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This 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.

Context:The safety of insulin in the treatment of type 2 diabetes mellitus (T2DM) has recently undergone scrutiny.Objective:The objective of the study was to characterize the risk of adverse events associated with glucose-lowering therapies in people with T2DM.Design and Setting:This was a retrospective cohort study using data from the UK General Practice Research Database, 2000–2010.Patients:Patients comprised 84 622 primary care patients with T2DM treated with one of five glucose-lowering regimens: metformin monotherapy, sulfonylurea monotherapy, insulin monotherapy, metformin plus sulfonylurea combination therapy, and insulin plus metformin combination therapy. There were 105 123 exposure periods.Main Outcome Measures:The risk of the first major adverse cardiac event, first cancer, or mortality was measured. Secondary outcomes included these individual constituents and microvascular complications.Results:In the same model, and using metformin monotherapy as the referent, the adjusted hazard ratio (aHR) for the primary end point was significantly increased for sulfonylurea monotherapy (1.436, 95% confidence interval [CI] 1.354–1.523), insulin monotherapy (1.808, 95% CI 1.630–2.005), and insulin plus metformin (1.309, 95% CI 1.150–1.491). In glycosylated hemoglobin/morbidity subgroups, patients treated with insulin monotherapy had aHRs for the primary outcome ranging from 1.469 (95% CI 0.978–2.206) to 2.644 (95% CI 1.896–3.687). For all secondary outcomes, insulin monotherapy had increased aHRs: myocardial infarction (1.954, 95% CI 1.479–2.583), major adverse cardiac events (1.736, 95% CI 1.441–2.092), stroke (1.432, 95% CI 1.159–1.771), renal complications (3.504, 95% CI 2.718–4.518), neuropathy (2.146, 95% CI 1.832–2.514), eye complications (1.171, 95% CI 1.057–1.298), cancer (1.437, 95% CI 1.234–1.674), or all-cause mortality (2.197, 95% CI 1.983–2.434). When compared directly, aHRs were higher for insulin monotherapy vs all other regimens for the primary end point and all-cause mortality.Conclusions:In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality. Differences in baseline characteristics between treatment groups should be considered when interpreting these results.

OBJECTIVETo assess the association of compliance with treatment (medication and clinic appointments) and all-cause mortality in people with insulin-treated type 2 diabetes.RESEARCH DESIGN AND METHODSData were extracted from U.K. general practice records and included patients (N = 15,984) who had diagnostic codes indicative of type 2 diabetes or who had received a prescription for an oral antidiabetic agent and were treated with insulin. Records in the 30 months before the index date were inspected for clinical codes (recorded at consultation) indicating medication noncompliance or medical appointment nonattendance. Noncompliance was defined as missing more than one scheduled visit or having at least one provider code for not taking medications as prescribed. Relative survival postindex date was compared by determining progression to all-cause mortality using Cox proportional hazards models.RESULTSThose identified as clinic nonattenders were more likely to be smokers, younger, have higher HbA1c, and have more prior primary care contacts and greater morbidity (P < 0.001). Those identified as medication noncompliers were more likely to be women (P = 0.001), smokers (P = 0.014), and have higher HbA1c, more prior primary care contacts, and greater morbidity (all P < 0.001). After adjustment for confounding factors, medication noncompliance (hazard ratio 1.579 [95% CI 1.167–2.135]), clinic nonattendance of one or two missed appointments (1.163 [1.042–1.299]), and clinic nonattendance of greater than two missed appointments (1.605 [1.356–1.900]) were independent risk factors for all-cause mortality.CONCLUSIONSMedication noncompliance and clinic nonattendance, assessed during routine care by primary care physicians or their staff, were independently associated with increased all-cause mortality in patients with type 2 diabetes receiving insulin.

BackgroundHypoglycaemic events, particularly nocturnal, affect health-related quality of life (HRQoL) via acute symptoms, altered behaviour and fear of future events. We examined the respective disutility associated with a single event of daytime, nocturnal, severe and non-severe hypoglycaemia.MethodsRepresentative samples were taken from Canada, Germany, Sweden, the United States and the United Kingdom. Individuals completed an internet-based questionnaire designed to quantify the HRQoL associated with different diabetes- and/or hypoglycaemia-related health states. HRQoL was measured on a utility scale: 1 (perfect health) to 0 (death) using the time trade-off method. Three populations were studied: 8286 respondents from the general population; 551 people with type 1 diabetes; and 1603 with type 2 diabetes. Respondents traded life expectancy for improved health states and evaluated the health states of well-controlled diabetes and diabetes with non-severe/severe and daytime/nocturnal hypoglycaemic events.ResultsIn the general population, non-severe nocturnal hypoglycaemic events were associated with a 0.007 disutility compared with 0.004 for non-severe daytime episodes, equivalent to a significant 63% increase in negative impact. Severe daytime and nocturnal events were associated with a 0.057 and a 0.062 disutility, respectively, which were not significantly different.ConclusionsThis study applies an established health economic methodology to derive disutilities associated with hypoglycaemia stratified by onset time and severity using a large multinational population. It reveals substantial individual and cumulative detrimental effects of hypoglycaemic events – particularly nocturnal – on HRQoL, reinforcing the clinical imperative of avoiding hypoglycaemia.

Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodiumglucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging. Key Summary PointsObesity is a complex metabolic disorder, with several licensed drug and surgical therapies currently available.Current therapies are often associated with inadequate efficacy or complications and side effects, limiting their use.Multiple pathophysiological mechanisms of obesity are recognized, though only few of these are manipulated using currently licensed therapies.Whilst most drug classes are in early stages of development and/or clinical trials, results are promising for multiple drug targets.

Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p=0.032. Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r=0.276, p=0.039, and tumour necrosis factor alpha soluble receptor I, r=0.351, p=0.008. Both IL-6 and BMI were predictive variables of insulin resistance r(2)=0.288, p<0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD.