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1.
Artigo em Inglês | MEDLINE | ID: mdl-33031736

RESUMO

BACKGROUND: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission. METHODS: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA1c <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. ß-cell function and biomarkers of tissue growth were also measured. FINDINGS: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm3 (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23). INTERPRETATION: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission. FUNDING: Diabetes UK.

2.
Diabetes Care ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023988

RESUMO

OBJECTIVE: To study the potential long-term benefits and possible complications of bariatric surgery in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In this register-based nationwide cohort study, we compared individuals with T1D and obesity who underwent Roux-en-Y gastric bypass (RYGB) surgery with patients with T1D and obesity matched for age, sex, BMI, and calendar time that did not undergo surgery. By linking the Swedish National Diabetes Register and Scandinavian Obesity Surgery Registry study individuals were included between 2007 and 2013. Outcomes examined included all-cause mortality, cardiovascular disease, stroke, heart failure, and hospitalization for serious hypo- or hyperglycemic events, amputation, psychiatric disorders, changes in kidney function, and substance abuse. RESULTS: We identified 387 individuals who had undergone RYGB and 387 control patients. Follow-up for hospitalization was up to 9 years. Analysis showed lower risk for cardiovascular disease (hazard ratio [HR] 0.43; 95% CI 0.20-0.9), cardiovascular death (HR 0.15; 95% CI 0.03-0.68), hospitalization for heart failure (HR 0.32; 95% CI 0.15-0.67) and stroke (HR 0.18; 95% CI 0.04-0.82) for the RYGB group. There was a higher risk for serious hyperglycemic events (HR 1.99; 95% CI 1.07-3.72) and substance abuse (HR 3.71; 95% CI 1.03-3.29) after surgery. CONCLUSIONS: This observational study suggests bariatric surgery may yield similar benefits on risk for cardiovascular outcomes and mortality in patients with T1D and obesity as for patients with type 2 diabetes. However, some potential serious adverse effects suggest need for careful monitoring of such patients after surgery.

3.
J Am Heart Assoc ; 9(20): e016564, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33030065

RESUMO

Background We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure. Methods and Results Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height2.7 (LVMI) was assessed by echocardiography at age 17. The metabolic profile was quantified via 1H-nuclear magnetic resonance spectroscopy at age 15. Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, prepregnancy BMI, prepregnancy height, household social class, adolescent birthweight, adolescent smoking, fruit and vegetable consumption, and physical activity)-adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually and jointly as principal components explaining 95% of the variance in the nuclear magnetic resonance platform and assessed whether the principal components for the metabolic traits added to the proportion of the association explained by putative cardiovascular risk factors (systolic and diastolic blood pressures, insulin, triglycerides, low-density lipoprotein cholesterol, and glucose). A 1 kg/m2 higher BMI was associated with a 0.70 g/m2.7 (95% CI, 0.53-0.88 g/m2.7) and 0.66 g/m2.7 (95% CI, 0.53-0.79 g/m2.7) higher LVMI in males (n=437) and females (n=536), respectively. Putative risk factors explained 3% (95% CI, 2%-5%) of this association in males, increasing to 10% (95% CI, 8%-13%) when including metabolic principal components. In females, the standard risk factors explained 3% (95% CI, 2%-5%) of the association and did not increase when including the metabolic principal components. Conclusions The addition of the nuclear magnetic resonance-measured metabolic traits appears to mediate more of the association of BMI on LVMI than the putative risk factors alone in adolescent males, but not females.

4.
Diabetes Obes Metab ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026143

RESUMO

AIM: The effect of the weekly exendin-based glucagon-like peptide-1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high-risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown. MATERIALS AND METHODS: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25-59.9 mL/min/1.73 m2 ], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium-glucose cotransporter-2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non-fatal myocardial infarction, non-fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m2 ). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non-inferiority of efpeglenatide versus placebo. RESULTS: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m2 , 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor. CONCLUSIONS: The results of the AMPLITUDE O trial will inform the use of exendin-based glucagon-like peptide-1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor.

5.
Comput Biol Med ; 126: 104043, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33065389

RESUMO

RECENT FINDINGS: Cardiovascular disease (CVD) is the leading cause of mortality and poses challenges for healthcare providers globally. Risk-based approaches for the management of CVD are becoming popular for recommending treatment plans for asymptomatic individuals. Several conventional predictive CVD risk models based do not provide an accurate CVD risk assessment for patients with different baseline risk profiles. Artificial intelligence (AI) algorithms have changed the landscape of CVD risk assessment and demonstrated a better performance when compared against conventional models, mainly due to its ability to handle the input nonlinear variations. Further, it has the flexibility to add risk factors derived from medical imaging modalities that image the morphology of the plaque. The integration of noninvasive carotid ultrasound image-based phenotypes with conventional risk factors in the AI framework has further provided stronger power for CVD risk prediction, so-called "integrated predictive CVD risk models. PURPOSE: of the review: The objective of this review is (i) to understand several aspects in the development of predictive CVD risk models, (ii) to explore current conventional predictive risk models and their successes and challenges, and (iii) to refine the search for predictive CVD risk models using noninvasive carotid ultrasound as an exemplar in the artificial intelligence-based framework. CONCLUSION: Conventional predictive CVD risk models are suboptimal and could be improved. This review examines the potential to include more noninvasive image-based phenotypes in the CVD risk assessment using powerful AI-based strategies.

6.
Diabetes Obes Metab ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33084149

RESUMO

AIMS: In EMPA-REG MET, in patients with type 2 diabetes mellitus (T2DM) on stable background metformin (≥1500 mg/day), empagliflozin versus placebo significantly improved glycated haemoglobin (HbA1c), body weight (BW), and systolic blood pressure (SBP) over 24 and ≤76 weeks. This analysis investigated empagliflozin treatment effects by baseline cardio-metabolic factors. MATERIALS AND METHODS: Patients aged ≥18 years with HbA1c ≥7.0 to ≤10.0% were included. Analysis of covariance compared change from baseline to weeks 24 and 76 in HbA1c, BW, and SBP by respective baseline categories (HbA1c <8.5/≥8.5%; BW <80/80-90/>90 kg, SBP <130/130-140/>140 mmHg). Analyses were also conducted with a model using continuous covariates of cardio-metabolic factors. RESULTS: In total, 637 patients (56.7% males; mean [SD] age 55.7 [9.9] years, HbA1c 7.9 [0.9] %, BW 81.2 [18.8] kg, SBP 129.4 [14.6] mmHg) received ≥1 dose of either empagliflozin 10 mg (n=217), or 25 mg (n=213), or placebo (n=207). At both time points, empagliflozin 10/25 mg versus placebo significantly (P<0.0001) reduced HbA1c and BW, with greater reductions in HbA1c at higher baseline HbA1c (P interaction week 24/76 categorical and continuous models: 0.0290/0.1431 and 0.0004/0.0042, respectively) and in BW (P interaction 0.1340/0.0012 and 0.0202/<0.0001, respectively). Both empagliflozin doses also significantly lowered SBP versus placebo at both time points, with similar efficacy by subgroups of baseline SBP. Adverse events were consistent with established empagliflozin safety profile across treatment groups. CONCLUSIONS: Empagliflozin, as add-on to metformin, decreases HbA1c and BW, particularly in patients with higher HbA1c and BW baseline values, and effectively lowers SBP. This article is protected by copyright. All rights reserved.

7.
Sci Rep ; 10(1): 17376, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060631

RESUMO

We examined changing patterns in cancer incidence and deaths in diabetes compared to the background population. A total of 457,473 patients with type 2 diabetes, included between 1998 and 2014, were matched on age, sex, and county to five controls from the population. Incidence, trends in incidence and post-cancer mortality for cancer were estimated with Cox regression and standardised incidence rates. Causes of death were estimated using logistic regression. Relative importance of risk factors was estimated using Heller's relative importance model. Type 2 diabetes had a higher risk for all cancer, HR 1.10 (95% CI 1.09-1.12), with highest HRs for liver (3.31), pancreas (2.19) and uterine cancer (1.78). There were lesser increases in risk for breast (1.05) and colorectal cancers (1.20). Type 2 diabetes patients experienced a higher HR 1.23 (1.21-1.25) of overall post-cancer mortality and mortality from prostate, breast, and colorectal cancers. By the year 2030 cancer could become the most common cause of death in type 2 diabetes. Persons with type 2 diabetes are at greater risk of developing cancer and lower chance of surviving it. Notably, hazards for specific cancers (e.g. liver, pancreas) in type 2 patients cannot be explained by obesity alone.

8.
Circ Genom Precis Med ; 13(5): 541-547, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33079603

RESUMO

BACKGROUND: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status. METHODS: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts. RESULTS: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. CONCLUSIONS: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.

9.
Pediatr Obes ; : e12725, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32914569

RESUMO

BACKGROUND: Maternal obesity is associated with offspring cardiometabolic risk. UPBEAT was a randomised controlled trial of an antenatal diet and physical activity intervention in 1555 women with obesity. The intervention was associated with lower gestational weight gain, healthier diet and metabolic profile in pregnancy, and reduced infant adiposity at six months. OBJECTIVE: We have investigated whether the UPBEAT intervention influenced childhood cardiometabolic outcomes or was associated with sustained improvements in maternal lifestyle 3-years after delivery. METHODS: In UPBEAT mother-child dyads at the 3-year follow-up, we assessed childhood blood pressure, resting pulse rate, and adiposity (body mass index, skinfold thicknesses, body fat, waist and arm circumferences) and maternal diet, physical activity, and anthropometry. RESULTS: 514 three-year-old children attended the appointment (49% intervention, 51% standard care). There was no difference in the main outcome of interest, subscapular skinfold thickness, between the trial arms (-0.30 mm, 95% confidence interval: -0.92, 0.31). However, the intervention was associated with a lower resting pulse rate (-5 bpm [-8.41, -1.07]). There was also a non-significant lower odds of overweight/obesity (OR 0.73; 0.50, 1.08). Maternal dietary improvements observed in the UPBEAT trial, including glycaemic load and saturated fat were maintained 3-years postpartum. CONCLUSION: This study has demonstrated that an antenatal dietary and physical activity intervention in women with obesity is associated with lower offspring pulse rate and sustained improvement in maternal diet. Whilst larger than previous cohorts, there remains potential for bias from attrition and these findings require validation in future cohorts.

10.
N Engl J Med ; 383(15): 1413-1424, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32865377

RESUMO

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/complicações , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico
11.
Circ Heart Fail ; 13(10): e007218, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32962410

RESUMO

Currently, South Asia accounts for a quarter of the world population, yet it already claims ≈60% of the global burden of heart disease. Besides the epidemics of type 2 diabetes mellitus and coronary heart disease already faced by South Asian countries, recent studies suggest that South Asians may also be at an increased risk of heart failure (HF), and that it presents at earlier ages than in most other racial/ethnic groups. Although a frequently underrecognized threat, an eventual HF epidemic in the densely populated South Asian nations could have dramatic health, social and economic consequences, and urgent interventions are needed to flatten the curve of HF in South Asia. In this review, we discuss recent studies portraying these trends, and describe the mechanisms that may explain an increased risk of premature HF in South Asians compared with other groups, with a special focus on highly relevant features in South Asian populations including premature coronary heart disease, early type 2 diabetes mellitus, ubiquitous abdominal obesity, exposure to the world's highest levels of air pollution, highly prevalent pretransition forms of HF such as rheumatic heart disease, and underdevelopment of healthcare systems. Other rising lifestyle-related risk factors such as use of tobacco products, hypertension, and general obesity are also discussed. We evaluate the prognosis of HF in South Asian countries and the implications of an anticipated HF epidemic. Finally, we discuss proposed interventions aimed at curbing these adverse trends, management approaches that can improve the prognosis of prevalent HF in South Asian countries, and research gaps in this important field.

12.
Atherosclerosis ; 312: 35-42, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971394

RESUMO

BACKGROUND AND AIMS: Mechanisms underlying the association between cardiovascular disease (CVD) and depression are unknown, and sex differences understudied. We investigated associations between a comprehensive set of measures of macro and microvascular disease and depressive symptoms in older men and women. METHODS: We performed cross-sectional analyses of the SABRE (Southall And Brent REvisited) population-based study. Participants (1396) attended clinic between 2008 and 2011 for assessment of subclinical macrovascular (carotid ultrasound, echocardiography, cerebral magnetic resonance imaging) and microvascular (retinopathy, nephropathy) disease, and depression. RESULTS: Mean age of 1396 participants was 69.5 years, and 76.2% were male. The median (interquartile range) of depression score was 1 [0, 2] for men and 1 [0, 3] for women. All measures of subclinical macro and microvascular disease were adversely associated with depressive symptoms, even when known CVD was excluded. Physical activity partly explained some of these relationships. The association between left atrial dimension index (LADI), a measure of chronic elevated left ventricular filling pressure, and depressive symptoms was stronger in women (regression coefficient 0.23 [95% CI 0.11, 0.35]) than men (0.07 [-0.01, 0.15]), p for interaction 0.06, on multivariable adjustment. CONCLUSIONS: Subclinical macro and microvascular disease is associated with depressive symptoms, even in the absence of established CVD. These were in part accounted for by physical activity. We observed stronger association between LADI and depressive symptoms in women than in men. The beneficial role of physical activity in abrogating the association between subclinical CVD and depression warrants further investigation.

13.
Am Heart J ; 229: 70-80, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32942043

RESUMO

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

14.
BMC Womens Health ; 20(1): 177, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795281

RESUMO

BACKGROUND: There may be changes in cognitive function in women going through the menopause. The current evidence remains unclear, however, whether these changes occur over and above those of general ageing. We aimed to evaluate the potential impact of the menopause (assessed by reproductive age and hormone levels) on cognitive function in women in mid-life accounting for the underlying effects of ageing. METHODS: The study was based on the follow up of women originally enrolled in pregnancy in a birth cohort when resident in the South West of England, UK between 1991 and 1992. Using up to three repeated measurements in 2411 women (mean age 51 at first assessment), we modelled changes in six cognitive function domains: immediate and delayed verbal episodic memory, working memory, processing speed, verbal intelligence and verbal fluency. The exposures of interest were reproductive age measured as years relative to the final menstrual period (FMP), chronological age and reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Müllerian hormone (AMH)). RESULTS: Processing speed (- 0.21 (95% CI - 0.36 to - 0.06) standard deviation (SD) difference per 10 years since FMP), immediate verbal episodic memory (- 0.15 (95% CI - 0.35 to 0.06)) and delayed verbal episodic memory (- 0.17 (95% CI - 0.37 to 0.03)) declined with reproductive age. Reproductive hormones were not robustly associated with processing speed, but FSH and LH were both negatively associated with immediate (- 0.08 (95% CI - 0.13 to - 0.02) SD difference per SD difference in hormone level) and delayed verbal episodic memory (- 0.08 (95% CI - 0.13 to - 0.03)). There was little consistent evidence of cognitive function declining with menopause in other cognitive domains. CONCLUSIONS: Of the cognitive domains tested only verbal episodic memory declined both in relation to age since the menopause and in conjunction with the reproductive hormones that reflect the menopause. This decline was independent of normal ageing and suggests that the menopause is associated with a mild impact on this specific domain of cognitive function.

15.
Lancet Diabetes Endocrinol ; 8(10): 823-833, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32798471

RESUMO

BACKGROUND: Diabetes has been associated with increased COVID-19-related mortality, but the association between modifiable risk factors, including hyperglycaemia and obesity, and COVID-19-related mortality among people with diabetes is unclear. We assessed associations between risk factors and COVID-19-related mortality in people with type 1 and type 2 diabetes. METHODS: We did a population-based cohort study of people with diagnosed diabetes who were registered with a general practice in England. National population data on people with type 1 and type 2 diabetes collated by the National Diabetes Audit were linked to mortality records collated by the Office for National Statistics from Jan 2, 2017, to May 11, 2020. We identified the weekly number of deaths in people with type 1 and type 2 diabetes during the first 19 weeks of 2020 and calculated the percentage change from the mean number of deaths for the corresponding weeks in 2017, 2018, and 2019. The associations between risk factors (including sex, age, ethnicity, socioeconomic deprivation, HbA1c, renal impairment [from estimated glomerular filtration rate (eGFR)], BMI, tobacco smoking status, and cardiovascular comorbidities) and COVID-19-related mortality (defined as International Classification of Diseases, version 10, code U07.1 or U07.2 as a primary or secondary cause of death) between Feb 16 and May 11, 2020, were investigated by use of Cox proportional hazards models. FINDINGS: Weekly death registrations in the first 19 weeks of 2020 exceeded the corresponding 3-year weekly averages for 2017-19 by 672 (50·9%) in people with type 1 diabetes and 16 071 (64·3%) in people with type 2 diabetes. Between Feb 16 and May 11, 2020, among 264 390 people with type 1 diabetes and 2 874 020 people with type 2 diabetes, 1604 people with type 1 diabetes and 36 291 people with type 2 diabetes died from all causes. Of these total deaths, 464 in people with type 1 diabetes and 10 525 in people with type 2 diabetes were defined as COVID-19 related, of which 289 (62·3%) and 5833 (55·4%), respectively, occurred in people with a history of cardiovascular disease or with renal impairment (eGFR <60 mL/min per 1·73 m2). Male sex, older age, renal impairment, non-white ethnicity, socioeconomic deprivation, and previous stroke and heart failure were associated with increased COVID-19-related mortality in both type 1 and type 2 diabetes. Compared with people with an HbA1c of 48-53 mmol/mol (6·5-7·0%), people with an HbA1c of 86 mmol/mol (10·0%) or higher had increased COVID-19-related mortality (hazard ratio [HR] 2·23 [95% CI 1·50-3·30, p<0·0001] in type 1 diabetes and 1·61 [1·47-1·77, p<0·0001] in type 2 diabetes). In addition, in people with type 2 diabetes, COVID-19-related mortality was significantly higher in those with an HbA1c of 59 mmol/mol (7·6%) or higher than in those with an HbA1c of 48-53 mmol/mol (HR 1·22 [95% CI 1·15-1·30, p<0·0001] for 59-74 mmol/mol [7·6-8·9%] and 1·36 [1·24-1·50, p<0·0001] for 75-85 mmol/mol [9·0-9·9%]). The association between BMI and COVID-19-related mortality was U-shaped: in type 1 diabetes, compared with a BMI of 25·0-29·9 kg/m2, a BMI of less than 20·0 kg/m2 had an HR of 2·45 (95% CI 1·60-3·75, p<0·0001) and a BMI of 40·0 kg/m2 or higher had an HR of 2·33 (1·53-3·56, p<0·0001); the corresponding HRs for type 2 diabetes were 2·33 (2·11-2·56, p<0·0001) and 1·60 (1·47-1·75, p<0·0001). INTERPRETATION: Deaths in people with type 1 and type 2 diabetes rose sharply during the initial COVID-19 pandemic in England. Increased COVID-19-related mortality was associated not only with cardiovascular and renal complications of diabetes but, independently, also with glycaemic control and BMI. FUNDING: None.


Assuntos
Betacoronavirus , Infecções por Coronavirus/mortalidade , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Pneumonia Viral/mortalidade , Vigilância da População , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Infecções por Coronavirus/diagnóstico , Bases de Dados Factuais/tendências , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Programas Nacionais de Saúde/tendências , Pandemias , Pneumonia Viral/diagnóstico , Vigilância da População/métodos , Fatores de Risco , Adulto Jovem
16.
Lancet Diabetes Endocrinol ; 8(10): 813-822, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32798472

RESUMO

BACKGROUND: Although diabetes has been associated with COVID-19-related mortality, the absolute and relative risks for type 1 and type 2 diabetes are unknown. We assessed the independent effects of diabetes status, by type, on in-hospital death in England in patients with COVID-19 during the period from March 1 to May 11, 2020. METHODS: We did a whole-population study assessing risks of in-hospital death with COVID-19 between March 1 and May 11, 2020. We included all individuals registered with a general practice in England who were alive on Feb 16, 2020. We used multivariable logistic regression to examine the effect of diabetes status, by type, on in-hospital death with COVID-19, adjusting for demographic factors and cardiovascular comorbidities. Because of the absence of data on total numbers of people infected with COVID-19 during the observation period, we calculated mortality rates for the population as a whole, rather than the population who were infected. FINDINGS: Of the 61 414 470 individuals who were alive and registered with a general practice on Feb 16, 2020, 263 830 (0·4%) had a recorded diagnosis of type 1 diabetes, 2 864 670 (4·7%) had a diagnosis of type 2 diabetes, 41 750 (0·1%) had other types of diabetes, and 58 244 220 (94·8%) had no diabetes. 23 698 in-hospital COVID-19-related deaths occurred during the study period. A third occurred in people with diabetes: 7434 (31·4%) in people with type 2 diabetes, 364 (1·5%) in those with type 1 diabetes, and 69 (0·3%) in people with other types of diabetes. Unadjusted mortality rates per 100 000 people over the 72-day period were 27 (95% CI 27-28) for those without diabetes, 138 (124-153) for those with type 1 diabetes, and 260 (254-265) for those with type 2 diabetes. Adjusted for age, sex, deprivation, ethnicity, and geographical region, compared with people without diabetes, the odds ratios (ORs) for in-hospital COVID-19-related death were 3·51 (95% CI 3·16-3·90) in people with type 1 diabetes and 2·03 (1·97-2·09) in people with type 2 diabetes. These effects were attenuated to ORs of 2·86 (2·58-3·18) for type 1 diabetes and 1·80 (1·75-1·86) for type 2 diabetes when also adjusted for previous hospital admissions with coronary heart disease, cerebrovascular disease, or heart failure. INTERPRETATION: The results of this nationwide analysis in England show that type 1 and type 2 diabetes were both independently associated with a significant increased odds of in-hospital death with COVID-19. FUNDING: None.


Assuntos
Betacoronavirus , Infecções por Coronavirus/mortalidade , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Mortalidade Hospitalar/tendências , Pneumonia Viral/mortalidade , Vigilância da População , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Comorbidade , Infecções por Coronavirus/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Inglaterra/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Pandemias , Pneumonia Viral/diagnóstico , Vigilância da População/métodos , Adulto Jovem
17.
PLoS One ; 15(8): e0238091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817712

RESUMO

BACKGROUND: It is now well recognised that the risk of severe COVID-19 increases with some long-term conditions (LTCs). However, prior research primarily focuses on individual LTCs and there is a lack of data on the influence of multimorbidity (≥2 LTCs) on the risk of COVID-19. Given the high prevalence of multimorbidity, more detailed understanding of the associations with multimorbidity and COVID-19 would improve risk stratification and help protect those most vulnerable to severe COVID-19. Here we examine the relationships between multimorbidity, polypharmacy (a proxy of multimorbidity), and COVID-19; and how these differ by sociodemographic, lifestyle, and physiological prognostic factors. METHODS AND FINDINGS: We studied data from UK Biobank (428,199 participants; aged 37-73; recruited 2006-2010) on self-reported LTCs, medications, sociodemographic, lifestyle, and physiological measures which were linked to COVID-19 test data. Poisson regression models examined risk of COVID-19 by multimorbidity/polypharmacy and effect modification by COVID-19 prognostic factors (age/sex/ethnicity/socioeconomic status/smoking/physical activity/BMI/systolic blood pressure/renal function). 4,498 (1.05%) participants were tested; 1,324 (0.31%) tested positive for COVID-19. Compared with no LTCs, relative risk (RR) of COVID-19 in those with 1 LTC was no higher (RR 1.12 (CI 0.96-1.30)), whereas those with ≥2 LTCs had 48% higher risk; RR 1.48 (1.28-1.71). Compared with no cardiometabolic LTCs, having 1 and ≥2 cardiometabolic LTCs had a higher risk of COVID-19; RR 1.28 (1.12-1.46) and 1.77 (1.46-2.15), respectively. Polypharmacy was associated with a dose response higher risk of COVID-19. All prognostic factors were associated with a higher risk of COVID-19 infection in multimorbidity; being non-white, most socioeconomically deprived, BMI ≥40 kg/m2, and reduced renal function were associated with the highest risk of COVID-19 infection: RR 2.81 (2.09-3.78); 2.79 (2.00-3.90); 2.66 (1.88-3.76); 2.13 (1.46-3.12), respectively. No multiplicative interaction between multimorbidity and prognostic factors was identified. Important limitations include the low proportion of UK Biobank participants with COVID-19 test data (1.05%) and UK Biobank participants being more affluent, healthier and less ethnically diverse than the general population. CONCLUSIONS: Increasing multimorbidity, especially cardiometabolic multimorbidity, and polypharmacy are associated with a higher risk of developing COVID-19. Those with multimorbidity and additional factors, such as non-white ethnicity, are at heightened risk of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Multimorbidade , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Polimedicação , Adulto , Idoso , Idoso de 80 Anos ou mais , Bancos de Espécimes Biológicos , Infecções por Coronavirus/etnologia , Infecções por Coronavirus/virologia , Grupos Étnicos , Feminino , Nível de Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/etnologia , Pneumonia Viral/virologia , Prevalência , Prognóstico , Estudos Prospectivos , Fatores de Risco , Autorrelato , Reino Unido/epidemiologia
18.
Eur J Nutr ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32851419

RESUMO

PURPOSE: Low blood 25-hydroxyvitamin D (25(OH)D) concentration has been proposed as a potential causal factor in COVID-19 risk. We aimed to establish whether baseline serum 25(OH)D concentration was associated with COVID-19 mortality, and inpatient confirmed COVID-19 infection, in UK Biobank participants. METHODS: UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including serum 25(OH)D concentration, were linked to COVID-19 mortality. Univariable and multivariable Cox proportional hazards regression analyses were performed for the association between 25(OH)D and COVID-19 death, and Poisson regression analyses for the association between 25(OH)D and severe COVID-19 infection. RESULTS: Complete data were available for 341,484 UK Biobank participants, of which 656 had inpatient confirmed COVID-19 infection and 203 died of COVID-19 infection. 25(OH)D concentration was associated with severe COVID-19 infection and mortality univariably (mortality per 10 nmol/L 25(OH)D HR 0.92; 95% CI 0.86-0.98; p = 0.016), but not after adjustment for confounders (mortality per 10 nmol/L 25(OH)D HR 0.98; 95% CI = 0.91-1.06; p = 0.696). Vitamin D insufficiency or deficiency was also not independently associated with either COVID-19 infection or linked mortality. CONCLUSIONS: Our findings do not support a potential link between 25(OH)D concentrations and risk of severe COVID-19 infection and mortality. Randomised trials are needed to prove a beneficial role for vitamin D in the prevention of severe COVID-19 reactions or death.

19.
J Am Heart Assoc ; 9(16): e016334, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32779505

RESUMO

Background Epeleuton is 15-hydroxy eicosapentaenoic acid ethyl ester, a second-generation synthetic n-3 fatty acid derivative of eicosapentaenoic acid. The primary objective was to assess the effect of epeleuton on markers of nonalcoholic fatty liver disease (NAFLD) with post hoc analyses of cardiometabolic markers. Methods and Results In a multicenter, randomized, double-blind, placebo-controlled trial, 96 adults with nonalcoholic fatty liver disease and body mass index 25 to 40 were randomized in a 1:1:1 ratio to receive epeleuton 2 g/day, epeleuton 1 g/day, or placebo for 16 weeks. A total of 27% of patients had diabetes mellitus. Primary end points of changes in alanine aminotransferase and liver stiffness did not improve at week 16. Secondary and post hoc analyses investigated changes in cardiometabolic markers. Epeleuton 2 g/day significantly decreased triglycerides, very-low-density lipoprotein cholesterol, and total cholesterol without increasing low-density lipoprotein cholesterol. Despite a low mean baseline hemoglobin A1C (HbA1C; 6.3±1.3%), epeleuton 2 g/day significantly decreased HbA1c (-0.4%; P=0.026). Among patients with baseline HbA1c >6.5%, epeleuton 2 g/day decreased HbA1c by 1.1% (P=0.047; n=26). Consistent dose-dependent reductions were observed for fasting plasma glucose, insulin, and insulin resistance indices. Epeleuton 2 g/day decreased circulating markers of cardiovascular risk and endothelial dysfunction. Epeleuton was well tolerated, with a safety profile not different from placebo. Conclusions While epeleuton did not meet its primary end points on alanine aminotransferase or liver stiffness, it significantly decreased triglycerides, HbA1C, plasma glucose, and inflammatory markers. These data suggest epeleuton may have potential for cardiovascular risk reduction and nonalcoholic fatty liver disease by simultaneously targeting hypertriglyceridemia, hyperglycemia, and systemic inflammation. Further trials are planned. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02941549.

20.
Diabetes Care ; 43(10): 2493-2499, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32801130

RESUMO

OBJECTIVE: To evaluate the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data. RESEARCH DESIGN AND METHODS: Anemia was defined as a hemoglobin measure of <11 g/dL. In the RCTs A Diabetes Outcome Progression Trial (ADOPT; n = 3,967) and UK Prospective Diabetes Study (UKPDS; n = 1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters. In the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n = 3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk. RESULTS: In ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones. In UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin. In ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years. In UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments. At years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group. In GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia. CONCLUSIONS: Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone.

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