Marc Evans

Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus.

BACKGROUNDnExaggerated postprandial lipemia (PPL) is a factor in atherogenesis, involving endothelial dysfunction and enhanced oxidative stress. We examined the effect of ciprofibrate therapy on these parameters in type 2 diabetes mellitus.nnnMETHODS AND RESULTSnTwenty patients entered a 3-month, double-blind, placebo-controlled study. Each subject was studied fasting and after a fatty meal, at baseline, and after 3 months of treatment. Glucose and lipid profiles were measured over an 8-hour postprandial period. Endothelial function (flow-mediated endothelium-dependent vasodilatation [FMD]) and oxidative stress (electron paramagnetic resonance spectroscopy) were measured after fasting and 4 hours postprandially. At baseline, both groups exhibited similar PPL and deterioration in endothelial function. After ciprofibrate, fasting and postprandial FMD values were significantly higher (from 3.8+/-1. 8% and 1.8+/-1.3% to 4.8+/-1.1% and 3.4+/-1.1%; P<0.05). This was mirrored by a fall in fasting and postprandial triglycerides (3. 1+/-2.1 and 6.6+/-4.1 mmol/L to 1.5+/-0.8 and 2.8+/-1.3 mmol/L, P<0. 05). Fasting and postprandial HDL cholesterol was also elevated (0. 9+/-0.1 and 0.8+/-0.1 mmol/L and 1.2+/-0.2 and 1.2+/-0.1 mmol/L, P<0. 05). There were no changes in total or LDL cholesterol. Fasting and postprandial triglyceride enrichment of all lipoproteins was attenuated, with cholesterol depletion of VLDL and enrichment of HDL. There were similar postprandial increases in oxidative stress in both groups at baseline, which was significantly attenuated by ciprofibrate (0.3+/-0.6 versus 1.5+/-1.1 U, P<0.05).nnnCONCLUSIONSnThis study demonstrates that fibrate therapy improves fasting and postprandial endothelial function in type 2 diabetes. Attenuation of PPL and the associated oxidative stress, with increased HDL cholesterol levels, may be important.

The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes

Post-prandial lipaemia (PPL) is a factor in atherogenesis and results in reversible endothelial dysfunction in healthy individuals. Oxidative stress and triglyceride (TG)-rich lipoproteins have been implicated. Type 2 diabetes (NIDDM) results in exaggerated PPL. We attempted to delineate the mechanisms of PPL induced, endothelial dysfunction (EF) and oxidative stress in 12 NIDDM and 12 matched healthy subjects. Subjects underwent a fat tolerance test, with endothelial function assessed by flow-mediated vasodilatation and oxidative stress measured by venous lipid-derived free radicals ex vivo and lipid peroxidation products over the postprandial phase. Fasting TG, post-prandial hypertriglyceridaemia and the TG enrichment of all lipoproteins was significantly greater in NIDDM. Post-prandial endothelial function inversely correlated with fasting HDL-C (r=-0.84, P=0.001) in both the control and NIDDM groups. The deterioration in EF in the NIDDM group also correlated with TG enrichment of VLDL and LDL. PPL in both groups also resulted in increased oxidative stress. The increment in free radicals correlated with TG enrichment of VLDL in both groups and was, therefore, greater in NIDDM. Thus, PPL -- with the production of TG-enrichment of VLDL -- results in endothelial dysfunction by an oxidative stress mechanism in both groups. The magnitude is greater in NIDDM. Fasting HDL-C appears to contribute to the protection of the endothelium against this phenomenon. Hence, exaggerated PPL associated with reduced HDL-C may be important in the pathogenesis of vascular disease, particularly in NIDDM.

Medical lipid-regulating therapy: current evidence, ongoing trials and future developments.

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage.The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L.A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage.A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.

Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions.

PURPOSE OF REVIEWnThe prevalence of type 2 diabetes globally is reaching epidemic proportions. Type 2 diabetes is strongly associated with increased risk of cardiovascular disease. Atherosclerosis is thought to arise as a result of a chronic inflammatory process within the arterial wall. Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherogenesis, either directly or through associated risk factors. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, pioglitazone and rosiglitazone, are insulin sensitizing agents, that are licensed for the management of hyperglycaemia. Growing evidence supports an array of additional effects of thiazolidinedione therapy, both immunomodulatory and antiinflammatory, which may attenuate atherogenesis in type 2 diabetes.nnnRECENT FINDINGSnStudies have shown that thiazolidinedione therapy may lead to risk factor modulation in type 2 diabetes. Thiazolidinediones treatment has been shown to reduce blood pressure, modify the atherogenic lipid profile associated with type 2 diabetes, reduce microalbuminuria and ameliorate the prothrombotic diathesis. Further evidence suggests that thiazolidinediones therapy inhibits the inflammatory processes which may be involved in atherosclerotic plaque initiation, propagation and destabilization.nnnSUMMARYnModification of insulin resistance by thiazolidinedione therapy in type 2 diabetes and the range of pleiotropic effects may not only impact on incident type 2 diabetes, but also on associated cardiovascular disease. Numerous large clinical endpoint studies are under way to investigate these issues.

DIABETIC DYSLIPIDAEMIA AND CORONARY HEART DISEASE : NEW PERSPECTIVES

Atherosclerotic macrovascular disease is the leading cause of both morbidity and mortality in non-insulin dependent diabetes mellitus. Endothelial dysfunction is a key, early and potentially reversible event in pathogenesis of atherosclerosis. Its occurrence in non-insulin dependent diabetes mellitus is well supported by both in-vitro and in-vivo studies. Non-insulin dependent diabetes mellitus results in diverse abnormalities of lipid and lipoprotein metabolism, in particular hypertriglyceridaemia, low levels of high density lipoprotein and abnormalities of post-prandial lipaemia. A variety of studies demonstrate the presence of enhanced oxidative stress in non-insulin dependent diabetes mellitus, with recent data implying an association between oxidative stress, post-prandial lipaemia and endothelial dysfunction in non-diabetic subjects. In this article based on in-vitro and human studies, we develop the hypothesis that endothelial dysfunction in non-insulin dependent diabetes mellitus is the consequence of the diabetic dyslipidaemia, in particular post-prandial lipaemia, and of oxidative stress on the action of nitric oxide. The practical applications of this theory provide potential therapeutic options which may reduce the risk of vascular disease in non-insulin dependent diabetes mellitus.

Restoration of Self-awareness of Hypoglycemia in Adults With Long-standing Type 1 Diabetes: Hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial. RESEARCH DESIGN AND METHODS Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies. RESULTS After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420–780] vs. 710 [460–1,260], P = 0.02; metanephrine, 2,412 [−3,026 to 7,279] vs. 5,180 [−771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation. CONCLUSIONS Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.

A retrospective, case-note survey of type 2 diabetes patients prescribed incretin-based therapies in clinical practice.

IntroductionWhile incretin-based therapies have been compared in clinical trials, data comparing their relative efficacy in clinical practice remain limited, particularly when prescribed according to clinical guidelines. This study assessed the clinical and cost-effectiveness of, and patient preference for, incretin-based therapies initiated according to the National Institute for Health and Clinical Excellence (NICE) recommendations in UK clinical practice.MethodsIn a retrospective chart audit, anonymized data were collected for patients receiving incretin-based therapy according to NICE recommendations in clinical practice in Wales, UK. Parameters assessed included glycated hemoglobin (HbA1c), weight, achievement of NICE treatment continuation criteria, adverse events, treatment discontinuation, and drug cost-effectiveness based on observed treatment effects. Treatment preference for a dipeptidyl peptidase-4 inhibitor (DPP-4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA) was assessed prospectively.ResultsPatients (1,114) were followed-up for a median of 48xa0weeks (256 received liraglutide, 148 received exenatide twice daily, and 710 received a DPP-4i). Liraglutide reduced HbA1c significantly more versus exenatide or DPP-4i (both Pxa0<xa00.05). Weight changes were similar for GLP-1RAs but significantly greater vs. DPP-4is (both Pxa0<xa00.05). NICE treatment continuation criteria were met by 32% and 24% of liraglutide 1.2xa0mg- and exenatide-treated patients (≥1% HbA1c reduction,xa0≥3% weight loss), and 61% of DPP-4i-treated patients (≥0.5% HbA1c reduction). Life-years gained per patient were 0.12, 0.08, and 0.07, and costs per quality-adjusted life-year were £16,505, £16,648, and £20,661 for liraglutide, exenatide, and DPP-4is, respectively. More patients (62.5%) preferred the GLP-1RA profile, with these patients having higher baseline body mass index score and HbA1c values, and longer diabetes duration than those preferring the DPP-4i profile.ConclusionWhen prescribed according to NICE recommendations, incretin-based therapies are both clinically and cost-effective options, with liraglutide providing greatest HbA1c reductions. Greater body weight reductions occur with GLP-1RAs compared with DPP-4is. Patients with higher baseline HbA1c and longer diabetes duration prefer a GLP-1RA profile versus a DPP-4i.

Healthcare resource implications of hypoglycemia-related hospital admissions and inpatient hypoglycemia: retrospective record-linked cohort studies in England

Objective Using a retrospective cohort study, the mean length of hospital stay (LoS) and total per-patient expenditure for hypoglycemia requiring admission to hospital were estimated. In a separate matched retrospective cohort study, the effect of inpatient hypoglycemia on LoS, expenditure, and risk of all-cause mortality while admitted was investigated. Methods The cohorts consisted of patients aged ≥18u2005years with a diagnosis of type 1 or 2 diabetes between January 1, 2002 and October 30, 2012 in the Clinical Practice Research Datalink database, who had initiated insulin treatment and had a recording of hypoglycemia in the same period. In the matched retrospective cohort study, exposed patients (who experienced hypoglycemia in hospital) were case-matched with patients who did not experience hypoglycemia during admission (unexposed). Generalized linear regression was used to estimate LoS. Risk of all-cause mortality was evaluated via logistic regression. Results In the retrospective cohort study (1131 patients), mean LoS was 5.46 (95% CI 4.62 to 6.45) days for type 1 diabetes, and 5.04 (95% CI 4.46 to 5.71) days for type 2 diabetes. Mean cost per admission was £1034 (95% CI £855 to £1253). In the matched retrospective cohort study (1079 pairs of patients), exposed patients had a mean LoS of 11.91u2005days (95% CI 10.96 to 12.94u2005days) versus 4.80 (95% CI 4.41 to 5.23) for unexposed patients, p<0.0001. Exposed patients had a higher mortality risk compared with unexposed patients (OR 1.439 (95% CI 1.060to 1.952), p=0.0195). Total average per-patient cost for exposed patients was GBP (£)2235, 40% (p<0.0001) higher than total average admission cost in unexposed patients. Conclusions Hypoglycemia has a significant negative impact on patient outcomes, healthcare resource use, and expenditure.

Association between dyslipidemia and vascular events in patients treated with statins: Report from the UK General Practice Research Database

OBJECTIVEnA retrospective cohort study was conducted to evaluate the association between low high-density lipoprotein cholesterol (HDL-C) and/or elevated triglycerides (TG) and cardiovascular (CV) and/or cerebrovascular (CB) events among patients with elevated low-density lipoprotein cholesterol (LDL-C) despite statin treatment.nnnMETHODSnPatient demographics, clinical characteristics, laboratory data, and CV/CB events, were collected from the UK General Practice Research Database. Abnormal lipid levels were defined using US and European clinical guidelines. The association between the frequency of CV/CB events among patients with HDL-C/TG abnormalities versus patients with isolated low LDL-C was estimated using multivariate Cox proportional hazards regression.nnnRESULTSnOf 19,843 statin-treated patients, 6823 had elevated LDL-C despite therapy for a mean follow-up of 1.99+/-1.06 years. Among these patients, 3115 (45.7%) also had HDL-C/TG abnormalities. A total of 715 patients (10.5%) experienced CV/CB events. In statin-treated patients not at LDL-C goal, the relative risk of a vascular event was 24% higher in patients with HDL-C/TG abnormalities (HR=1.24, 95% CI: 1.06-1.46, p=0.006) than in patients without HDL-C/TG abnormalities. Additional variables that were associated with a significantly increased risk of CV/CB events included age (p<0.0001), gender (p=0.027), and medication possession ratio (p<0.0001), while diabetes mellitus (p<0.0001), hypertension (p<0.0001), 10-year Framingham risk score>30% (p=0.005), statin dose (p<0.0001), and LDL-C level at baseline (p<0.0001) were associated with a significantly decreased risk of CV/CB events.nnnCONCLUSIONnAmong statin-treated patients with elevated LDL-C from UK clinical practices, reduced HDL-C and/or elevated TGs were associated with a significantly increased relative risk of CV/CB events.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape)

To test the hypothesis that a ‘basal plus’ regimenuf8ffadding once‐daily main‐meal fast‐acting insulin to basal insulin once dailyuf8ffwould be non‐inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction.