Cardiovascular risk factors early in the course of treatment in people with type 2 diabetes without established cardiovascular disease: A population-based observational retrospective cohort study.

AIMS: To characterise the cardiovascular risk of people with type 2 diabetes without established cardiovascular disease but with risk factors, relative to those with established cardiovascular disease, to provide information on which patients could benefit from early use of glucose-lowering therapies that also reduce cardiovascular risk. METHODS: Data from people with type 2 diabetes initiating second-line glucose-lowering medication were retrieved from the UK Clinical Practice Research Datalink GOLD database and linked with Hospital Episode Statistics and Office for National Statistics (2001-2016). Cox proportional hazards models were used to estimate relative risks of major adverse cardiovascular events within groups defined by the presence of selected risk factors in people without versus with established cardiovascular disease. RESULTS: Of 53,182 individuals, 19.4% had established cardiovascular disease (i.e. a prior cardiovascular event). Over 5-7 years' follow-up, the rate of major adverse cardiovascular events was 14.0 and 49.6 events/1000 person-years without and with established cardiovascular disease, respectively (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.26, 0.29). Compared with a reference HR 1.0 for participants with established cardiovascular disease, estimated glomerular filtration rate <60 mL/min was the single factor associated with the highest risk of major adverse cardiovascular events (HR 0.75, 95% CI 0.70, 0.81) and mortality (HR 1.12, 95% CI 1.07, 1.18) in people with type 2 diabetes without established cardiovascular disease. The combination of chronic kidney disease with older age, smoking and/or dyslipidaemia was associated with a similarly high risk of cardiovascular events in people with type 2 diabetes and without cardiovascular disease compared with those having established cardiovascular disease. CONCLUSIONS: These analyses provide important information to identify people who may benefit from primary prevention of cardiovascular disease. Modifiable cardiovascular risk factors should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).

Erenumab Decreases Headache-Related Sick Leave Days and Health Care Visits: A Retrospective Real-World Study in Working Patients with Migraine.

INTRODUCTION: The prevalence of migraine is highest among working age individuals, and this disease is associated with an increased number of sick leaves and health care visits, as well as lost productivity. Erenumab, the first monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway, is effective in decreasing the monthly number of migraine days, but evidence of its impact on the number of sick leave days and health care visits in patients with migraine is limited. METHODS: This retrospective registry study focused on occupationally active patients with migraine treated with erenumab at a Finnish private health care provider, Terveystalo. Erenumab responders, defined as patients who had at least two unique prescriptions of erenumab and no prescription of other CGRP inhibitor (CGRPi), were followed for 12 months prior to and after erenumab treatment initiation (index), and the change in the number of headache-related and all-cause sick leave days, health care visits and prescriptions for other medications during this period were assessed from the registry data. The same outcomes were assessed in an age- and sex-matched control group of migraine patients not receiving CGRPi to control for potential changes in patient behavior and health care practices during the COVID-19 pandemic. RESULTS: Altogether, 162 patients who were entitled to employer-sponsored health care received erenumab and met the 12-month follow-up requirements. In the responder group (n = 82; 50.1%) headache-related sick leave days were reduced by 73.9% (p = 0.035) and health care visits by 44.6% (p < 0.001) in the 12 months following treatment initiation compared to the period of 12 months prior to treatment. All-cause sick leave days were reduced by 19.4% and all-cause health care visits by 13.5%, but these changes were not statistically significant. Triptan prescriptions decreased by 30.4% (p = 0.012) and other prophylactic treatments by 31.5% (p = 0.004). No significant changes were observed in the corresponding outcomes in the migraine control group during the same period. CONCLUSIONS: The results of this registry study suggest that in addition to the effect on the monthly number of migraine days documented in clinical trials, erenumab can significantly reduce the number of headache-related sick leave days and health care visits in employed patients with migraine managed in routine clinical practice.

The Effect of Early Response to GLP-1 RA Therapy on Long-Term Adherence and Persistence Among Type 2 Diabetes Patients in the United States.

BACKGROUND: Treatment adherence and persistence are crucial to achieve glycemic control in patients with type 2 diabetes (T2D). Early response to a new therapy may lead to improved treatment adherence and associated outcomes. OBJECTIVE: To assess the effect of early response to glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy, as indicated by reduced hemoglobin A1c (A1c) and body weight, on long-term adherence and persistence. METHODS: Adults aged ≥ 18 years with T2D initiated with GLP-1 RA therapy after January 1, 2010, were identified from the IBM Explorys Therapeutic Dataset. Patients were required to have health care utilization ≥ 6 months before and ≥ 18 months after the index prescription. Changes in A1c and body weight from baseline through 6 months were assessed for all patients; early response was defined by > 1% reduction in A1c and > 3% reduction in body weight within 3-6 months. Adherence (assessed as the proportion of days covered [PDC] ≥ 80%) and nonpersistence/discontinuation (indicated by a gap in therapy ≥ 60 days) over 18 months were evaluated among early responders versus nonresponders. Multivariable logistic regression was used to assess the effect of early response to GLP-1 RA therapy on adherence and discontinuation over 18 months. RESULTS: Among 8,329 identified patients, 33.3% and 31.2% experienced early response as indicated by reductions in A1c > 1% point and in body weight > 3% from baseline, respectively. Significantly higher proportions (P < 0.001) of early responders in both reduced A1c and body weight were adherent over 18 months compared with patients without an early response (A1c: 45.0% vs. 37.1%; body weight: 43.3% vs. 38.0%). Significantly lower proportions (P < 0.001) of early responders discontinued over 18 months compared with patients without an early response (A1c: 61.4% vs. 67.9%; body weight: 61.9% vs. 67.5%). After controlling for baseline demographic and clinical characteristics including baseline weight, baseline A1c, oral antidiabetes drug use, insulin use, and the presence of comorbidity of diabetes, patients were more likely to be adherent over 18 months if they had reductions in A1c > 1% (OR = 1.59, 95% CI = 1.36-1.85) or body weight reduction > 3% (OR = 1.18, 95% CI = 1.02-1.36) at 3-6 months compared with those without an early response. Similarly, the early responders had significantly lower likelihood of discontinuation compared with those without early response (A1c > 1%; OR = 0.62, 95% CI = 0.53-0.72; body weight > 3%; OR = 0.81, 95% CI = 0.70-0.94). CONCLUSIONS: Early response to GLP-1 RA therapy was associated with significantly increased adherence and reduced likelihood of discontinuation. DISCLOSURES: Funding to conduct this study was provided to IBM Watson Health by Novo Nordisk A/S. The analysis was conducted independently by IBM Watson Health. Novo Nordisk A/S and IBM Watson Health collaborated on study design and interpretation of results. At the time of this study, Durden and Laing were employed by IBM Watson Health and received funding from Novo Nordisk to conduct this study. Fowler is employed by IBM Watson Health. Panton and Mocevic were employed by Novo Nordisk while this study was conducted. A portion of these results were presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018; April 23-26, 2018; Boston, MA, where it was awarded with a bronze ribbon.

Effectiveness of Liraglutide and Lixisenatide in the Treatment of Type 2 Diabetes: Real-World Evidence from The Health Improvement Network (THIN) Database in the United Kingdom.

INTRODUCTION: The glucagon-like peptide-1 receptor agonists liraglutide and lixisenatide are effective at reducing glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Although liraglutide has demonstrated superior efficacy in head-to-head clinical trials, real-world evidence of comparative effectiveness is lacking. This observational study aimed to assess the effectiveness of liraglutide versus lixisenatide in UK clinical practice. METHODS: Electronic medical records from The Health Improvement Network (THIN) UK primary care database were analyzed. Patients aged ≥18 years, diagnosed with T2DM, and prescribed liraglutide or lixisenatide between 01 May 2013 and 31 December 2015 were included in the study. Adjusted linear regression models compared the difference in mean change in HbA1c, body mass index (BMI), and systolic blood pressure (SBP) after 12-month follow-up. The proportion of patients achieving glycemic control (HbA1c <6.5%, <7.0%, <7.5%); HbA1c reduction >1%; and weight reduction ≥3% within 12 months were determined. Cox proportional hazards modeling was used to evaluate the effect of treatment on time to achieving HbA1c and weight reduction targets. Healthcare resource use (HCRU) (GP, secondary care, hospitalizations) was compared using analysis of covariance. RESULTS: The primary outcome was assessed in 579 liraglutide and 213 lixisenatide new users. Fully adjusted linear regression indicated that liraglutide reduced HbA1c significantly more than lixisenatide (mean treatment difference -0.30; 95% CI -0.56, -0.04; p = 0.025). Compared to lixisenatide, liraglutide recipients were 2.5 times more likely to achieve HbA1c <6.5% (p = 0.0002). Liraglutide users were also more likely to achieve HbA1c <7.0% (HR 2.10; p < 0.0001), <7.5% (HR 1.65; p < 0.0001), and >1% HbA1c reduction (HR 1.29; p = 0.0002). BMI and SBP reductions were greater for the liraglutide group but results were not significant. HCRU was comparable between treatment groups. CONCLUSION: These results from the THIN database indicate that liraglutide treatment provided better outcomes related to glycemic control. FUNDING: Novo Nordisk.

Clinical Effectiveness of Liraglutide in Type 2 Diabetes Treatment in the Real-World Setting: A Systematic Literature Review.

INTRODUCTION: In clinical trials, liraglutide has proven to be an effective drug for the treatment of type 2 diabetes mellitus (T2DM). The real-world effectiveness of liraglutide has been investigated in numerous studies. The aim of this systematic literature review is to collate evidence on the real-world clinical effectiveness of liraglutide. METHODS: A review of publications from Medline, EMBASE, the Cochrane Library, and conference proceedings was conducted to identify observational studies that assessed the clinical effectiveness of liraglutide in real-world clinical practice. This review was conducted according to the National Institute of Health and Care Excellence (NICE) guidance. No language or time limits were applied, except to the conference proceedings (2013-2015). Endpoints for data extraction were decided a priori. Study quality appraisal was done for full-text journal articles. RESULTS: Of 124 publications included in the review, 43 were full-text articles. Liraglutide significantly reduces glycated hemoglobin (HbA1c) within 6 months of initiating treatment (mean change in HbA1c from baseline: -0.9% to -2.2%; HbA1c <7.0%: 29.5-65.0%). The NICE composite endpoint (HbA1c reduction ≥1% and weight reduction ≥3%) was met in 16.9-47.0% of patients with liraglutide treatment. Liraglutide therapy led to a mean change in absolute weight from baseline of -1.3 to -8.65 kg. Liraglutide treatment was well tolerated in patients with T2DM. The rate of occurrence of hypoglycemia with liraglutide monotherapy was ≤0.8%. Hypoglycemia was more common in patients taking antidiabetic medications (0.0-15.2%) together with liraglutide. The beneficial glycemic and weight effect of liraglutide therapy in patients with T2DM was maintained for at least 12 months. CONCLUSION: Evidence from observational studies reflecting real-world clinical practice demonstrates that liraglutide therapy improves glycemic control with a low risk of hypoglycemia, and is associated with significant weight loss in patients with T2DM. These observations are consistent with clinical trial findings. FUNDING: Novo Nordisk A/S, Søborg, Denmark.

Cadmium may impair prostate function as measured by prostate specific antigen in semen: A cross-sectional study among European and Inuit men.

We investigated the association between cadmium in blood and the concentration of the prostate specific antigen (PSA) in semen, including the modifying effects of zinc or the CAG polymorphism in the androgen receptor (AR). Blood and semen samples were collected from 504 partners of pregnant women in Greenland, Poland and Ukraine. We found an inverse trend between cadmium and PSA (log(ß) = -0.121, 95% confidence interval (CI): -0.213; -0.029, P = 0.0103) in Greenlandic men. Similar results were observed in men with a high number of CAG repeats (CAG 24) (log(ß) = -0.231, 95% CI: -0.363; -0.098, P = 0.0009). Inverse trends between cadmium and PSA were found when semen zinc concentrations were below the median value for men from Ukraine and Greenland. These outcomes suggest that cadmium may impair prostate function, as measured by PSA in semen, while high zinc levels and a low number of CAG repeats protects against this action.

Risk of ischemic heart disease following occupational exposure to welding fumes: a systematic review with meta-analysis.

PURPOSE: Air pollution has been linked to an increased risk of ischemic heart disease (IHD), but less is known about occupational exposure to welding fumes and the risk of IHD. The objective of this paper was to review the epidemiological evidence on causal links between welding fume exposure and risk of IHD and to investigate whether the risk of IHD depends on specific welding characteristics. METHODS: A systematic search in Medline 1979-2013 and EMBASE 1974-2013 identified 18 epidemiological studies with at least one risk estimate of IHD morbidity or mortality among workers exposed to welding fumes. Following an assessment of completeness of reporting, confounding, and bias, each risk estimate was characterized as more or less reliable. Pooled risk estimates were computed across studies by random effect meta-analyses. RESULTS: The weighted relative risk (RR) for IHD following exposure to welding fumes was 1.09 [95 % confidence interval (CI) 1.00, 1.19]. We calculated a RR of 1.39 (95 % CI 0.96, 2.02) among studies using an internal reference group and 1.08 (95 % CI 0.99, 1.18) for studies using an external reference group. An increased risk was observed for acute myocardial infarction RR = 1.69 (95 % CI 1.18, 2.42) and other IHDs RR = 1.06 (95 % CI 0.98, 1.14). There was too limited evidence to evaluate the risk of IHD related to specific welding characteristics. CONCLUSION: Several studies indicate that welding is associated with a moderately increased risk of IHD; however, bias and confounding cannot be ruled out with reasonable confidence.

Occupational lifting, fetal death and preterm birth: findings from the Danish National Birth Cohort using a job exposure matrix.

OBJECTIVE: We examined the association between occupational lifting during pregnancy and risk of fetal death and preterm birth using a job exposure matrix (JEM). METHODS: For 68,086 occupationally active women in the Danish National Birth Cohort, interview information on occupational lifting was collected around gestational week 16. We established a JEM based on information from women, who were still pregnant when interviewed. The JEM provided mean total loads lifted per day within homogeneous exposure groups as informed by job and industry codes. All women were assigned an exposure estimate from the JEM. We used Cox regression models with gestational age as underlying time variable and adjustment for covariates. RESULTS: We observed 2,717 fetal deaths and 3,128 preterm births within the study cohort. No exposure-response relation was observed for fetal death, but for women with a prior fetal death, we found a hazard ratio (HR) of 2.87 (95% CI 1.37, 6.01) for stillbirth (fetal death ≥22 completed gestational weeks) among those who lifted >200 kg/day. For preterm birth, we found an exposure-response relation for primigravid women, reaching a HR of 1.43 (95% CI 1.13, 1.80) for total loads >200 kg per day. These findings correspond to an excess fraction of 11% for stillbirth and 10% for preterm birth. CONCLUSION: We found an increased risk of stillbirth among women with a prior fetal death, who lifted >200 kg/day, and an exposure-response relationship between occupational lifting and preterm birth among primigravid women. The study adds to a large body of prospective studies on occupational lifting and adverse pregnancy outcomes by refined exposure assessment.

Environmental mercury exposure, semen quality and reproductive hormones in Greenlandic Inuit and European men: a cross-sectional study.

Several animal studies indicate that mercury is a male reproductive toxicant, but human studies are few and contradictory. We examined semen characteristics and serum levels of reproductive hormones in relation to environmental exposure to mercury. Blood and semen samples were collected from 529 male partners of pregnant women living in Greenland, Poland and Ukraine between May 2002 and February 2004. The median concentration of the total content of mercury in whole blood was 9.2 ng ml(-1) in Greenland (0.2-385.8 ng ml(-1)), 1.0 ng ml(-1) in Poland (0.2-6.4 ng ml(-1)) and 1.0 ng ml(-1) in Ukraine (0.2-4.9 ng ml(-1)). We found a significantly positive association between the blood levels of mercury and serum concentration of inhibin B in men from Greenland (ß=0.074, 95% confidence interval (CI)=0.021 to 0.126) and in an analysis including men from all three regions (ß=0.067, 95% CI=0.024 to 0.110). The association may be due to beneficial effects of polyunsaturated fatty acids (PUFAs), which are contained in seafood and fish. No significant association (P>0.05) was found between blood concentrations of mercury and any of the other measured semen characteristics (semen volume, total sperm count, sperm concentration, morphology and motility) and reproductive hormones (free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and LH × testosterone) in any region. In conclusion, the findings do not provide evidence that environmental mercury exposure in Greenlandic and European men with median whole blood concentration up to 10 ng ml(-1) has adverse effects on biomarkers of male reproductive health.