Sodium-glucose co-transporter-2 inhibitor cardiovascular outcome trials and generalizability to English primary care.

AIM: To identify people in English primary care with equivalent cardiovascular risk to participants in the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) cardiovascular outcome trials (CVOTs). A secondary objective was to report the usage of SGLT-2is. METHODS: Cross-sectional analysis of people registered with participating practices in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network on the 31 December 2016. We derived: (1) proportions of the primary care population eligible for inclusion in each SGLT-2i CVOT (CANVAS, DECLARE, EMPA-REG and VERTIS); (2) characteristics of the eligible population compared with trial participants (demographics, disease duration and vascular risk); and (3) differences within the eligible population prescribed SGLT-2is. RESULTS: The proportions of people with type 2 diabetes (N = 84 394) meeting the inclusion criteria for each CVOT were: DECLARE 27% [95% confidence interval (CI) 26.5-27.1]; CANVAS 17% (16.6-17.1); VERTIS 7% (7.1-7.4); and EMPA-REG 7% (6.5-6.8). Primary care populations fulfilling inclusion criteria were 5-8 years older than trial cohorts, and <10% with inclusion criteria of each trial were prescribed an SGLT-2i; a greater proportion were men, and of white ethnicity. CONCLUSIONS: There was variation in proportions of the primary care type 2 diabetes population fulfilling inclusion criteria of SGLT-2i CVOTs. The more stringent the inclusion criteria, the lower the proportion identified in a primary care setting. Prescription rates for SGLT-2is were low in this national database, and there were demographic disparities in prescribing.

A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.

AIMS: To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). METHODS: We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. RESULTS: The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. CONCLUSIONS: In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.

Obstructive sleep apnoea in Type 2 diabetes mellitus: increased risk for overweight as well as obese people included in a national primary care database analysis.

AIMS: To determine obstructive sleep apnoea prevalence in people with Type 2 or Type 1 diabetes in a national primary care setting, stratified by BMI category, and to explore the relationship between patient characteristics and obstructive sleep apnoea. METHODS: Using the Royal College of General Practitioners Research and Surveillance Centre database, a cross-sectional analysis was conducted. Diabetes type was identified using a seven-step algorithm and was grouped by Type 2 diabetes, Type 1 diabetes and no diabetes. The clinical characteristics of these groups were analysed, BMI-stratified obstructive sleep apnoea prevalence rates were calculated, and a multilevel logistic regression analysis was completed on the Type 2 diabetes group. RESULTS: Analysis of 1 275 461 adult records in the Royal College of General Practitioners Research and Surveillance Centre network showed that obstructive sleep apnoea was prevalent in 0.7%. In people with Type 2 diabetes, obstructive sleep apnoea prevalence increased with each increasing BMI category, from 0.5% in those of normal weight to 9.6% in those in the highest obesity class. By comparison, obstructive sleep apnoea prevalence rates for these BMI categories in Type 1 diabetes were 0.3% and 4.3%, and in those without diabetes 1.2% and 3.9%, respectively. Obstructive sleep apnoea was more prevalent in men than women in both diabetes types. When known risk factors were adjusted for, there were increased odds ratios for obstructive sleep apnoea in people with Type 2 diabetes in the overweight and higher BMI categories. CONCLUSIONS: Obstructive sleep apnoea was reported in people with both types of diabetes across the range of overweight categories and not simply in the highest obesity class.

Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP-treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease.

Management of type 2 diabetes: the current situation and key opportunities to improve care in the UK.

In common with global trends, the number of individuals with type 2 diabetes in the UK is rising, driven largely by obesity. The increasing prevalence of younger individuals with type 2 diabetes is of particular concern because of the accelerated course of diabetes-related complications that is observed in this population. The importance of good glycaemic control in the prevention of microvascular complications of diabetes is widely accepted, and there is a growing body of evidence to support a benefit in the reduction of cardiovascular events in the long term. Despite the importance of maintaining a healthy weight for the prevention of type 2 diabetes, the results from trials of lifestyle intervention strategies to reduce body weight have been disappointing. New glucose-lowering agents offer some promise in this regard, offering an opportunity to combat the dual burden of hyperglycaemia and obesity simultaneously. The timing and appropriate choice of glucose-lowering therapy has never been more complex as a result of rising prevalence of obesity in the young, concomitant obesity in some 90% of adults with type 2 diabetes and an ever-increasing range of therapeutic options. The present review evaluates performance measures specific to weight and glycaemic control in type 2 diabetes in the UK using data from the Quality and Outcomes Framework in England and Wales, and the Scottish Diabetes Survey. Potential barriers to improvement in standards of care for people with type 2 diabetes are considered, including patient factors, clinical inertia and the difficulties in translating therapeutic guidelines into everyday clinical practice.

Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for Adult Refsum Disease.

BACKGROUND: Adult Refsum's Disease (ARD) is caused by defects in the pathway for alpha-oxidation of phytanic acid (PA). Treatment involves restricting the dietary intake of phytanic acid by reducing the intake of dairy-derived fat. The adequacy of micronutrient intake in patients with ARD is unknown. METHODS: Patients established on the Chelsea low-PA diet had general diet macronutrients, vitamins and trace elements assessed using 7-day-weighed intakes and serial 24-h recalls. Intakes were compared with biochemical assessments of nutritional status for haematinics (ferritin), trace elements (copper, zinc, iron, selenium), water- (vitamin B6 , B12 and folate) and fat-soluble vitamins (A, D, E and K). RESULTS: Eleven subjects (four women, seven men) were studied. Body mass index was 27 ± 5 kg/m(2) (range 19-38). All subjects had high sodium intakes (range 1873-4828 mg). Fat-soluble vitamin insufficiencies occurred in some individuals (vitamin A, n = 2; vitamin D, n = 6; vitamin E, n = 3; vitamin K, n = 10) but were not coincident. Vitamin B6 levels were normal or elevated (n = 6). Folate and 5-methyltetrahydrofolate concentrations were normal. Metabolic vitamin B12 insufficiency was suspected in four subjects based on elevated methylmalonic acid concentrations. Low copper and selenium intakes were noted in some subjects (n = 7, n = 2) but plasma levels were adequate. Iron, ferritin and zinc intakes and concentrations were normal. CONCLUSION: Subjects with ARD can be safely managed on the Chelsea low PA without routine micronutrient supplementation. Sodium intake should be monitored and reduced. Periodic nutritional screening may be necessary for fat-soluble vitamins, vitamin B12 , copper or selenium.

Precision evaluation of panoramic morphometric index measurement's performed by experienced clinicians and dental students.

Osteoporosis is a chronic degenerative disease of bones in which the primary type of it affects generally women after postmenopause. According to the literature the panoramic indices are valuable morphometric and visual tools to detect the disorder in a n early and asymptomnatic stage. The goals of study were to evaluate the reproducibility of mandibular cortical and panoramic indices and to assess population-specific index parameters. Panoramic radiographs of 50 osteoporotic (age = 65,1 ? 5,9) and 36 control (age = 66,4 ? 7,1) women were evaluated for the cortical (MCI) and panoramic (PMI) indices by 2 experienced clinicians and 40 dental students with basic clinical experiences. Statistical analysis of data was preformed using SPSS software. the result of MCI and PMI indexes demonstrated high interobserver agreement between the two clinicians but in MCI data, recorded by the clinicians and students, showed statistically significant differences. On the other hand the mean and threshold values of the indices proved to be different from what we had expected from other surveys. Although the panoramic images are taken for specific dental indications that would improve the screening efficiency of osteoporosis when the clinician recognizes the signs of it on the radiographs.

Can protein biomarkers provide an index of coronary artery calcification in patients with Type 2 diabetes?

OBJECTIVES: By exploring differences between patients with high and low coronary artery calcification score (CACS), a plasma protein biomarker might be identified as an alternative to CACS screening. METHODS: We selected stored samples (12 per group) from a cohort study of patients with Type 2 diabetes and CACS >1000 or <100 Agatston units, with matching for age, BMI, blood pressure, lipids and lipoproteins and fibrinogen. Multiplex, immunobead-based assay or ELISA measured 18 cardiovascular-related protein biomarkers. SELDI-TOF mass spectrometry (MS) screened for proteins differing significantly between high and low CACS. RESULTS: Only monocyte chemotactic protein-1 was higher in the high compared with the low CACS group but concentrations overlapped appreciably. On SELDI-TOF MS, several mass/charge ratio peak intensities significantly discriminated high and low CACS but these differences were not confirmed in larger samples from the cohort. CONCLUSIONS: Plasma protein biomarkers are unlikely to provide an effective alternative to measurement of CACS.

Metabolic-inflammatory changes, and accelerated atherosclerosis in HIV patients: rationale for preventative measures.

Human immunodeficiency virus (HIV)-infected patients are at a significantly higher risk from coronary heart diseases (CHD) and myocardial infarction (MI) compared to gender- and age-matched non-infected individuals. Combination antiretroviral therapy (cART) has transformed a fatal illness into a chronic stable condition. However, cART induces metabolic abnormalities in HIV-infected patients, while its role in vascular atherosclerosis is still under investigation. The use of cART is linked to inflammation - a key mechanism in atherosclerotic progression and destabilisation that precedes clinical events like MI. There is evidence of visceral fat abnormal distribution in HIV infected patients, and inflammatory changes in HIV infected patients drive the initiation, progression and, ultimately, thrombotic clinical complications induced by atherosclerosis. Visceral adipose tissue, a virtual factory for manufacturing pro-inflammatory mediators, affects the liver function. The inflamed liver promotes the development of pro-atherogenic dyslipidaemia. Pro-inflammatory cytokines released by adipocytes travel to the skeletal muscles and other peripheral tissues, worsening insulin sensitivity and leading to hyperglycaemia. Increased high sensitivity C-reactive protein (hs-CRP) inflammatory marker is associated with endothelial dysfunction in HIV-infected patients. Increased levels of monocytic nuclear factor kappa-B (NFkappa-B), a master switch in the inflammatory cascade, are documented in patients with elevated hs-CRP levels. It can be assumed that, as a result of NFkappa-B activation, hs-CRP up-regulates cytokines that contribute to MI by recruiting leukocytes and promoting thrombosis. This review focuses on the association of HIV-infection, metabolic abnormalities and known mechanisms involved in inducing accelerated atherosclerosis and inflammation in HIV-infected patients, as well as the role of lipid lowering agents in potentially preventing CHD.

Insulin for type 2 diabetes: choosing a second-line insulin regimen.

UNLABELLED: Guidance has been published on the choice of initial insulin regimen for patients with type 2 diabetes [NPH (isophane) insulin or a long-acting insulin analogue] but not on how to choose a second regimen when glycaemic control becomes unsatisfactory. AIMS: To develop pragmatic clinical guidance for choosing a second-line insulin regimen tailored to the individual needs of patients with type 2 diabetes after failure of first-line insulin therapy. METHODS: Formulation of a consensus by expert panel based on published evidence and best clinical practice, taking into account patient preferences, lifestyle and functional capacity. RESULTS: Six patient-dependent factors relevant to the choice of second-line insulin regimen and three alternative insulin regimens (twice-daily premixed, basal-plus and basal-bolus) were identified. The panel recommended one or more insulin regimens compatible with each factor, emphasising the fundamental importance of a healthy lifestyle that includes exercise and weight reduction. These recommendations were incorporated into an algorithm to provide pragmatic guidance for clinicians. CONCLUSION: The three alternative insulin regimens offer different benefits and drawbacks and it is important to make the right choice to optimise outcomes for patients.

S-nitrosoglutathione-containing hydrogel increases dermal blood flow in streptozotocin-induced diabetic rats.

BACKGROUND: Endothelial dysfunction is characterized by decreased vasodilatory capacity of the arterioles mainly due to the reduced release of nitric oxide (NO). Application of NO donors may prevent or even reverse the consequences of endothelial dysfunction, such as diabetic leg ulcers. OBJECTIVES: To investigate the vasodilatory capacity and the possible side-effects of topical application of an NO donor-containing hydrogel in diabetic rats. METHODS: S-nitrosoglutathione (GSNO) was incorporated in Pluronic F127 hydrogel and applied on the foot sole skin of healthy and streptozotocin-induced diabetic rats. Blood flow was monitored using a laser-Doppler probe. Nitrotyrosine formation, a possible side-effect of GSNO action, was evaluated by Western blotting of skin protein extracts. Systemic circulatory side-effects were investigated by monitoring blood pressure and heart rate during the application. RESULTS: The hydrogel alone did not induce any changes in microvascular flow, while GSNO-containing hydrogel caused a twofold increase in perfusion. This effect was similar in diabetic and healthy animals. Topical GSNO application did not increase the nitrotyrosine content of skin proteins, nor did it have any effect on blood pressure or heart rate. CONCLUSIONS: Dermal application of GSNO may be an effective treatment for promoting the local vasodilation in both healthy and diabetic states, without inducing protein nitration or alterations in blood pressure or heart rate.

Coronary calcification, homocysteine, C-reactive protein and the metabolic syndrome in Type 2 diabetes: the Prospective Evaluation of Diabetic Ischaemic Heart Disease by Coronary Tomography (PREDICT) Study.

AIMS: The PREDICT Study aims to determine: (i) the association between cardiovascular risk factors and coronary artery calcification score (CACS) obtained by electron beam tomography and (ii) the predictive value of CACS for coronary heart disease (CHD) events in Type 2 diabetes. METHODS: Having previously reported relationships between CACS and conventional risk factors, we have now studied the novel risk factors, plasma high-sensitivity C-reactive protein (CRP) and homocysteine, insulin resistance, serum apoprotein A1 and B concentrations, the serum triglyceride/high-density lipoprotein cholesterol ratio and metabolic syndrome (International Diabetes Federation definition) in 573 subjects of the PREDICT Type 2 diabetes cohort. RESULTS: In univariate analyses, the only significant positive novel correlate of CACS was homocysteine (P = 0.0004). CRP was increased in those with detectable calcification, but decreased with increasing calcification score (P = 0.006). In a multivariate model that included all significant univariate correlates, CACS was independently associated with age (P < 0.0001), waist-hip ratio (P < 0.02), male gender (P < 0.05) and duration of diabetes (P < 0.05), but the association with homocysteine was no longer significant. The negative association between CACS and CRP remained in multivariate analysis, and was independent of statin use. CONCLUSIONS: Age was the major factor influencing CACS in Type 2 diabetes, with weaker contributions from waist hip-ratio and duration of diabetes. Other novel cardiovascular risk factors appear to have little positive effect.

Erectile dysfunction and statin treatment in high cardiovascular risk patients.

Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy. In this prospective observational study, International Index of Erectile Function (IIEF) scores were measured in 93 men attending cardiovascular risk clinics. Cardiovascular risk factors and drug therapies were assessed prior to initiation and after 6 months of statin therapy. Prior to statin therapy, the median IIEF score was 21 (range 0-25), and 57% had impairment of erectile function. After statin therapy, IIEF scores were reduced to 6.5 (range 0-25) (p < 0.001), and 22% experienced new onset ED. Before statin therapy no correlation was observed between IIEF score and any individual cardiovascular risk factor. After 6 months of statin therapy, correlations were observed between lower IIEF scores (r = 0.62; p < 0.001) and age and diabetes and weakly with smoking. Differences in dose, relative efficacy or relative lipophilicity of statin prescribed showed no correlation with change in IIEF score. This study suggests ED following statin therapy is more likely in patients with severe endothelial dysfunction due to established cardiovascular risk factors including age, smoking and diabetes.

The association of coronary calcium score and conventional cardiovascular risk factors in Type 2 diabetic subjects asymptomatic for coronary heart disease (The PREDICT Study).

AIM: To determine the association between coronary calcification score (CACS) obtained by electron beam computed tomography (EBCT) and cardiovascular risk factors in Type 2 diabetic subjects entered into a prospective cohort study. METHODS: Type 2 diabetic subjects attending routine hospital diabetic clinics without known coronary heart disease (CHD) underwent EBCT to measure CACS. Demographic data were obtained and conventional cardiovascular risk factors were measured at baseline. RESULTS: Four hundred and ninety-five subjects were assessed of whom 67.7% were male. They had a mean (SD) age of 62.9 (7.1) years, with median (inter-quartile range) duration of diabetes of 8 (4-13) years. None had a history of coronary artery disease. Forty-five per cent were receiving lipid-lowering agents (including 36% statins). In a univariate analysis, there were significant associations between increased CACS and age, duration of diabetes, male gender, waist-hip ratio (WHR), systolic blood pressure, and the use of statins. In a multivariate model adjusting for the possible interaction of these and other factors, the significant association between CACS and WHR, systolic blood pressure, male gender and statin use remained. CONCLUSIONS: The close association between CACS and WHR and the association with systolic blood pressure suggest that coronary calcification may be particularly linked to the metabolic syndrome in Type 2 diabetes.

Smell testing: an additional tool for identification of adult Refsum's disease.

BACKGROUND: Adult Refsum's disease (ARD) is characterised by the presence of retinitis pigmentosa, ataxia, deafness, sensory neuropathy, and bony changes. The diagnosis is confirmed by the presence of phytanic acidaemia. Although reduced smell function has been described in ARD, its value in the diagnosis of the condition has not been fully evaluated. OBJECTIVE: To investigate the prevalence and degree of olfactory dysfunction in patients with ARD. METHOD: The olfactory function of 16 patients with ARD was assessed using the quantitative University of Pennsylvania Smell Identification Test (UPSIT). RESULTS: All patients had complete anosmia or grossly impaired smell function with a mean UPSIT score of 14.7 (SD 4.7) (normal > 34) despite having been treated with an appropriate diet for a median of 15 years (range 1-25). CONCLUSIONS: Identification of ARD patients can be facilitated by using the UPSIT in combination with the presence of retinitis pigmentosa, even if they have no neurological or bony features. Phytanic acid screening should be performed in any patient manifesting these two signs.

Predicting synthetic accessibility: application in drug discovery and development.

The estimation and use of synthetic accessibility in the drug discovery process is discussed. A distinction is drawn between synthetic feasibility and accessibility and the practical uses of an accessibility score are examined. Various techniques used in the estimation of accessibility are described and their utility and potential accuracy compared.