Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD.

PURPOSE: Some classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). METHODS: Four cross-sections of people with T2DM aged 18-90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FINDINGS: Around 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9-9.1%) and 8.9% (8.6-9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0-19.5%) and 21.2% (20.6-21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0-24.4%) and 25.9% (25.2-26.6%) in January 2017 to 41.3% (39.5-43.0%) and 45.5% (44.7-46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. IMPLICATIONS: Although use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit.

Childhood emotional problems and self-perceptions predict weight gain in a longitudinal regression model.

BACKGROUND: Obesity and weight gain are correlated with psychological ill health. We predicted that childhood emotional problems and self-perceptions predict weight gain into adulthood. METHODS: Data on around 6,500 individuals was taken from the 1970 Birth Cohort Study. This sample was a representative sample of individuals born in the UK in one week in 1970. Body mass index was measured by a trained nurse at the age of 10 years, and self-reported at age 30 years. Childhood emotional problems were indexed using the Rutter B scale and self-report. Self-esteem was measured using the LAWSEQ questionnaire, whilst the CARALOC scale was used to measure locus of control. RESULTS: Controlling for childhood body mass index, parental body mass index, and social class, childhood emotional problems as measured by the Rutter scale predicted weight gain in women only (least squares regression N = 3,359; coefficient 0.004; P = 0.032). Using the same methods, childhood self-esteem predicted weight gain in both men and women (N = 6,526; coefficient 0.023; P < 0.001), although the effect was stronger in women. An external locus of control predicted weight gain in both men and women (N = 6,522; coefficient 0.022; P < 0.001). CONCLUSION: Emotional problems, low self-esteem and an external locus of control in childhood predict weight gain into adulthood. This has important clinical implications as it highlights a direction for early intervention strategies that may contribute to efforts to combat the current obesity epidemic.

Determinants of initial inhaled corticosteroid use in patients with GOLD A/B COPD: a retrospective study of UK general practice.

Initial use of inhaled corticosteroid therapy is common in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) A or B chronic obstructive pulmonary disease, contrary to GOLD guidelines. We investigated UK prescribing of inhaled corticosteroid therapy in these patients, to identify predictors of inhaled corticosteroid use in newly diagnosed chronic obstructive pulmonary disease patients. A cohort of newly diagnosed GOLD A/B chronic obstructive pulmonary disease patients was identified from the UK Clinical Practice Research Datalink (June 2005-June 2015). Patients were classified by prescribed treatment, with those receiving inhaled corticosteroid-containing therapy compared with those receiving long-acting bronchodilators without inhaled corticosteroid. In all, 29,815 patients with spirometry-confirmed chronic obstructive pulmonary disease were identified. Of those prescribed maintenance therapy within 3 months of diagnosis, 63% were prescribed inhaled corticosteroid-containing therapy vs. 37% prescribed non-inhaled corticosteroid therapy. FEV1% predicted, concurrent asthma diagnosis, region, and moderate exacerbation were the strongest predictors of inhaled corticosteroid use in the overall cohort. When concurrent asthma patients were excluded, all other co-variates remained significant predictors. Other significant predictors included general practitioner practice, younger age, and co-prescription with short-acting bronchodilators. Trends over time showed that initial inhaled corticosteroid prescriptions reduced throughout the study, but still accounted for 47% of initial prescriptions in 2015. These results suggest that inhaled corticosteroid prescribing in GOLD A/B patients is common, with significant regional variation that is independent of FEV1% predicted. EARLY-STAGE CHRONIC LUNG DISEASE: OVERUSE OF INHALED STEROIDS IN THE UK: Inhaled steroids are often prescribed to early-stage chronic lung disease patients in the UK despite guidelines to the contrary. Patients newly diagnosed with early-stage chronic obstructive pulmonary disease (COPD) should not be prescribed inhaled corticosteroids (ICS), because they carry an increased risk of side effects such as pneumonia and osteoporosis. ICS should be reserved for patients with severe COPD and frequent exacerbations. James Chalmers at the Scottish Centre for Respiratory Research, Dundee, and co-workers examined prescribed medication data from the UK spanning 10 years, to determine key predictors of ICS prescription during early-stage COPD. Of 29,815 patients identified, an average of 63% were prescribed ICS upon diagnosis, regardless of disease severity. Younger patients were more likely to receive ICS, possibly due to co-morbidity with chronic asthma, and particular UK regions and medical practices prescribed ICS more readily than others.

UK-specific cost-effectiveness of tiotropium + olodaterol fixed-dose combination versus other LAMA + LABA combinations in patients with COPD.

OBJECTIVE: The aim of this study is to assess the cost-effectiveness of other long-acting muscarinic antagonist + long-acting ß2 agonist combinations in comparison with Spiolto® Respimat® (tiotropium + olodaterol fixed-dose combination [FDC]) for maintenance treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease. METHODS: A previously published individual-level Markov model was adapted for the perspective of the UK health care system, in line with recommendations from the National Institute for Health and Care Excellence. Individuals progressed through the model based on their forced expiratory volume in 1 second (FEV1) value at baseline and the post-improvement FEV1 value. Changes in FEV1 were taken from a mixed treatment comparison. Costs were obtained from a published cost-utility analysis of tiotropium in the treatment of chronic obstructive pulmonary disease in the UK. Uncertainty was assessed by deterministic and probabilistic sensitivity analysis. RESULTS: Duaklir® Genuair® (aclidinium bromide + formoterol fumarate FDC) and the free-dose combination of tiotropium + salmeterol were dominated by tiotropium + olodaterol FDC. The quality-adjusted life years and costs were identical for Ultibro® Breezhaler® (indacaterol + glycopyrronium FDC) and Anoro™ Ellipta® (umeclidinium + vilanterol FDC) compared with tiotropium + olodaterol FDC, resulting in identical incremental cost-effectiveness ratios. CONCLUSION: This analysis shows tiotropium + olodaterol FDC to be a cost-effective option for the maintenance treatment of adults with chronic obstructive pulmonary disease in the UK.

Cost-effectiveness of tiotropium versus glycopyrronium in moderate to very severe chronic obstructive pulmonary disease in Canada, Spain, Sweden, and the UK.

OBJECTIVES: Tiotropium (TIO), Spiriva® Handihaler®, is a well-established bronchodilator, LAMA (long acting muscarinic antagonist), for the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). Clinical evidence from the SPARK trial suggests that TIO is superior to glycopyrronium (GLY), Seebri® Breezhaler®, in terms of severe exacerbations. This modeling study assessed the cost-effectiveness of TIO versus GLY for Canada (CAN), Spain (ESP), Sweden (SWE), and the UK, making use of this new clinical evidence. METHODS: A Markov cohort model, with moderate to very severe (Global Initiative for Chronic Obstructive Lung Disease II-IV) COPD patients, was populated with efficacy data from the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) and SPARK trials as well as costs, utilities, and epidemiological data relevant for each country. Treatment efficacy was modeled as improvements in lung function, quality-adjusted life years (QALYs), and as a lowering of the risk of exacerbations (rate of exacerbations). Risks of exacerbations differed between cohorts based on data from SPARK. Health and cost outcomes were simulated over an approximate lifetime horizon, starting from the age of 65 years. Robustness of results was validated in deterministic sensitivity analyses. RESULTS: Over the lifetime horizon, patients treated with TIO accumulated -623 (CAN), 1,066 (ESP), 1,137 (SWE), and -169 (UK), respectively, in incremental costs (€2014). TIO generated better health outcomes compared to GLY in all countries, 0.21 (CAN), 0.25 (ESP), 0.23 (SWE), and 0.23 (UK) in incremental QALYs. The cost per QALY gained was found to be €4,281 and €1,137 for ESP and SWE, respectively, while TIO was found to be cost saving in CAN and the UK. The results were mainly driven by the relative risk of severe exacerbations found in SPARK (GLY/TIO relative risk: 1.43, 95% confidence interval: 1.05-1.97, P=0.025). CONCLUSION: The results from this study show that TIO is a cost-effective treatment compared to GLY in moderate to very severe COPD. The cost per QALY is well below the existing implicit and explicit willingness-to-pay thresholds.

The burden of chronic obstructive pulmonary disease associated with maintenance monotherapy in the UK.

BACKGROUND: This study characterized a cohort of chronic obstructive pulmonary disease (COPD) patients on maintenance bronchodilator monotherapy for ≥6 months to establish their disease burden, measured by health care utilization. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and linked to Hospital Episode Statistics. The monotherapy period spanned the first prescription of a long-acting ß2-adrenergic agonist or a long-acting muscarinic antagonist until the end of the study (December 31, 2013) or until step up to dual/triple therapy, for example, addition of another long-acting bronchodilator, an inhaled corticosteroid, or both. A minimum of four consecutive prescriptions and 6 months on continuous monotherapy were required. Patients <50 years old at first COPD diagnosis or with another significant respiratory disease before starting monotherapy were excluded. Disease burden was evaluated by measuring patients' rate of face-to-face interactions with a health care professional (HCP), COPD-related exacerbations, hospitalizations, and referrals. RESULTS: A cohort of 8,811 COPD patients (95% Global initiative for chronic Obstructive Lung Disease stage A/B) on maintenance monotherapy was identified between 2002 and 2013; 45% of these patients were still on monotherapy by the end of the study. Median time from first COPD diagnosis to first monotherapy prescription was 56 days, while the median time on maintenance bronchodilator monotherapy was 2 years. The median number of prescriptions was 14. On average, patients had 15 HCP interactions per year, and one in ten patients experienced a COPD exacerbation (N=8,811). One in 50 patients were hospitalized for COPD per year (n=4,848). CONCLUSION: The average monotherapy-treated patient had a higher than average HCP interaction rate. We also identified a large cohort of patients who were stepped up to triple therapy despite a low rate of exacerbations. The use of the new class of long-acting muscarinic antagonist/long-acting ß2-adrenergic agonist fixed-dose combinations may provide a useful step-up treatment option in such monotherapy patients, before the use of inhaled corticosteroids.

Development of an enhanced health-economic model and cost-effectiveness analysis of tiotropium + olodaterol Respimat® fixed-dose combination for chronic obstructive pulmonary disease patients in Italy.

BACKGROUND: The objective of this study was to compare the cost-effectiveness of the fixed-dose combination (FDC) of tiotropium + olodaterol Respimat(®) FDC with tiotropium alone for patients with chronic obstructive pulmonary disease (COPD) in the Italian health care setting using a newly developed patient-level Markov model that reflects the current understanding of the disease. METHODS: While previously published models have largely been based around a cohort approach using a Markov structure and GOLD stage stratification, an individual-level Markov approach was selected for the new model. Using patient-level data from the twin TOnado trials assessing Tiotropium + olodaterol Respimat(®) FDC versus tiotropium, outcomes were modelled based on the trough forced expiratory volume (tFEV1) of over 1000 patients in each treatment arm, tracked individually at trial visits through the 52-week trial period, and after the trial period it was assumed to decline at a constant rate based on disease stage. Exacerbation risk was estimated based on a random-effects logistic regression analysis of exacerbations in UPLIFT. Mortality by age and disease stage was estimated from an analysis of TIOSPIR trial data. Cost of bronchodilators and other medications, routine management, and costs of treatment for moderate and severe exacerbations for the Italian setting were included. A cost-effectiveness analysis was conducted over a 15-year time horizon from the perspective of the Italian National Health Service. RESULTS: Aggregating total costs and quality-adjusted life years (QALYs) for each treatment cohort over 15 years and comparing tiotropium + olodaterol Respimat(®) FDC with tiotropium alone, resulted in mean incremental costs per patient of €1167 and an incremental cost-effectiveness ratio (ICER) of €7518 per additional QALY with tiotropium + olodaterol Respimat(®) FDC. The lung function outcomes observed for tiotropium + olodaterol Respimat(®) FDC in TOnado drove the results in terms of slightly higher mean life-years (12.24 versus 12.07) exacerbation-free months (11.36 versus 11.32) per patient and slightly fewer moderate and severe exacerbations per patient-year (0.411 versus 0.415; 0.21 versus 0.24) versus tiotropium. Probabilistic sensitivity analyses showed tiotropium + olodaterol Respimat(®) FDC to be the more cost-effective treatment in 95.2% and 98.4% of 500 simulations at thresholds of €20,000 and €30,000 per QALY respectively. CONCLUSION: Tiotropium + olodaterol Respimat(®) FDC is a cost-effective bronchodilator in the maintenance treatment of COPD for the Italian health care system.

The changing epidemiology of meningococcal disease in North America 1945-2010.

The epidemiology of Invasive Meningococcal Disease (IMD) is distinct in the United States and Canada compared with other countries. This review describes the incidence, mortality and vaccination strategies relevant to IMD in these countries over the past 65 y. The incidence of IMD has remained consistently low in both countries during this period. Serogroup B and serogroup C have been the most prominent disease-causing serogroups. Notably, serogroup Y has recently become an important cause of IMD in the USA, but has not been as prominent in Canada. Periodic rises in incidence have been characterized by local outbreaks that have raised public concern, especially those caused by serogroup C in Canada, and serogroup B in the USA. Case fatality rates have remained consistent at around 10-20%, but vary by age and serogroup. Recent outbreaks have led to the introduction of vaccination programs for both outbreak control and routine immunization.

Association of a Serotonin Receptor 2A Gene Polymorphism with Visual Sustained Attention in Early-Onset Schizophrenia Patients and their Non-Psychotic Siblings.

The serotonin receptor 2A gene polymorphism is associated with attentional processes in schizophrenia. However, the specificity of the underlying cognitive constructs affected within this domain requires further elucidation. We carried out the first investigation of whether the TC/CC genotype of the 5-HT2A T102C polymorphism confers impairments in early-onset schizophrenia (EOS; onset of psychotic symptoms before age 18) but not in healthy siblings, the putative mechanism being that serotonergic inhibitory modulation of prefrontal dopamine is impaired in the presence of the C allele which in turn is a genetic risk marker for schizophrenia. Fifty-three EOS outpatients and 46 of their non-psychotic siblings (no current Axis I diagnoses) were genotyped for 5-HT2A T102C polymorphism. The Positive and Negative Syndrome Scale (PANSS) was used to assess symptomatology severity. Diagnostic classification was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Structured Clinical Interview. The Degraded-Stimulus Continuous Performance Test (DS-CPT) was used to measure sustained focused attention. As predicted, EOS probands produced fewer correct responses (hit rate) and demonstrated poorer perceptual sensitivity compared with the healthy siblings. The C allele at codon 102 was associated with fewer correct responses compared with the TT genotype. There was no significant relationship between the polymorphism and clinical parameters, as measured using the PANSS. Our findings suggest that the C allele may be related to sustained attentional impairments in EOS.

Association study of POMC variants with body composition measures and nutrient choice.

Genome linkage scans and candidate gene studies have implicated the pro-opiomelanocortin (POMC) locus in traits related to food intake, metabolic function, and body mass index. Here we investigate single nucleotide polymorphisms at the POMC locus in order to evaluate the influence of its genetic variance on body fat distribution and diet in a sample of middle-aged men from The Netherlands. 366 Dutch males from the Hamlet cohort were asked detailed questions about food choice, nutrient intake and exercise. Furthermore, their weight and body fat composition were measured. Each cohort member was genotyped for a set of single nucleotide polymorphisms (SNPs) at the POMC locus. Regression analysis, adjusted for several covariates, was used to test for the association between genetic variants and the phenotypes measured. POMC variation was associated with waist:hip ratio, visceral fat and abdominal fat (rs6713532, P=0.020, 0.019, and 0.021, respectively), and nutrient choice (rs1042571, P=0.034), but in light of limited power and multiple testing these results should be taken with caution. POMC is a strong candidate for involvement in appetite regulation as supported by animal, physiological, and genetic studies and variation at the POMC locus may affect an individual's energy intake which in turn leads to variation in body composition and body fat.

Eating disorders and obesity: two sides of the same coin?

The eating disorders anorexia and bulimia nervosa have traditionally been regarded as entirely separate from obesity. Eating disorders have been regarded as Western culture-bound syndromes, arising in societies with excessive emphasis on weight, shape and appearance, and best treated by psychological therapies, in particular cognitive behavioural therapy or family-based interventions. In contrast, obesity has been considered a medical illness with metabolic and genetic origins, and thought to be best treated by mainstream medicine, involving dietary, drug or surgical treatment. We believe that this polarisation is fundamentally flawed, and research and treatment of both types of disorder would be better served by greater appreciation of the psychosocial components of obesity and the biological and genetic components of eating disorders. There are similarities in phenotype (such as excessive attempts at weight control, binge eating behaviours) and in risk factors (such as low self-esteem, external locus of control, childhood abuse and neglect, dieting, media exposure, body image dissatisfaction, weight-related teasing and shared susceptibility genes). One example of shared genetic risk is the brain-derived neurotrophic factor (BNDF) gene, in which the valine allele of the Val66Met amino acid polymorphism predisposes to obesity, whereas the methionine allele predisposes to eating disorders. Thus the evidence suggests that these disorders will have both shared and distinct susceptibility factors; some will predispose to both types of disorder, some will push in opposite directions, and some will separate them.