (P<0.005 and P<0.05, respectively). ER niacin also significantly increased HDL apoA-I pool size (6088±292 versus 5675±305 mg; P<0.001), and this was attributed to a lower HDL apoA-I fractional catabolic rate (0.33±0.01 versus 0.37±0.02 pools/d; P<0.005), with no significant changes in HDL apoA-I production (20.93±0.63 versus 21.72±0.85 mg/kg per day; P=0.28). Conclusions—ER niacin increases HDL apoA-I concentration in statin-treated subjects with type 2 diabetes mellitus by lowering apoA-I fractional catabolic rate. The effect on HDL metabolism was independent of the reduction in plasma triglyceride with ER niacin treatment. Whether this finding applies to other dyslipidemic populations remains to be investigated.

Niacin improves small artery vasodilatory function and compliance in statin-treated type 2 diabetic patients.

We investigated the effect of niacin (nicotinic acid prolonged release) on forearm vasodilatory function and arterial compliance in statin-treated type 2 diabetic patients with endothelial dysfunction. In a parallel group study, we randomised 15 subjects, with LDL-cholesterol ≤2.5 mmol/L, to niacin (dose titrated to 1500 mg/day over 8 weeks, then maintained for a further 12 weeks) or no additional treatment. Niacin increased maximal post-ischaemic forearm blood flow (mean ± SEM 6.4±2.4 vs. —2.3±1.2 ml/100 ml/min, p = 0.001) and small artery compliance (1.3±0.8 vs. —2.3±1.1 ml/mmHg, p = 0.01) compared with no additional treatment, but did not alter large artery compliance, blood pressure nor heart rate. Niacin decreased serum triglycerides by 47% (p = 0.04), with no change in LDL-cholesterol, HDL-cholesterol, apolipoprotein (Apo) B-100 nor ApoA-I (p > 0.05). Adding niacin to statin therapy improves small artery vasodilatory function and compliance in type 2 diabetes. This may relate to a decrease in serum triglycerides and/or a direct benefit of niacin on vascular biology.

Improving cardiovascular outcomes among Aboriginal Australians: Lessons from research for primary care

Background: The Aboriginal people of Australia have much poorer health and social indicators and a substantial life expectancy gap compared to other Australians, with premature cardiovascular disease a major contributor to poorer health. This article draws on research undertaken to examine cardiovascular disparities and focuses on ways in which primary care practitioners can contribute to reducing cardiovascular disparities and improving Aboriginal health. Methods: The overall research utilised mixed methods and included data analysis, interviews and group processes which included Aboriginal people, service providers and policymakers. Workshop discussions to identify barriers and what works were recorded by notes and on whiteboards, then distilled and circulated to participants and other stakeholders to refine and validate information. Additional engagement occurred through circulation of draft material and further discussions. This report distils the lessons for primary care practitioners to improve outcomes through management that is attentive to the needs of Aboriginal people. Results: Aspects of primordial, primary and secondary prevention are identified, with practical strategies for intervention summarised. The premature onset and high incidence of Aboriginal cardiovascular disease make prevention imperative and require that primary care practitioners understand and work to address the social underpinnings of poor health. Doctors are well placed to reinforce the importance of healthy lifestyle at all visits to involve the family and to reduce barriers which impede early care seeking. Ensuring better information for Aboriginal patients and better integrated care for patients who frequently have complex needs and multi-morbidities will also improve care outcomes. Conclusion: Primary care practitioners have an important role in improving Aboriginal cardiovascular care outcomes. It is essential that they recognise the special needs of their Aboriginal patients and work at multiple levels both outside and inside the clinic for prevention and management of disease. A toolkit of proactive and holistic opportunities for interventions is proposed.

Prevalence and predictors of abnormal arterial function in statin-treated type 2 diabetes mellitus patients

Arterial dysfunction (AD) in type 2 diabetes mellitus (T2DM) predicts cardiovascular events. The objective was to investigate the prevalence and predictors of AD in statin-treated T2DM patients. We measured flow-mediated (FMD) and nitrate-mediated (NMD) brachial artery dilatation in 86 statin-treated T2DM patients. Patients were classified into 2 groups: normal arterial function (FMD ≥3.7% with NMD ≥11.9%) or AD (FMD <3.7% with or without NMD <11.9%). Endothelial dysfunction without smooth muscle cell dysfunction (ED) was defined as FMD less than 3.7% with NMD of at least 11.9%, and endothelial dysfunction with smooth muscle cell dysfunction (ED/SMD) was defined as FMD less than 3.7% with NMD less than 11.9%. Predictors of arterial function were investigated using linear and logistic regression methods. The prevalence of AD was 33.7% (23.2% with ED and 10.5% with ED/SMD). In multivariate linear regression, history of hypertension (P < .01), statin dose (P < .05), and estimated glomerular filtration rate (eGFR) (P = .02) were significant predictors of FMD. Sex (P < .01) and creatinine (P = .03) or eGFR (P = .02) predicted NMD. In multivariate logistic regression, the independent predictors of AD were history of hypertension (odds ratio [OR], 8.79; 95% confidence interval, 2.14-36.12; P < .01), age (OR, 1.08; 1.01-1.17; P = .03), and statin dose (OR, 0.33; 0.12-0.87; P = .02). A history of hypertension (OR, 8.99; 1.87-43.26; P < .01) was the sole independent predictor of ED; eGFR (OR, 0.01; 0.00-0.26; P < .01) independently predicted ED/SMD. Our data suggest that one third of statin-treated diabetic patients have residual AD, mainly due to ED alone. Earlier identification and treatment of hypertension and renal impairment may improve AD and further decrease cardiovascular risk in such patients.