Safety and glycemic control with insulin degludec use in clinical practice: results from a 3-year Japanese post-marketing surveillance study.

Introduction: Insulin degludec (degludec) is a basal insulin with a long duration of action. This post-marketing surveillance study monitored safety and glycemic control during use of degludec for 3 years in normal clinical practice in Japan. Materials and methods: This multicenter, open-label, observational study included patients with diabetes receiving degludec in Japan between 2013 and 2019. The primary outcome was incidence of adverse events occurring over 3 years of treatment. The pre-specified, secondary outcomes were severe hypoglycemic episodes and changes in HbA1c and fasting plasma glucose levels. Results: Of 4167 patients enrolled, 4022 were included in the safety assessments and 3918 in the assessments of glycemic control. Mean age was 58.9 years; 74.1% of patients had type 2 diabetes, and mean HbA1c at baseline was 8.7%. Adverse events and serious adverse events were observed in 19.1% and 8.9% of patients, respectively. Cardiac disorders and neoplasms were reported in 2.0% and 1.8% of patients, respectively, with the majority of these incidents reported as serious adverse events. Adverse drug reactions were seen in 8.0% of patients, mainly hypoglycemia. Hypoglycemic events were observed in 5.6% of patients, and severe hypoglycemic events in 1.7%. No serious allergic or injection-site reactions were seen. Respective changes (from baseline to 3 years' observation) in HbA1c and fasting plasma glucose levels were - 0.55% and - 36.3 mg/dL, and 19.6% of patients reached HbA1c < 7.0%. Conclusions: Using degludec for 3 years in normal clinical practice had a good safety and tolerability profile. Improvements in glycemic control were also seen. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00657-7.

Fetal Overgrowth and Preterm Delivery in Women With Type 1 Diabetes Using Insulin Pumps or Multiple Daily Injections: A Post Hoc Analysis of the EVOLVE Study Cohort.

OBJECTIVE: To compare the risk of fetal overgrowth and preterm delivery in pregnant women with type 1 diabetes (T1D) treated with insulin pumps versus multiple daily injections (MDI) and examine whether possible differences were mediated through improved glycemic control or gestational weight gain during pregnancy. RESEARCH DESIGN AND METHODS: The risk of pregnancy and perinatal outcomes were evaluated in a cohort of 2,003 pregnant women with T1D enrolled from 17 countries in a real-world setting during 2013-2018. RESULTS: In total, 723 women were treated with pumps and 1,280 with MDI. At inclusion (median gestational weeks 8.6 [interquartile range 7-10]), pump users had lower mean HbA1c (mean ± SD 50.6 ± 9.8 mmol/mol [6.8 ± 0.9%] vs. 53.6 ± 13.8 mmol/mol [7.1 ± 1.3%], P < 0.001), longer diabetes duration (18.4 ± 7.8 vs. 14.4 ± 8.2 years, P < 0.001), and higher prevalence of retinopathy (35.3% vs. 24.4%, P < 0.001). Proportions of large for gestational age (LGA) offspring and preterm delivery were 59.0% vs. 52.2% (adjusted odds ratio [OR] 1.36 [95% CI 1.09; 1.70], P = 0.007) and 39.6% vs. 32.1% (adjusted OR 1.46 (95% CI 1.17; 1.82), P < 0.001), respectively. The results did not change after adjustment for HbA1c or gestational weight gain. CONCLUSIONS: Insulin pump treatment in pregnant women with T1D, prior to the widespread use of continuous glucose monitoring or automated insulin delivery, was associated with a higher risk of LGA offspring and preterm delivery compared with MDI in crude and adjusted analyses. This association did not appear to be mediated by differences in glycemic control as represented by HbA1c or by gestational weight gain.

Congenital malformations among offspring of women with type 1 diabetes who use insulin pumps: a prospective cohort study.

AIMS/HYPOTHESIS: Continuous subcutaneous insulin infusion by insulin pump is often superior in improving glycaemic control compared with conventional multiple daily insulin injection (MDI). However, whether pump treatment leads to improved pregnancy outcomes in terms of congenital malformations and perinatal death remains unknown. The present aim was to evaluate the risk of malformations and perinatal and neonatal death in pregnant women with type 1 diabetes treated with pump or MDI. METHODS: We performed a secondary analysis of a prospective multinational cohort of 2088 pregnant women with type 1 diabetes in a real-world setting who were treated by pump (n=750) or MDI (n=1338). ORs for offspring with congenital malformations or perinatal or neonatal death were calculated using crude data and by logistic regression on propensity score-matched data. RESULTS: At enrolment (gestational week 8; 95% CI 4, 14), pump users had a higher educational level (university degree: 37.3% vs 25.1%; p<0.001) and better glycaemic control (mean HbA1c: 51±10 mmol/mol [6.8±0.9%] vs 54±14 mmol/mol [7.1±1.3%], p<0.001) compared with MDI users. Moreover, a greater proportion of pump users had an HbA1c level below 75 mmol/mol (9%) (97.6% vs 91.9%, p<0.001), and more often reported taking folic acid supplementation (86.3% vs 74.8%; p<0.001) compared with MDI users. All clinically important potential confounders were balanced after propensity score matching, and HbA1c remained lower in pump users. The proportion of fetuses with at least one malformation was 13.5% in pump users vs 11.2% in MDI users (crude OR 1.23; 95% CI 0.94, 1.61; p=0.13; propensity score-matched (adjusted) OR 1.11; 95% CI 0.81, 1.52; p=0.52). The proportion of fetuses with at least one major malformation was 2.8% in pump users vs 3.1% in MDI users (crude OR 0.89; 95% CI 0.52, 1.51; p=0.66; adjusted OR 0.78; 95% CI 0.42, 1.45; p=0.43), and the proportions of fetuses carrying one or more minor malformations (but no major malformations) were 10.7% vs 8.1% (crude OR 1.36; 95% CI 1.00, 1.84; p=0.05; adjusted OR 1.23; 95% CI 0.87, 1.75; p=0.25). The proportions of perinatal and neonatal death were 1.6% vs 1.3% (crude OR 1.23; 95% CI 0.57, 2.67; p=0.59; adjusted OR 2.02; 95% CI 0.69, 5.93; p=0.20) and 0.3% vs 0.3% (n=2 vs n=4, p=not applicable), respectively. CONCLUSIONS/INTERPRETATIONS: Insulin pump treatment was not associated with a lower risk of congenital malformations, despite better glycaemic control in early pregnancy compared with MDI. Further studies exploring the efficacy and safety of pump treatment during pregnancy are needed.

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).

Characteristics of pregnant women with diabetes using injectable glucose-lowering drugs in the EVOLVE study.

AIMS: To examine clinical parameters, glycemic control, folic acid supplementation, and the presence of other chronic diseases during early pregnancy in the EVOLVE study population (women with pre-existing diabetes treated with injectable glucose-lowering drugs). METHODS: Cross-sectional baseline evaluation of EVOLVE: an international, multicenter, non-interventional study investigating the safety of injectable glucose-lowering drugs in pregnant women with pre-existing type 1 (T1D) or type 2 diabetes (T2D). Data were collected at enrollment visit interviews before gestational week 16. RESULTS: In total, 2383 women from 17 mainly European countries were enrolled in the study: 2122 with T1D and 261 with T2D; mean age was 31 and 33 years, and duration of diabetes was 15 and 6 years, respectively. For women with T1D or T2D, 63% and 75%, respectively, received basal and rapid-acting insulin, 36% and 3% rapid-acting insulin only, 0.7% and 14.0% basal insulin only, 0.2% and 5.4% premix insulin, 0.0% and 1.2% injectable glucagon-like peptide-1 receptor agonist treatment without insulin. In women with T1D or T2D, respectively, during early pregnancy, 59% and 62% had HbA1c <7.0% (53 mmol/mol); 16% and 36% reported not taking folic acid before or during early pregnancy. Overall, >40% of women had ≥1 chronic concomitant condition (predominantly thyroid disease or hypertension). Retinopathy was the most commonly reported diabetic complication. The most commonly reported previous pregnancy complication was miscarriage. CONCLUSIONS: Baseline data from this large multinational population of women with pre-existing diabetes indicate that sub-optimal glycemic control, poor pregnancy planning, and chronic concomitant conditions were common in early pregnancy.

Glycaemic Control in People with Diabetes Starting Treatment with Fast-Acting Insulin Aspart: a US Database Study.

INTRODUCTION: This study investigated glycaemic control in individuals with type 1 (T1D) or type 2 diabetes (T2D) 6 months after initiating fast-acting insulin aspart (faster aspart) in a real-world setting. METHODS: This was a single-arm, observational study using extracted patient data from the IBM® Explorys® database (USA) for individuals with T1D or T2D initiating faster aspart (at least one prescription of faster aspart) in the study period 1 January 2018 to 27 October 2020. Clinical characteristics, including age, body mass index, and baseline HbA1c, were extracted, as well as recorded events of hypoglycaemia. The primary endpoint was the change in HbA1c from baseline to 6 months. RESULTS: A total of 787 individuals were included; 36.6% of these individuals had T1D and 63.4% had T2D (of whom 46.9% were new users of rapid-acting insulin when initiating faster aspart [T2D new users] and 53.1% were switching from another rapid-acting insulin to faster aspart [T2D switchers]). For individuals with T1D, T2D new users, or T2D switchers, estimated mean change in HbA1c from baseline to 6 months was - 0.20% (95% CI - 0.53, 0.14; p  =  0.252), - 1.00% (95% CI -  1.34, -  0.67; p < 0.0001), and - 0.70% (95% CI - 1.06, - 0.35; p = 0.0001), respectively. In the baseline HbA1c > 8.5% subgroup, there was a significant estimated decrease in HbA1c from baseline to 6 months in individuals with T1D (-  1.2% [95% CI - 1.80, -  0.60]; p = 0.0001) or T2D (- 0.6% [95% CI - 0.92, -  0.35]; p <  0.0001). Event rates of hypoglycaemia after 12 months were 0.68, 0.38, and 0.59 events/year for individuals with T1D, T2D new users, and T2D switchers, respectively. CONCLUSION: US IBM® Explorys® data demonstrated a clinically relevant reduction in HbA1c 6 months after initiating faster aspart treatment for individuals with T2D, but not T1D overall, although patients with baseline HbA1c > 8.5% had significant HbA1c reductions regardless of diabetes type.

Risk of Major Congenital Malformations or Perinatal or Neonatal Death With Insulin Detemir Versus Other Basal Insulins in Pregnant Women With Preexisting Diabetes: The Real-World EVOLVE Study.

OBJECTIVE: To compare the risk of severe adverse pregnancy complications in women with preexisting diabetes. RESEARCH DESIGN AND METHODS: Multinational, prospective cohort study to assess the prevalence of newborns free from major congenital malformations or perinatal or neonatal death (primary end point) following treatment with insulin detemir (detemir) versus other basal insulins. RESULTS: Of 1,457 women included, 727 received detemir and 730 received other basal insulins. The prevalence of newborns free from major congenital malformations or perinatal or neonatal death was similar between detemir (97.0%) and other basal insulins (95.5%) (crude risk difference 0.015 [95% CI -0.01, 0.04]; adjusted risk difference -0.003 [95% CI -0.03, 0.03]). The crude prevalence of one or more congenital malformations (major plus minor) was 9.4% vs. 12.6%, with a similar risk difference before (-0.032 [95% CI -0.064, 0.000]) and after (-0.036 [95% CI -0.081, 0.009]) adjustment for confounders. Crude data showed lower maternal HbA1c during the first trimester (6.5% vs. 6.7% [48 vs. 50 mmol/mol]; estimated mean difference -0.181 [95% CI -0.300, -0.062]) and the second trimester (6.1% vs. 6.3% [43 vs. 45 mmol/mol]; -0.139 [95% CI -0.232, -0.046]) and a lower prevalence of major hypoglycemia (6.0% vs. 9.0%; risk difference -0.030 [95% CI -0.058, -0.002]), preeclampsia (6.4% vs. 10.0%; -0.036 [95% CI -0.064, -0.007]), and stillbirth (0.4% vs. 1.8%; -0.013 [95% CI -0.024, -0.002]) with detemir compared with other basal insulins. However, differences were not significant postadjustment. CONCLUSIONS: Insulin detemir was associated with a similar risk to other basal insulins of major congenital malformations, perinatal or neonatal death, hypoglycemia, preeclampsia, and stillbirth.

Understanding Patients' Willingness to Pay for Biphasic Insulin Aspart 30/70 in a Pen Device for Type 2 Diabetes Treatment in an Out-of-Pocket Payment Market.

OBJECTIVE: Our objective was to investigate willingness to pay (WTP) for biphasic insulin aspart 30/70 (BIAsp 30) in patients with type 2 diabetes mellitus (T2DM) in India. METHODS: A multicenter, prospective, non-interventional, preference study was conducted that assessed WTP for BIAsp 30 in an insulin pen (FlexPen® or Penfill® device) in patients in India with T2DM previously treated with biphasic human insulin (BHI) in vials and believed to be able to pay for treatment. The primary endpoint was the proportion of patients willing to continue to pay for BIAsp 30 after 12 weeks' treatment. Secondary endpoints included the change from baseline in treatment and device satisfaction and patient preferences for treatment attributes as assessed by a nested discrete-choice experiment. RESULTS: Overall, 54.9% (n = 277/505) of participants were male; the mean age was 56.4 years; diabetes duration was 10.9 years; 63.8% had a body mass index ≥ 25 kg/m2; > 75% had an annual household income > 150,000 Indian rupees (INR). After 12 weeks' treatment, 96.4% of patients were willing to pay for BIAsp 30. Mean treatment and device satisfaction significantly improved from baseline (p < 0.0001). Patients were willing to pay INR3576 (95% confidence interval [CI] 2755-4398) for improved glycemic control, INR688 (95% CI 383-994) for a device upgrade (vial/syringe to an insulin pen), or INR327 (95% CI 95-560) to avoid major hypoglycemia. Patients would need to be compensated INR44 (95% CI 56-32) per minor hypoglycemic event. CONCLUSIONS: In India, patients with T2DM previously treated with BHI were willing to pay for BIAsp 30 in an insulin pen. Furthermore, treatment and device satisfaction improved after this therapeutic switch. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03374774.

A Retrospective Database Study of Liraglutide Persistence Associated with Glycemic and Body Weight Control in Patients with Type 2 Diabetes.

INTRODUCTION: In both randomized controlled trials and real-world studies, liraglutide has demonstrated glycemic and body weight benefits in patients with type 2 diabetes. However, persistence with diabetes medication can be challenging. This study compared glycated hemoglobin (HbA1c) and other outcomes in patients with type 2 diabetes who continued treatment with liraglutide for over 12 months with those who discontinued treatment earlier, in a real-life setting. METHODS: This is a retrospective study of adult patients with type 2 diabetes from Maccabi Healthcare Services in Israel, who initiated treatment with liraglutide from 2010 to 2015. Mean HbA1c and body weight change from initiation to after 24 months was compared between patients who received liraglutide for at least 12 months ("continuers") and those who discontinued within the first year ("discontinuers"). Adjustment for HbA1c, body weight, and other potentially confounding factors was performed using 1:1 propensity score matching. RESULTS: The 3580 patients comprised 2695 continuers and 885 discontinuers; 882 patients per group were matched. A significant (p < 0.001) reduction in HbA1c (- 0.80% vs - 0.32%) was seen in continuers compared with discontinuers, despite higher insulin usage (70.2% vs 59.0%; p < 0.001), and a higher proportion of patients using ≥ 3 oral glucose-lowering drugs (20.6% vs 6.2%; p < 0.001) at 24 months among discontinuers. Mean body weight reduction was greater in continuers than discontinuers (3.57 vs 1.25 kg; p < 0.001). CONCLUSION: In a real-world setting, persistent use of liraglutide was associated with good glycemic and body weight control. FUNDING: Novo Nordisk Health Care AG.

Alcohol consumption and its interaction with adiposity-associated genetic variants in relation to subsequent changes in waist circumference and body weight.

BACKGROUND: Studies have suggested a link between alcohol intake and adiposity. However, results from longitudinal studies have been inconsistent, and a possible interaction with genetic predisposition to adiposity measures has often not been taken into account. OBJECTIVE: To examine the association between alcohol intake recorded at baseline and subsequent annual changes in body weight (∆BW), waist circumference (ΔWC) and WC adjusted for BMI (ΔWCBMI), and to test for interaction with genetic predisposition scores based on single nucleotide polymorphisms (SNPs) associated with various forms of adiposity. METHOD: This study included a total of 7028 adult men and women from MONICA, the Diet, Cancer and Health cohort (DCH), and the Inter99 studies. We combined 50 adiposity-associated SNPs into four scores indicating genetic predisposition to BMI, WC, WHRBMI and all three traits combined. Linear regression was used to examine the association of alcohol intake (drinks of 12 g (g) alcohol/day) with ΔBW, ΔWC, and ΔWCBMI, and to examine possible interactions with SNP-scores. Results from the analyses of the individual cohorts were combined in meta-analyses. RESULTS: Each additional drink/day was associated with a ΔBW/year of -18.0 g (95% confidence interval (CI): -33.4, -2.6, P = 0.02) and a ΔWC of -0.3 mm/year (-0.5, -0.0, P = 0.03). In analyses of women only, alcohol intake was associated with a higher ΔWCBMI of 0.5 mm/year (0.2, 0.9, P = 0.002) per drink/day. Overall, we found no statistically significant interactions between the four SNP-scores and alcohol intake in relation to changes in adiposity measures. However in analyses of women separately, we found interaction between the complete score of all 50 SNPs and alcohol intake in relation to ΔBW (P for interaction = 0.03). No significant interaction was observed among the men. CONCLUSION: Alcohol intake was associated with a decrease in BW and WC among men and women, and an increase in WCBMI among women only. We found no strong indication that these associations depend on a genetic predisposition to adiposity. TRIAL REGISTRATION: Registry: ClinicalTrials.gov Trial number: CT00289237 , Registered: 19 September 2005 retrospectively registered.

Effect of general health screening and lifestyle counselling on incidence of diabetes in general population: Inter99 randomised trial.

We aimed to examine the effect of a large population-based multifactorial screening and lifestyle intervention programme on 10-year incidence of diabetes. In a randomised trial of the general Danish population initiated in 1999-2001 59,616 men and women aged 30-60years were assigned to a five year screening and lifestyle counselling programme (n=11,629) or control group (n=47,987) and followed for ten years in nationwide registers. Intention to treat was applied and risk of diabetes was modeled by Cox regression and expressed as hazard ratios (HRs). We found that 1692 individuals had diabetes at baseline. Among 57,924 individuals without diabetes at baseline, 1267 emigrated, 2593 died and 3369 (Intervention group=684, Control group=2685) developed diabetes. We saw no significant difference in diabetes incidence between the groups after 10-year follow-up (Grey's test: p=0.22). In the first year of follow-up, incidence of diabetes was significantly higher in the intervention group than the control group (HR=1.68, 95%CI 1.29 to 2.29). We observed no difference in incidence of diabetes between the groups in the follow-up intervals from 1 to 6years or after 6-10years (HR=0.94, 0.83 to 1.06; HR=1.03, 0.91 to 1.17). Inviting the general population to participate in a repeated screening and lifestyle counselling programme over five years did not result in lower incidence of diabetes after 10years of follow-up. As expected, significantly more individuals were diagnosed with diabetes in the intervention group during the first year, but this was not followed by a decrease in the following years. TRIALS REGISTRATION: Clinical trials NCT00289237.

Interactions between genetic variants associated with adiposity traits and soft drinks in relation to longitudinal changes in body weight and waist circumference.

BACKGROUND: Intake of sugar-sweetened beverages is associated with obesity, and this association may be modified by a genetic predisposition to obesity. OBJECTIVE: We examined the interactions between a molecular genetic predisposition to various aspects of obesity and the consumption of soft drinks, which are a major part of sugar-sweetened beverages, in relation to changes in adiposity measures. DESIGN: A total of 4765 individuals were included in the study. On the basis of 50 obesity-associated single nucleotide polymorphisms that are associated with body mass index (BMI), waist circumference (WC), or the waist-to-hip ratio adjusted for BMI (WHRBMI), the following 4 genetic predisposition scores (GRSs) were constructed: a complete genetic predisposition score including all 50 single nucleotide polymorphisms (GRSComplete), a genetic predisposition score including BMI-associated single nucleotide polymorphisms (GRSBMI), a genetic predisposition score including waist circumference-associated single nucleotide polymorphisms (GRSWC), and a genetic predisposition score including the waist-to-hip ratio adjusted for BMI-associated single nucleotide polymorphisms (GRSWHR). Associations between soft drink intake and the annual change (Δ) in body weight (BW), WC, or waist circumference adjusted for BMI (WCBMI) and possible interactions with the GRSs were examined with the use of linear regression analyses and meta-analyses. RESULTS: For each soft drink serving per day, soft drink consumption was significantly associated with a higher ΔBW of 0.07 kg/y (95% CI: 0.01, 0.13 kg/y; P = 0.020) but not with the ΔWC or ΔWCBMI In analyses of the ΔBW, we showed an interaction only with the GRSWC (per risk allele for each soft drink serving per day: -0.06 kg/y; 95% CI: -0.10, -0.02 kg/y; P = 0.006). In analyses of the ΔWC, we showed interactions only with the GRSBMI and GRSComplete [per risk allele for each soft drink serving per day: 0.05 cm/y (95% CI: 0.02, 0.09 cm/y; P = 0.001) and 0.05 cm/y (95% CI: 0.02, 0.07 cm/y; P = 0.001), respectively]. Nearly identical results were observed in analyses of the ΔWCBMI CONCLUSIONS: A genetic predisposition to a high WC may attenuate the association between soft drink intake and BW gain. A genetic predisposition to high BMI as well as a genetic predisposition to high BMI, WC, and WHRBMI combined may strengthen the association between soft drink intake and WC gain. However, the public health impact may be limited.

Serum 25-Hydroxyvitamin D Status and Longitudinal Changes in Weight and Waist Circumference: Influence of Genetic Predisposition to Adiposity.

Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) and changes in measures of adiposity have shown inconsistent results, and interaction with genetic predisposition to obesity has rarely been examined. We examined whether 25(OH)D was associated with subsequent annual changes in body weight (ΔBW) or waist circumference (ΔWC), and whether the associations were modified by genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHRBMI). The study was based on 10,898 individuals from the Danish Inter99, the 1958 British Birth Cohort and the Northern Finland Birth Cohort 1966. We combined 42 adiposity-associated Single Nucleotide Polymorphisms (SNPs) into four scores indicating genetic predisposition to BMI, WC and WHRBMI, or all three traits combined. Linear regression was used to examine the association between serum 25(OH)D and ΔBW or ΔWC, SNP-score × 25(OH)D interactions were examined, and results from the individual cohorts were meta-analyzed. In the meta-analyses, we found no evidence of an association between 25(OH)D and ΔBW (-9.4 gram/y per 10 nmol/L higher 25(OH)D [95% CI: -23.0, +4.3; P = 0.18]) or ΔWC (-0.06 mm/y per 10 nmol/L higher 25(OH)D [95% CI: -0.17, +0.06; P = 0.33]). Furthermore, we found no statistically significant interactions between the four SNP-scores and 25(OH)D in relation to ΔBW or ΔWC. Thus, in view of the narrow CIs, our results suggest that an association between 25(OH)D and changes in measures of adiposity is absent or marginal. Similarly, the study provided evidence that there is either no or very limited dependence on genetic predisposition to adiposity.

The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample.

INTRODUCTION: The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population. METHODS: Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model. RESULTS: We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks. CONCLUSION: Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.

The Association of Reproductive Hormone Levels and All-Cause, Cancer, and Cardiovascular Disease Mortality in Men.

CONTEXT: Testosterone (T) levels have been associated with mortality, but controversy exists. OBJECTIVE: Our objective was to investigate associations between serum levels of total T, SHBG, free T, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up. DESIGN: This was a prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up. SETTING AND PARTICIPANTS: A total of 5350 randomly selected men from the general population aged 30, 40, 50, 60, or 70 years at baseline participated. MAIN OUTCOMES AND MEASURES: All-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality were the main outcomes. RESULTS: A total of 1533 men died during the follow-up period; 428 from CVD and 480 from cancer. Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.14-1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR, 1.23; 95% CI, 1.06-1.43; HR, 1.23; 95% CI 1.06-1.43). No association to T levels was found. Higher LH levels were associated with increased cancer mortality (HR, 1.42; 95% CI, 1.10-1.84) independently of smoking status. Lower CVD mortality was seen for men with T in the highest quartile compared to lowest (HR, 0.72; 95% CI, 0.53-0.98). Furthermore, negative trends were seen for SHBG and free T in relation to CVD mortality, however insignificant. CONCLUSION: The observed positive association of LH and LH/T, but not T, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency.

Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.

OBJECTIVES: To investigate, using a Mendelian randomisation approach, whether heavier smoking is associated with a range of regional adiposity phenotypes, in particular those related to abdominal adiposity. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730 in the CHRNA5-CHRNA3-CHRNB4 gene region) as a proxy for smoking heaviness, of the associations of smoking heaviness with a range of adiposity phenotypes. PARTICIPANTS: 148,731 current, former and never-smokers of European ancestry aged ≥ 16 years from 29 studies in the consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Waist and hip circumferences, and waist-hip ratio. RESULTS: The data included up to 66,809 never-smokers, 43,009 former smokers and 38,913 current daily cigarette smokers. Among current smokers, for each extra minor allele, the geometric mean was lower for waist circumference by -0.40% (95% CI -0.57% to -0.22%), with effects on hip circumference, waist-hip ratio and body mass index (BMI) being -0.31% (95% CI -0.42% to -0.19), -0.08% (-0.19% to 0.03%) and -0.74% (-0.96% to -0.51%), respectively. In contrast, among never-smokers, these effects were higher by 0.23% (0.09% to 0.36%), 0.17% (0.08% to 0.26%), 0.07% (-0.01% to 0.15%) and 0.35% (0.18% to 0.52%), respectively. When adjusting the three central adiposity measures for BMI, the effects among current smokers changed direction and were higher by 0.14% (0.05% to 0.22%) for waist circumference, 0.02% (-0.05% to 0.08%) for hip circumference and 0.10% (0.02% to 0.19%) for waist-hip ratio, for each extra minor allele. CONCLUSIONS: For a given BMI, a gene variant associated with increased cigarette consumption was associated with increased waist circumference. Smoking in an effort to control weight may lead to accumulation of central adiposity.

Standardizing serum 25-hydroxyvitamin D data from four Nordic population samples using the Vitamin D Standardization Program protocols: Shedding new light on vitamin D status in Nordic individuals.

Knowledge about the distributions of serum 25-hydroxyvitamin D (25(OH)D) concentrations in representative population samples is critical for the quantification of vitamin D deficiency as well as for setting dietary reference values and food-based strategies for its prevention. Such data for the European Union are of variable quality making it difficult to estimate the prevalence of vitamin D deficiency across member states. As a consequence of the widespread, method-related differences in measurements of serum 25(OH)D concentrations, the Vitamin D Standardization Program (VDSP) developed protocols for standardizing existing serum 25(OH)D data from national surveys around the world. The objective of the present work was to apply the VDSP protocols to existing serum 25(OH)D data from a Danish, a Norwegian, and a Finnish population-based health survey and from a Danish randomized controlled trial. A specifically-selected subset (n 100-150) of bio-banked serum samples from each of the studies were reanalyzed for 25(OH)D by LC-MS/MS and a calibration equation developed between old and new 25(OH)D data, and this equation was applied to the entire data-sets from each study. Compared to estimates based on the original serum 25(OH)D data, the percentage vitamin D deficiency (< 30 nmol/L) decreased by 21.5% in the Danish health survey but by only 1.4% in the Norwegian health survey; but was relatively unchanged (0% and 0.2%) in the Finish survey or Danish RCT, respectively, following VDSP standardization. In conclusion, standardization of serum 25(OH)D concentrations is absolutely necessary in order to compare serum 25(OH)D concentrations across different study populations, which is needed to quantify and prevent vitamin D deficiency.