Background To reduce their overall substantially increased risk of cardiovascular disease and premature mortality, smoking cessation is especially important for people with diabetes. However, the effect of weight change after quitting smoking on the long-term health consequences of smoking cessation is unclear. We aimed to examine smoking cessation and subsequent weight change in relation to incident cardiovascular disease events and mortality among adults with type 2 diabetes. Methods In this population-based cohort study, we analysed data from people with type 2 diabetes from two prospective cohorts in the USA: the Nurses' Health Study (1976-2014) and the Health Professionals Follow-Up Study (1986-2014). We included participants from both cohorts who either had prevalent type 2 diabetes or were diagnosed during the study, and who were either current smokers or never smokers without cardiovascular disease or cancer at diagnosis of diabetes. Information on demographics, newly diagnosed diseases, medical history, and lifestyle factors, including smoking status and weight change, was updated every 2 years through validated questionnaires. We assessed the incidence of cardiovascular disease and all-cause and cause-specific mortality among recent quitters (within 6 years of stopping) and long-term quitters (>6 years) associated with weight change within 6 years of smoking cessation among people with type 2 diabetes. We did a multivariable-adjusted Cox proportional hazard models to estimate hazard ratios (HRs) for the associations of smoking cessation and weight change on the outcomes. Findings Of 173 229 total cohort participants (121700 from the Nurses' Health Study and 51 529 from the Health Professionals Follow-Up Study), 10 809 people with type 2 diabetes were included in the incident cardiovascular disease analysis and 9688 were included in the mortality analysis. 2580 incident cases of cardiovascular disease occurred during 153 166 person-years of follow-up, and 3827 deaths occurred during 152 811 person-years of followup. Recent quitters (2-6 consecutive years since smoking cessation) without weight gain within the first 6 years of quitting had a significantly lower risk of cardiovascular disease than people who continued to smoke (multivariable-adjusted HR 0.83 [95% CI 0.70-0.99] among all recent quitters, 0.77 [0.62-0.95] among recent quitters without weight gain, 0.99 [0.70-1- 41] among recent quitters with weight gain of 0.1-5-0 kg, 0.89 [0.65-1.23] among recent quitters with weight gain of >5.0 kg, and 0.72 [0. 61-0.84] among longer-term quitters [>6 consecutive years since smoking cessation]). Weight gain within 6 years after smoking cessation did not attenuate the inverse relation between long-term cessation and all-cause mortality (multivariable-adjusted HR 0.69 [95% CI 0.58-0-82] among long-term quitters without weight gain, 0.57 [0- 45-0 71] among long-term quitters with weight gain of 0.1-5.0 kg, and 0.51 [0.42-0.62] among long-term quitters with weight gain of >5.0 kg), with similar results observed for cardiovascular disease and cancer mortality. Interpretation Smoking cessation without subsequent weight gain is associated with a reduced risk of cardiovascular disease and mortality among smokers with type 2 diabetes. Weight gain after smoking cessation attenuates the reduction in risk of developing cardiovascular disease, but does not attenuate the beneficial effect of smoking cessation with respect to mortality. These findings confirm the overall health benefits of quitting smoking among people with type 2 diabetes, but also emphasise the importance of weight management after smoking cessation to maximise its health benefits. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
Background National investigations on the interaction of insulin resistance, beta-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and beta-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. Methods In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011-12 (baseline) and invited participants to attend follow-up visits in 2014-16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, dinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and beta-cell dysfunction (HOMA of beta-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. Findings 94952 participants (31517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6.70, 95% CI 6.08-7.39; per unit increase in Z score: HR 2.17, 95% CI 2.10-2.24) than low HOMA-B (quartile 1 vs 4: 4.08, 3.72-4.48; per unit decrease in Z score: 1.92, 1.85-2.00). Approximately 24.4% (95% CI 23.6-25.2) of the incident diabetes could be attributed to insulin resistance and 12.4% (11.2-13.7) could be attributed to beta-cell dysfunction. The HRs for diabetes were 1.83 (95% CI 1.72-1.95) per unit increase in Z score of HOMA-IR and 2.03 (1.86-2.21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding H Rs for diabetes were 2.02 (1.93-2.11) and 1.88 (1.79-1.98) among participants with obesity (p(interaction) =0.0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. Interpretation Insulin resistance shows a stronger association with incident diabetes than does beta-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and beta-cell dysfunction, these findings should be interpreted with caution. Copyright (C) 2019 Published by Elsevier Ltd. All rights reserved.
Background Considering the global burden of diabetes and associated cardiovascular disease, an urgent need exists for the best treatment, which should be based on the best available evidence. We examined the association between glucose-lowering medications and a broad range of cardiovascular outcomes, and assessed the strength of evidence for these associations. Methods For this umbrella review we searched PubMed, Embase, and the Cochrane Library to identify systematic reviews and meta-analyses of randomised controlled trials examining the cardiovascular safety of glucose-lowering medications. Cardiovascular outcomes examined included major adverse cardiovascular events, cardiovascular death, myocardial infarction, stroke, heart failure, unstable angina, and atrial fibrillation. For each meta-analysis, we estimated the relative risk (RR) and 95% CI. We also created an evidence map showing the plausible benefits or harms of each intervention and the certainty of the evidence. Findings We examined 232 meta-analyses evaluating ten classes of diabetes drugs. We identified six risk and 38 protective associations showing a high strength of evidence. Six associations increased the risk of cardiovascular disease, including glimepiride (stroke [RR 2.01; 95% CI 1.02-3.98]), rosiglitazone (myocardial infarction [1.28; 1.02-1.62] and heart failure [1.72, 1.31-2.27]), and pioglitazone (heart failure [1.40; 1.16-1.69]). 38 associations decreased the risk of cardiovascular disease, including glucagon-like peptide-1 receptor agonists as a class (major adverse cardiovascular events [RR 0.88; 95% CI 0.84-0.92], death from cardiovascular disease [0.87; 0.81-0.94], myocardial infarction [0.92; 0.86-0.99], stroke [0.84; 0.77-0.93], and heart failure [0.90; 0.83-0.99]), albiglutide (major adverse cardiovascular events [0.81; 0.68-0.96], myocardial infarction [0.77; 0.64-0.92], and heart failure [0.71; 0.55-0.93]), dulaglutide (stroke [0.78; 0.64-0.96]), exenatide (major adverse cardiovascular events [0.91; 0.83-1.00]), liraglutide (major adverse cardiovascular events [0.86; 0.77-0.96]), semaglutide (major adverse cardiovascular events [0.76; 0.62-0.92] and stroke [0.67; 0.45-1.00]), sodium-glucose co-transporter-2 inhibitors as a class (major adverse cardiovascular events [0.87; 0.82-0.93], death from cardiovascular disease [0.82; 0.75-0.90], myocardial infarction [0.86; 0.78-0.94], and heart failure [0.68; 0.63-0.73]), canagliflozin (major adverse cardiovascular events [0.84; 0.75-0.93], death from cardiovascular disease [0.82; 0.71-0.96], and heart failure [0.65; 0.54-0.78]), dapagliflozin (heart failure [0.70; 0.60-0.82]), empagliflozin (major adverse cardiovascular events [0.85; 0.77-0.94], death from cardiovascular disease [0.62; 0.50-0.78], and heart failure [0.64; 0.53-0.77]), and pioglitazone (major adverse cardiovascular events [0.84; 0.74-0.96], myocardial infarction [0.80; 0.67-0.95], and stroke [0.79; 0.65-0.95]). Interpretation We found varied levels of evidence for the associations between diabetes drugs and cardiovascular outcomes; some drugs raised the risk of cardiovascular disease, whereas others showed benefit. Copyright (C) 2020 Elsevier Ltd. All rights reserved.
Background Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. Methods In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. Findings We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3.1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2.2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11.8% vs 10.0%; adjusted risk difference 2.43%, 95% CI 0.43 to 4.81; odds ratio [OR] 1.24, 1.04 to 1 .48; p=0.015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0.0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7.3% vs 10.0%, adjusted risk difference -2.91, -4.49 to -0.88; OR 0.70, 0.55 to 0.91; p=0.0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0.0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0.0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (p(interaction)=0.10). Each 1 SD increase in FT 4 concentration was associated with a 21 g lower birthweight (-25 to -17; p< 0.0001), with a higher effect estimate for measurement in the third trimester than the first or second. Interpretation Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. Copyright (C) 2020 Esevier Ltd. All rights reserved.
Diabetes is one of the most important comorbidities linked to the severity of all three known human pathogenic coronavirus infections, including severe acute respiratory syndrome coronavirus 2. Patients with diabetes have an increased risk of severe complications including Adult Respiratory Distress Syndrome and multi-organ failure. Depending on the global region, 20-50% of patients in the coronavirus disease 2019 (COVID-19) pandemic had diabetes. Given the importance of the link between COVID-19 and diabetes, we have formed an international panel of experts in the field of diabetes and endocrinology to provide some guidance and practical recommendations for the management of diabetes during the pandemic. We aim to briefly provide insight into potential mechanistic links between the novel coronavirus infection and diabetes, present practical management recommendations, and elaborate on the differential needs of several patient groups.
The coronavirus disease 2019 pandemic is wreaking havoc on society, especially health-care systems, including disrupting bariatric and metabolic surgery. The current limitations on accessibility to non -urgent care undermine postoperative monitoring of patients who have undergone such operations. Furthermore, like most elective surgery, new bariatric and metabolic procedures are being postponed worldwide during the pandemic. When the outbreak abates, a backlog of people seeking these operations will exist. Hence, surgical candidates face prolonged delays of beneficial treatment. Because of the progressive nature of obesity and diabetes, delaying surgery increases risks for morbidity and mortality, thus requiring strategies to mitigate harm. The risk of harm, however, varies among patients, depending on the type and severity of their comorbidities. A triaging strategy is therefore needed. The traditional weight -centric patient -selection criteria do not favour cases based on actual clinical needs. In this Personal View, experts from the Diabetes Surgery Summit consensus conference series provide guidance for the management of patients while surgery is delayed and for postoperative surveillance. We also offer a strategy to prioritise bariatric and metabolic surgery candidates on the basis of the diseases that are most likely to be ameliorated postoperatively. Although our system will be particularly germane in the immediate future, it also provides a framework for long-term clinically meaningful prioritisation.
Background Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11 beta-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease. Methods LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18-75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1.5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1-30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13-24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35-48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of =ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, openlabel period (ie, period 2, week 24) without up-titration during weeks 13-24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat ( full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete. Findings Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40.0 years (31.0-49.0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13.7 [95% CI 3.7-53.4]; p<0.0001). At week 24, 72 (53%; 95% CI 43.9-61.1) of 137 patients maintained a complete response without up-titration after week 12. Most common adverse events (ie, occurred in >25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase. Interpretation Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease.
Background Socioeconomic development is widely regarded as contributing to improved nutrition in children. We aimed to assess the association between socioeconomic indicators and child and adolescent nutritional status, and the differences in this association between urban and rural areas. Methods We extracted data from the 1995, 2000, 2005, 2010, and 2014 cycles of the Chinese National Survey on Students' Constitution and Health. We analysed these data for three nutritional outcomes-stunting, thinness, and overweight and obesity-in children and adolescents aged between 7 and 18 years, as defined by WHO standards and classifications. We included three socioeconomic indicators-gross domestic product (GDP) per capita, Engel coefficient (the proportion of household income spent on food), and urbanisation ratio-at both national and subnational levels for each survey year. We used logistic regression models to estimate the association between socioeconomic indicators and child nutritional status, and used prevalence odds ratios (ORs) to assess the urban-rural disparity for nutritional status over time. We also used generalised additive models to evaluate differences in associations between socioeconomic and nutritional status between urban and rural areas. Findings We included 1 054 602 participants ( 204 932 in 1995; 209 167 in 2000; 225 213 in 2005; 208 136 in 2010; 207 154 in 2014) with complete records on age, sex, nationality, height, and weight in the final analyses, and the final dataset contained 29 provinces ( Hong Kong, Macau, Taiwan, Chongqing, and Tibet were excluded) with complete socioeconomic indicator information and student nutritional status information. From 1995 to 2014, the mean stunting prevalence in Chinese children and adolescents decreased from 8.1% (95% CI 8.0-8.2) to 2.4% (2.4-2.5), and the mean thinness prevalence declined from 7.5% (7.4-7.6) to 4.1% (4.0-4.2). Overweight and obesity mean prevalence increased from 5.3% (5.2-5.4) to 20.5% (20.4-20.7). We observed an inverse association between socioeconomic indicators and mean stunting and thinness prevalence, and found a positive association between socioeconomic indicators and overweight and obesity prevalence. The urban-rural disparity in nutritional status gradually diminished, with the prevalence ORs approaching equivalence over time. More rapid improvement of socioeconomic indicators was associated with changed nutritional status in children and adolescents, but with differences across urban and rural settings. The association between socioeconomic status and overweight and obesity was stronger in rural than in urban areas. Improvements (reductions) in the Engel coefficient were accompanied by a greater reduction of stunting and thinness in rural than in urban areas. Interpretation Although socioeconomic development has been accompanied by continued improvements in stunting and thinness, a marked increase has occurred in overweight and obesity in Chinese children and adolescents, particularly in rural areas. There is a pressing need for policy actions to extend beyond an emphasis on economic growth alone, and to focus on promotion of healthy diets and physical activity. Copyright (C) 2019 Elsevier Ltd. All rights reserved.