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.

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.

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.

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.

Prevalence of renal artery stenosis in subjects with type 2 diabetes and coexistent hypertension.

OBJECTIVE: To assess the prevalence of renal artery stenosis (RAS) in subjects with type 2 diabetes and coexistent hypertension by using magnetic resonance angiography (MRA) of the renal arteries, to assess clinical and biochemical predictors of RAS, and to assess the hemodynamic significance of RAS, by using the captopril test (a measure of the response of plasma renin activity to a single oral dose of captopril). RESEARCH DESIGN AND METHODS: A total of 117 subjects with type 2 diabetes and coexistent hypertension between 40 and 70 years of age and with creatinine concentrations < 150 micromol/l were recruited from two inner-city general diabetes clinics. All subjects underwent MRA of the renal arteries. In a subgroup of 85 subjects, data concerning possible clinical and biochemical predictors of RAS were collected, and the captopril test was performed. For comparison of a continuous variable between subjects with a positive MRA and those with a negative MRA, the Mann-Whitney test was used. For comparison of a discrete variable between subjects with a positive MRA and those with a negative MRA, Fisher's exact test was used. RESULTS: The prevalence of RAS detected by using MRA in 117 hypertensive type 2 diabetic subjects was 17%; 19 subjects had unilateral RAS, and only 1 subject had bilateral RAS. A femoral bruit was significantly more common in subjects with a positive MRA versus subjects with a negative MRA (21 vs. 0%; Fisher's exact test P < 0.005); however, other clinical features of atherosclerotic disease were not statistically associated. Greater duration of hypertension and treatment with statins were features of subjects with RAS (P < 0.05). The captopril test was negative in all subjects, although the antihypertensive response to oral captopril was significantly greater in subjects with RAS detected by MRA. CONCLUSIONS: RAS is common in hypertensive type 2 diabetic subjects. The presence of a femoral bruit is a useful predictive clinical marker. The captopril test is not useful in predicting the hemodynamic significance of RAS in this patient group.

Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study.

OBJECTIVE: To determine whether serum lipid intervention, in addition to conventional diabetes treatment, could alter cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 164 type 2 diabetic subjects (117 men, 47 women) without a history of clinical cardiovascular disease randomized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospectively for a minimum of 3 years. Serial biochemical and noninvasive vascular assessments, carotid and femoral artery B-mode ultrasound measurements, and those pertaining to coronary heart disease (CHD)--clinical history, the World Health Organization (WHO) cardiovascular questionnaire, and resting and exercise electrocardiogram (ECG)--were recorded. RESULTS: Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride (-32 vs. 4%, P = 0.001), total cholesterol (-7 vs. -0.3%, P = 0.004), and total-to-HDL cholesterol ratio (-12 vs. -0.0%, P = 0.001), and an increase in HDL cholesterol (6 vs. -2%, P = 0.02) as compared with placebo. There was a trend toward a greater reduction of fibrinogen (-18 vs. -6%, P = 0.08) at 3 years. No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease. In those treated with bezafibrate, there was a significant reduction (P = 0.01, log-rank test) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infarction. CONCLUSIONS: Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease, although the lower rate of "definite CHD events" in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease.

Low-density lipoproteins increase intracellular calcium in aequorin-loaded platelets.

Low-density lipoproteins activate isolated human platelets. The mechanism of this activation is unknown, but may involve increased phosphoinositide turnover. We have examined the effect of low-density lipoproteins on intracellular calcium concentrations in platelets loaded with the photoprotein aequorin. The lipoproteins induced concentration-dependent increases in intracellular calcium, associated with shape change and aggregation. These responses could be partially inhibited by the removal of extracellular calcium and by pre-incubation with acetylsalicylic acid. They were also antagonised by agents which increase cellular concentrations of cyclic adenosine and guanosine monophosphates. It is not clear whether the platelet-lipoprotein interaction involves a 'classical' lipoprotein receptor.

Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.

Flexible alignment of small molecules.

A method is presented for flexibly aligning small molecules. The method accepts a collection of small molecules with 3D coordinates as input and computes a collection of alignments. Each alignment is given a score, which quantifies the quality of the alignment both in terms of internal strain and overlap of molecular features. The results of several computational experiments on pairs of compounds with known binding conformations are used to systematically and objectively tune the parameters for the method. The results indicate the method's utility for the elucidation of pharmacophores and comparative field analysis.

Current awareness

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Prediction; 7 Prevention; 8 Intervention: a&rpar General; b&rpar Pharmacology; 9 Pathology: a&rpar General; b&rpar Cardiovascular; c&rpar Neurological; d&rpar Renal; 10 Endocrinology & Metabolism; 11 Nutrition; 12 Animal Studies; 13 Techniques. Within each section, articles are listed in alphabetical order with respect to author (8 Weeks journals - Search completed at 19th Apr. 2000)

Comparison of an immunochemical assay for plasma fibrinogen and a turbidimetric thrombin clotting technique to discriminate hyperlipidaemic patients from healthy controls.

Plasma samples from patients attending a lipid clinic (n = 14) and healthy control subjects (n = 21) were assayed for fibrinogen using an immunochemical method (radial immunodiffusion) and a turbidimetric assay based on the thrombin clotting technique. The patients had significantly higher plasma fibrinogen concentrations than controls by both methods, but there was significant overlap between the two groups when fibrinogen was assayed by the thrombin clotting technique; there was almost complete separation of the two groups using the immunochemical assay. This difference in overlap could not be attributed to the presence or absence of fibrinogen degradation products. These findings may have important implications for the choice of method for determining plasma fibrinogen when assays are used for the assessment of cardiovascular risk. It is recommended that plasma fibrinogen should be assayed by both an immuno-chemical and a thrombin clotting method.

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.