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The parameters derived from reservoir-excess pressure analysis have prognostic utility in several populations. However, evidence in type 2 diabetes (T2DM) remains scarce. We determined if these parameters were associated with T2DM and whether they would predict cardiovascular events in individuals with T2DM. We studied 306 people with T2DM with cardiovascular disease (CVD; DMCVD, 70.4±7.8 years), 348 people with T2DM but without CVD (diabetes mellitus, 67.7±8.4 years), and 178 people without T2DM or CVD (control group [CTRL], 67.2±8.9 years). Reservoir-excess pressure analysis–derived parameters, including reservoir pressure integral, peak reservoir pressure, excess pressure integral, systolic rate constant, and diastolic rate constant, were obtained by radial artery tonometry. Reservoir pressure integral was lower in DMCVD and diabetes mellitus than CTRL. Peak reservoir pressure was lower, and excess pressure integral was greater in DMCVD than diabetes mellitus and CTRL. Systolic rate constant was lower in a stepwise manner among groups (DMCVD< diabetes mellitus P

Aims/hypothesis Stillbirth risk is increased in pregnancy complicated by diabetes. Fear of stillbirth has major influence on obstetric management, particularly timing of delivery. We analysed population-level data from Scotland to describe timing of stillbirths in women with diabetes and associated risk factors. Methods A retrospective cohort of singleton deliveries to mothers with type 1 (n = 3778) and type 2 diabetes (n = 1614) from 1 April 1998 to 30 June 2016 was analysed using linked routine care datasets. Maternal and fetal characteristics, HbA1c data and delivery timing were compared between stillborn and liveborn groups. Results Stillbirth rates were 16.1 (95% CI 12.4, 20.8) and 22.9 (95% CI 16.4, 31.8) per 1000 births in women with type 1 (n = 61) and type 2 diabetes (n = 37), respectively. In women with type 1 diabetes, higher HbA1c before pregnancy (OR 1.03 [95% CI 1.01, 1.04]; p = 0.0003) and in later pregnancy (OR 1.06 [95% CI 1.04, 1.08]; p 95th centile born to women with type 2 diabetes (n = 15 stillbirths, 402 livebirths). A high proportion of stillborn infants were male among mothers with type 2 diabetes (81.1% vs 50.5% livebirths, p = 0.0002). A third of stillbirths occurred at term, with highest rates in the 38th week (7.0 [95% CI 3.7, 12.9] per 1000 ongoing pregnancies) among mothers with type 1 diabetes and in the 39th week (9.3 [95% CI 2.4, 29.2]) for type 2 diabetes. Conclusions/interpretation Maternal blood glucose levels and BMI are important modifiable risk factors for stillbirth in diabetes. Babies at extremes of weight centiles are at most risk. Many stillbirths occur at term and could potentially be prevented by change in routine care and delivery policies. Electronic supplementary material The online version of this article (10.1007/s00125-019-4943-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Aims/hypothesis The aim of this work was to examine whether glycaemic control has improved in those with type 1 diabetes in Scotland between 2004 and 2016, and whether any trends differed by sociodemographic factors. Methods We analysed records from 30,717 people with type 1 diabetes, registered anytime between 2004 and 2016 in the national diabetes database, which contained repeated measures of HbA1c. An additive mixed regression model was used to estimate calendar time and other effects on HbA1c. Results Overall, median (IQR) HbA1c decreased from 72 (21) mmol/mol [8.7 (4.1)%] in 2004 to 68 (21) mmol/mol (8.4 [4.1]%) in 2016. However, all of the improvement across the period occurred in the latter 4 years: the regression model showed that the only period of significant change in HbA1c was 2012–2016 where there was a fall of 3 (95% CI 1.82, 3.43) mmol/mol. The largest reductions in HbA1c in this period were seen in children, from 69 (16) mmol/mol (8.5 [3.6]%) to 63 (14) mmol/mol (7.9 [3.4]%), and adolescents, from 75 (25) mmol/mol (9.0 [4.4]%) to 70 (23) mmol/mol (8.6 [4.3]%). Socioeconomic status (according to Scottish Index of Multiple Deprivation) affected the HbA1c values: from the regression model, the 20% of people living in the most-deprived areas had HbA1c levels on average 8.0 (95% CI 7.4, 8.9) mmol/mol higher than those of the 20% of people living in the least-deprived areas. However this difference did not change significantly over time. From the regression model HbA1c was on average 1.7 (95% CI 1.6, 1.8) mmol/mol higher in women than in men. This sex difference did not narrow over time. Conclusions/interpretation In this high-income country, we identified a modest but important improvement in HbA1c since 2012 that was most marked in children and adolescents. These changes coincided with national initiatives to reduce HbA1c including an expansion of pump therapy. However, in most people, overall glycaemic control remains far from target levels and further improvement is badly needed, particularly in those from more-deprived areas. Electronic supplementary material The online version of this article (10.1007/s00125-019-4900-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

We would like to thank Ostergaard et al. (1) for their perspective on our article (2), which includes a suggestion for using lifetime prediction models to estimate disease-free life expectancy. The lifetime prediction models previously published are primarily based on Cox proportional hazards models including age as timescale (3). We have used Poisson models that facilitate the inclusion of multiple timescales such as age and diabetes duration. Both modeling approaches estimate a hazard function for the event of interest as well as for the competing event of death, and with both approaches these hazard functions can be used to estimate lifetime risk and disease-free life expectancy. As pointed out by Ostergaard et al., risk prediction should ideally cover a long time horizon, and in that sense estimating lifetime risk may seem attractive. Models predicting diseases …

AIMS: To examine candidate insulin resistance single nucleotide polymorphisms (SNPs) for associations with glycemic control, insulin resistance, BMI, and complications in an observational type 1 diabetes (T1D) cohort: the Pittsburgh Epidemiology of Diabetes Complications (EDC) study.METHODS: In 422 European-ancestry participants, we assessed associations using additive models between 15 candidate SNPs and 25-year mortality, cardiovascular disease, microalbuminuria, overt nephropathy and proliferative retinopathy, and 25-year mean HbA1c, estimated glucose disposal rate (eGDR, inverse measure of insulin resistance), and BMI.RESULTS: The A allele of rs12970134 was associated with higher mean HbA1c (β = +0.34 ± 0.09, p = 0.00009) and nominally associated with worse eGDR (p = 0.02). Further analyses suggest the HbA1c association may be modified by diabetes therapy regimen: rs12970134 AA genotype was associated with higher HbA1c under non-intensive therapy conditions (CONCLUSIONS: rs12970134, near MC4R, is strongly associated with HbA1c in this cohort. Further exploration of this genomic region is warranted, as it may hold promise for discovering new therapeutic targets to improve glycemic control in T1D.

Introduction Glucagon-like peptide 1 receptor agonists (GLP1RAs) are licensed for the treatment of type 2 diabetes (T2D). They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in terms of glycaemia, and in some cases, reducing CV events) in extensive randomised controlled trials (RCTs). However, there remain concerns regarding the generalisability of these findings (to those ineligible for RCT participation) and about non-CV safety. For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of RCTs findings to broader populations and explore safety, for which RCTs are not usually powered, in more detail. Method We did a pre-planned and registered (PROSPERO registration CRD42020165720) systematic review of population-based studies investigating GLP1RA effectiveness and safety, following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Results A total of 22 studies were identified (including 200,148 participants and 396,457 person-years of follow-up) exploring exposure to GLP1RA class, exenatide and liraglutide (the only individual drugs with treatment effect estimates identified) on mortality, cardiovascular disease (CVD), acute pancreatitis (AP), pancreatic cancer (PC), thyroid cancer (TC), acute renal failure (ARF), diabetic retinopathy (DR), breast cancer (BC) and hypoglycaemia. For CV and mortality outcomes, studies confirmed the associated safety of these drugs. For liraglutide, point estimate (PE) range (PER) major adverse cardiovascular events (MACE) (0.53–0.95) and PER heart failure (0.34–1.22) were similar in direction to the beneficial effect observed in RCTs for MACE but varied widely for heart failure. For safety outcomes, exposure was not associated with AP (PER 0.50–1.17), PC (PER 0.40–1.54), BC (PER 0.90–1.51) or hypoglycaemia (PER 0.59–1.06). Only one study was identified exploring each of TC (no evidence of association, hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.98–2.19), renal outcomes (no evidence of association, HR 0.77, 95% CI 0.42–1.41) and DR (no evidence of association, HR 0.67, 95% CI 0.51–0.90). Conclusion In T2D, GLP1RAs appear safe from the CV perspective and (for liraglutide) may have associated benefit in primary as well as secondary CVD prevention. For non-CV safety, GLP1RA exposure was not associated with an increased risk of AP, PC, BC or hypoglycaemia; the other outcomes had too few studies to draw firm conclusions and should be explored further. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01021-1.

BackgroundThe effect of vaccination for COVID-19 on onward transmission is unknown.MethodsA national record linkage study determined documented COVID-19 cases and hospitalisations in unvaccinated household members of vaccinated and unvaccinated healthcare workers from 8th December 2020 to 3rd March 2021. The primary endpoint was COVID-19 14 days following the first dose.ResultsThe cohort comprised of 194,362 household members (mean age 31·1 ± 20·9 years) and 144,525 healthcare workers (mean age 44·4 ± 11·4 years). 113,253 (78·3%) of healthcare workers received at least one dose of the BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine and 36,227 (25·1%) received a second dose. There were 3,123 and 4,343 documented COVID-19 cases and 175 and 177 COVID-19 hospitalisations in household members of healthcare workers and healthcare workers respectively. Household members of vaccinated healthcare workers had a lower risk of COVID-19 case compared to household members of unvaccinated healthcare worker (rate per 100 person-years 9·40 versus 5·93; HR 0·70, 95% confidence interval [CI] 0·63 to 0·78). The effect size for COVID-19 hospitalisation was similar, with the confidence interval crossing the null (HR 0·77 [95% CI 0·53 to 1·10]). The rate per 100 person years was lower in vaccinated compared to unvaccinated healthcare workers for documented (20·13 versus 8·51; HR 0·45 [95% CI 0·42 to 0·49]) and hospitalized COVID-19 (0·97 versus 0·14; HR 0·16 [95% CI 0·09 to 0·27]). Compared to the period before the first dose, the risk of documented COVID-19 case was lower at ≥ 14 days after the second dose for household members (HR 0·46 [95% CI 0·30to 0·70]) and healthcare workers (HR 0·08 [95% CI 0·04 to 0·17]).InterpretationVaccination of health care workers was associated with a substantial reduction in COVID-19 cases in household contacts consistent with an effect of vaccination on transmission.

Digital, Background Diabetes is a major risk factor for erectile dysfunction, however, the effect of GLP-1 receptor agonists on erectile dysfunction is unknown. We aimed to assess the incidence, prevalence, and progression of erectile dysfunction in men treated with dulaglutide compared with placebo, and to determine whether dulaglutide's effect on erectile dysfunction was consistent with its effect on other diabetes-related outcomes. Methods The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was a double-blind, placebo-controlled randomised trial of the effect of dulaglutide on cardiovascular outcomes. REWIND was done at 371 sites in 24 countries. Men and women aged older than 50 years with type 2 diabetes, who had either a previous cardiovascular event or cardiovascular risk factors, were randomly assigned (1:1) to receive either dulaglutide or placebo. Participating men were offered the opportunity to complete the standardised International Index of Erectile Function (IIEF) questionnaire at baseline, 2 years, 5 years, and study end. We did an exploratory analysis, in which we included participants who completed a baseline and at least 1 follow-up IIEF questionnaire. The primary outcome for these analyses was the first occurrence of moderate or severe erectile dysfunction following randomisation, assessed by the erectile function subscores on IIEF. This analysis was part of the REWIND trial, which is registered with ClinicalTrials.gov, NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 3725 (70·1%) of 5312 male participants with a mean age of 65·5 years (SD 6·4 years) were analysed, of whom 1487 (39·9%) had a history of cardiovascular disease, and 2104 (56·5%) had moderate or severe erectile dysfunction at baseline. The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85–0·99, p=0·021). Men in the dulaglutide group also had a lesser fall in erectile function subscore compared with the placebo group, with a least square mean difference of 0·61 (95% CI 0·18–1·05, p=0·006). Interpretation Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes., Ciencias Médicas y de la Salud

SHu reports grants from Health Protection Scotland during the conduct of the study. TMC reports grants from Diabetes UK (18/0005786). CR reports grants from Public Health Scotland and UK Research and Innovation. Background We aimed to ascertain the cumulative risk of fatal or critical care unit-treated COVID-19 in people with diabetes and compare it with that of people without diabetes, and to investigate risk factors for and build a cross-validated predictive model of fatal or critical care unit-treated COVID-19 among people with diabetes. Methods In this cohort study, we captured the data encompassing the first wave of the pandemic in Scotland, from March 1, 2020, when the first case was identified, to July 31, 2020, when infection rates had dropped sufficiently that shielding measures were officially terminated. The participants were the total population of Scotland, including all people with diabetes who were alive 3 weeks before the start of the pandemic in Scotland (estimated Feb 7, 2020). We ascertained how many people developed fatal or critical care unit-treated COVID-19 in this period from the Electronic Communication of Surveillance in Scotland database (on virology), the RAPID database of daily hospitalisations, the Scottish Morbidity Records-01 of hospital discharges, the National Records of Scotland death registrations data, and the Scottish Intensive Care Society and Audit Group database (on critical care). Among people with fatal or critical care unit-treated COVID-19, diabetes status was ascertained by linkage to the national diabetes register, Scottish Care Information Diabetes. We compared the cumulative incidence of fatal or critical care unit-treated COVID-19 in people with and without diabetes using logistic regression. For people with diabetes, we obtained data on potential risk factors for fatal or critical care unit-treated COVID-19 from the national diabetes register and other linked health administrative databases. We tested the association of these factors with fatal or critical care unit-treated COVID-19 in people with diabetes, and constructed a prediction model using stepwise regression and 20-fold cross-validation. Findings Of the total Scottish population on March 1, 2020 (n=5 463 300), the population with diabetes was 319 349 (5·8%), 1082 (0·3%) of whom developed fatal or critical care unit-treated COVID-19 by July 31, 2020, of whom 972 (89·8%) were aged 60 years or older. In the population without diabetes, 4081 (0·1%) of 5 143 951 people developed fatal or critical care unit-treated COVID-19. As of July 31, the overall odds ratio (OR) for diabetes, adjusted for age and sex, was 1·395 (95% CI 1·304–1·494; p

Objectives To investigate:(1) the risk of severe COVID-19 in those eligible for shielding, and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population. Design Matched case-control study (REACT-SCOT). Setting Population of Scotland from 1 March 2020 to 28 January 2021. Participants All 160307 diagnosed cases of COVID-19 and 1564782 controls matched for age, sex and primary care practice, linked with all 204913 individuals identified as eligible for shielding by Public Health Scotland. Main outcome measure Severe COVID-19, defined as cases that entered critical care or were fatal. Results With those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 5.3 (95% CI 5.0 to 5.7, p=4 × 10−527) in those with moderate risk conditions and 7.6 (95% CI 7.1 to 8.3, p=1 × 10−527) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.6 (95% CI 9.6 to 19.2, p=8 × 10−50). In both the shielded and the general population, the risk of severe COVID-19 increased with the number of adults but decreased with the number of school-age children in the household. Severe COVID-19 was strongly associated with recent exposure to hospital (defined as 5 to 14 days before presentation date): rate ratio 12.6 (95% CI 11.7 to 13.6, p=2 × 10−989) overall. In a case-crossover analysis with less recent exposure only (15 to 24 days before first testing positive) as reference category, the rate ratio associated with recent exposure only was 6.3 (95% CI 3.6 to 11.1, p=2 × 10−10). Among those eligible for shielding, the population attributable risk fraction (PARF) of severe cases for recent exposure to hospital was 36%. In the general population the PARF for recent exposure to hospital peaked at 46% in May 2020 and again at 64% in December 2020. Conclusions The effectiveness of shielding vulnerable individuals was limited by the inability to control transmission in hospital and from other adults in the household. For solid organ transplant recipients, in whom the efficacy of vaccines is uncertain, these results support a policy of offering vaccination to household contacts. Mitigating the impact of the epidemic requires control of nosocomial transmission. Summary What is already known on this topic? Individuals designated as “clinically extremely vulnerable” – about 3% of the population – have been advised to shield themselves during the COVID-19 epidemic The effectiveness of this shielding programme has not been evaluated. What this study adds Hospital-acquired infection has made a substantial contribution to the burden of COVID-19 in the population, accounting for more than half of severe cases in early December 2020. For vulnerable individuals to be shielded, the risk of hospital-acquired infection must be reduced and support must be provided for other adults in the household to co-isolate with the vulnerable individual. Solid organ transplant recipients are at the highest risk; vaccination of household contacts should be considered for this group.

Supplemental Digital Content is available in the text., Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (Passociation ≤5×10−8) associations with PAD in 449 548 (Ncases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], Pdiabetes=2.5×10−9, Pinteractionwithdiabetes=5.3×10−7). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], Psmokers=9.3×10−10, Pinteractionwithsmoking=3.9×10−5). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.

AimTo determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status.MethodsRegression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial.ResultsIn 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (−0.012 mm, 95% CI −0.021 to −0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI −0.008 to 0.014; p = .5767); and similarly in non-current smokers (−0.008 mm, 95% CI −0.015 to −0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI −0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (−0.020 mm, 95% CI −0.034 to −0.006; p = .0067) but not in ever-smokers (−0.006 mm, 95% CI −0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term.ConclusionsThis subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.

Doi, Yasuji/0000-0002-8368-0827; galvani, marcello/0000-0001-5897-667X; Gislason, Gunnar H/0000-0002-0548-402X; Taskinen, Marja-Riitta/0000-0002-6229-3588; Sherwood, Matthew/0000-0002-4305-5883; Malynovsky, Yaroslav V/0000-0002-9118-1104; Viktorova, vic-inna@mail.ru I.A./0000-0001-8728-2722; bastos, jose/0000-0002-9526-3123; Yang, Eric H/0000-0003-4889-7454; Rudenko, Anatoliy Viktorovich/0000-0003-1099-1613; Novotny, Vojtech/0000-0003-3521-9945; Nikolaev, Konstantin/0000-0003-4601-6203; Reshetko, Olga/0000-0003-3107-7636; Leonardi, Sergio/0000-0002-4800-6132; Muenzel, Thomas/0000-0001-5503-4150; Ushakov, Alexei V/0000-0002-7020-4442; Tse, Hung Fat/0000-0002-9578-7808; Podoleanu, Cristian/0000-0001-9987-2519; Raffel, Owen C/0000-0001-5470-7050; Khasanov, Niiaz/0000-0002-7760-0763; Chumakova, Galina A/0000-0002-2810-6531; Ersanli, Murat/0000-0003-1847-3087; cornel, jan hein/0000-0002-1006-2112; Abbate, Antonio/0000-0002-1930-785X; Racca, Vittorio/0000-0002-4465-3789; Urina-Triana, Miguel A/0000-0001-6003-4622; Rasputina, Lesia/0000-0003-1230-4039; Racca, Vittorio/0000-0002-4465-3789; Reis, Gilmar/0000-0002-4847-1034; Sandhu, Manjinder/0000-0003-2538-2079; Keskin, Kudret/0000-0002-9049-1530; PAREPA, IRINEL/0000-0002-7571-9015; Manakshe, Gajendra/0000-0002-4983-4271; Nicolau, Jose C/0000-0002-9680-3689; Strelnieks, Aldis/0000-0003-3493-2562; Budaj, Andrzej/0000-0002-6395-2098; Marin, Francisco/0000-0001-7246-7708; Wongpraparut, Nattawut/0000-0002-1541-3313; Yuan, Zuyi/0000-0002-4141-0298; Jeong, Myung Ho/0000-0003-2424-810X; Mostovoy, Yuriy/0000-0002-7041-1230; Pepine, Carl/0000-0002-6011-681X; Lopez-Jaramillo, Patricio/0000-0002-9122-8742; Garcia-Lledo, Alberto/0000-0002-8986-2584; Tesloianu, Nicolae-Dan/0000-0002-1007-3022; Kosmacheva, Elena/0000-0001-8600-0199; Kunz Sebba Barroso Souza, Weimar/0000-0002-1265-1930; Katz, Amos/0000-0003-0422-934X; Tunon, Jose/0000-0002-1373-0999; Acevedo, Monica/0000-0002-7989-6633; Hove, Jens/0000-0002-5600-5623; Yakushin, Sergey/0000-0001-7202-742X; Gonzalez Juanatey, Jose Ramon/0000-0001-9681-3388; Lyamina, Nadezhda/0000-0001-6939-3234; Aylward, Philip/0000-0002-5358-8552; Apostolovic, Svetlana/0000-0001-9015-297X; Airaksinen, Juhani/0000-0002-0193-568X; Nahhas, Prof. Dr. Ahmed/0000-0002-2887-8187; Barbarash, Olga/0000-0002-4642-3610, WOS: 000475553300016, PubMed: 31272931, Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1: 1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0.65-1.30 mmol/L. in this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA(1c) or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. the primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials. gov, number NCT01663402. Findings At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2.20-2.28 mmol/L), after 4 months' treatment with alirocumab (0.80 mmol/L), or after 4 months' treatment with placebo (2.25-2.28 mmol/L). in the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78-2.46, p, Sanofi; Regeneron Pharmaceuticals, Sanofi and Regeneron Pharmaceuticals.

We investigated associations of quantitative levels of N-glycans with hemoglobin A1c (HbA1c), renal function and renal function decline in type 1 diabetes. We measured 46 total N-glycan peaks (GPs) on 1565 serum samples from the Scottish Diabetes Research Network Type 1 Bioresource Study (SDRNT1BIO) and a pool of healthy donors. Quantitation of absolute abundance of each GP used 2AB-labeled mannose-3 as a standard. We studied cross-sectional associations of GPs and derived measures with HbA1c, albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR), and prospective associations with incident albuminuria and final eGFR. All GPs were 1.4 to 3.2 times more abundant in SDRTN1BIO than in the healthy samples. Absolute levels of all GPs were slightly higher with higher HbA1c, with strongest associations for triantennary trigalactosylated disialylated, triantennary trigalactosylated trisialylated structures with core or outer arm fucose, and tetraantennary tetragalactosylated trisialylated glycans. Most GPs showed increased abundance with worsening ACR. Lower eGFR was associated with higher absolute GP levels, most significantly with biantennary digalactosylated disialylated glycans with and without bisect, triantennary trigalactosylated trisialylated glycans with and without outer arm fucose, and core fucosylated biantennary monogalactosylated monosialylated glycans. Although several GPs were inversely associated prospectively with final eGFR, cross-validated multivariable models did not improve prediction beyond clinical covariates. Elevated HbA1c is associated with an altered N-glycan profile in type 1 diabetes. Although we could not establish GPs to be prognostic of future renal function decline independently of HbA1c, further studies to evaluate their impact in the pathogenesis of diabetic kidney disease are warranted.

Background The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models. Results Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82–0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80–0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87–0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82–0.99) p = 0.028]. Conclusions These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk. Clinical Trial Registration:https://www.clinicaltrials.gouv. Unique Identifier NCT01394952).

Background The 2019 ESC/EASD European Guidelines for Diabetes, Prediabetes and Coronary Artery Disease introduced a paradigm shift in the management of patients with type 2 diabetes (T2D) at high risk for or already established cardiovascular (CV) disease by recommending a GLP-1 receptor agonist (GLP-1 RA) as initial glucose lowering therapy in patients without any previous antihyperglycaemic treatment. This recommendation has been questioned since outcome trials of GLP-1-RA were usually conducted with metformin as background therapy. Purpose The aim of this report is to determine whether the effect of dulaglutide on cardiovascular events varies according to baseline metformin therapy. It was tested by a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Methods REWIND, a multicentre, double-blind, placebo-controlled trial, comprised 9901 participants (women: 46.3%; mean age: 66.2 years) with T2D and either a previous CV event (31%) or a high CV risk (69%). They were randomised (1:1) to either sc. dulaglutide (1.5 mg/week) or placebo in addition to standard of care. The primary outcome was the first of a composite of non-fatal myocardial infarction or stroke or CV death. Secondary outcomes were a microvascular composite endpoint, all-cause death and heart failure. The effect of dulaglutide study outcomes in patients with and without baseline metformin was evaluated by means of a Cox regression hazard model with baseline metformin, dulaglutide assignment and the interaction between dulaglutide and metformin as independent variables. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using a Cox regression model with additional adjustments for factors that differed at baseline between people on vs. those not on baseline metformin selected by a backward regression model. A p Results Patients without metformin at baseline (n=1864; 19%) were older, leaner, more likely to be women and had a higher proportion of prior CV events, heart failure and renal disease than patients with metformin (n=8037; 81%). During a median follow-up of 5.4 years (IQR 5.1–5.9), the primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without metformin. There was no significant difference in the effect of dulaglutide on the primary outcome in the groups with vs. without metformin at baseline (HR 0.93 [CI 0.82–1.06] vs. 0.78 [CI 0.61–0.99]; p for interaction=0.16). The effect of dulaglutide on the secondary outcomes was also not modified by concomitant metformin use (all interaction p>0.1). Conclusion This exploratory analysis suggests that the cardioprotective effect of dulaglutide does not depend on baseline metformin therapy. This supports the recommendation of using agents with proven cardioprotective efficacy without metformin in patients with diabetes and additional cardiac risk factors. Figure 1. Forest plot Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Eli Lilly and Company

Background/Introduction Diabetic kidney disease affects up to 40% of people with diabetes and is associated with higher cardiovascular (CV) risk. REWIND was a multicentre, randomised, double-blind, placebo-controlled trial with a primary outcome of first occurrence of the composite endpoint of CV death, nonfatal myocardial infarction, or nonfatal stroke (Major Adverse Cardiovascular Event [MACE]-3). Dulaglutide treatment reduced the incidence of MACE-3 in patients with type 2 diabetes (T2D) with or without established CV disease. Purpose This REWIND post hoc subgroup analysis evaluated the effect of dulaglutide on MACE-3 in patients with an eGFR Methods Eligible patients were those ≥50 years old with T2D who had either a previous CV event or CV risk factors. Patients were randomised (1:1) to dulaglutide 1.5 mg or placebo, both in addition to standard of care. A Cox proportional hazards model with treatment, eGFR subgroup ( Results At baseline, 2,199 of 9,901 patients (22.2%) had an eGFR Conclusions Regardless of baseline eGFR or albuminuria status, dulaglutide reduces MACE-3 outcomes in patients with T2D and established CV disease or multiple CV risk factors. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Eli Lilly and Company

ObjectiveTo assess the risk of hospital admission for coronavirus disease 2019 (covid-19) among patient facing and non-patient facing healthcare workers and their household members.DesignNationwide linkage cohort study.SettingScotland, UK, 1 March to 6 June 2020.ParticipantsHealthcare workers aged 18-65 years, their households, and other members of the general population.Main outcome measureAdmission to hospital with covid-19.ResultsThe cohort comprised 158 445 healthcare workers, most of them (90 733; 57.3%) being patient facing, and 229 905 household members. Of all hospital admissions for covid-19 in the working age population (18-65 year olds), 17.2% (360/2097) were in healthcare workers or their households. After adjustment for age, sex, ethnicity, socioeconomic deprivation, and comorbidity, the risk of admission due to covid-19 in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazard ratio 0.81 (95% confidence interval 0.52 to 1.26) and 0.86 (0.49 to 1.51), respectively). In models adjusting for the same covariates, however, patient facing healthcare workers, compared with non-patient facing healthcare workers, were at higher risk (hazard ratio 3.30, 2.13 to 5.13), as were household members of patient facing healthcare workers (1.79, 1.10 to 2.91). After sub-division of patient facing healthcare workers into those who worked in “front door,” intensive care, and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (hazard ratio 2.09, 1.49 to 2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of hospital admission with covid-19 was less than 0.5%, but it was 1% and above in older men with comorbidity.ConclusionsHealthcare workers and their households contributed a sixth of covid-19 cases admitted to hospital. Although the absolute risk of admission was low overall, patient facing healthcare workers and their household members had threefold and twofold increased risks of admission with covid-19.

OBJECTIVE End-stage kidney disease (ESKD) is a life-threatening complication of diabetes that can be prevented or delayed by intervention. Hence, early detection of people at increased risk is essential. RESEARCH DESIGN AND METHODS From a population-based cohort of 5,460 clinically diagnosed Danish adults with type 1 diabetes followed from 2001 to 2016, we developed a prediction model for ESKD accounting for the competing risk of death. Poisson regression analysis was used to estimate the model on the basis of information routinely collected from clinical examinations. The effect of including an extended set of predictors (lipids, alcohol intake, etc.) was further evaluated, and potential interactions identified in a survival tree analysis were tested. The final model was externally validated in 9,175 adults from Denmark and Scotland. RESULTS During a median follow-up of 10.4 years (interquartile limits 5.1; 14.7), 303 (5.5%) of the participants (mean [SD] age 42.3 [16.5] years) developed ESKD, and 764 (14.0%) died without having developed ESKD. The final ESKD prediction model included age, male sex, diabetes duration, estimated glomerular filtration rate, micro- and macroalbuminuria, systolic blood pressure, hemoglobin A1c, smoking, and previous cardiovascular disease. Discrimination was excellent for 5-year risk of an ESKD event, with a C-statistic of 0.888 (95% CI 0.849; 0.927) in the derivation cohort and confirmed at 0.865 (0.811; 0.919) and 0.961 (0.940; 0.981) in the external validation cohorts from Denmark and Scotland, respectively. CONCLUSIONS We have derived and validated a novel, high-performing ESKD prediction model for risk stratification in the adult type 1 diabetes population. This model may improve clinical decision making and potentially guide early intervention.

Background The objectives of this study were to identify risk factors for severe coronavirus disease 2019 (COVID-19) and to lay the basis for risk stratification based on demographic data and health records. Methods and findings The design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the national database followed by entry to a critical care unit or death within 28 days or a death certificate with COVID-19 as underlying cause. Up to 10 controls per case matched for sex, age, and primary care practice were selected from the national population register. For this analysis—based on ascertainment of positive test results up to 6 June 2020, entry to critical care up to 14 June 2020, and deaths registered up to 14 June 2020—there were 36,948 controls and 4,272 cases, of which 1,894 (44%) were care home residents. All diagnostic codes from the past 5 years of hospitalisation records and all drug codes from prescriptions dispensed during the past 240 days were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio 21.4 (95% CI 19.1–23.9, p = 8 × 10−644). Univariate rate ratios for conditions listed by public health agencies as conferring high risk were 2.75 (95% CI 1.96–3.88, p = 6 × 10−9) for type 1 diabetes, 1.60 (95% CI 1.48–1.74, p = 8 × 10−30) for type 2 diabetes, 1.49 (95% CI 1.37–1.61, p = 3 × 10−21) for ischemic heart disease, 2.23 (95% CI 2.08–2.39, p = 4 × 10−109) for other heart disease, 1.96 (95% CI 1.83–2.10, p = 2 × 10−78) for chronic lower respiratory tract disease, 4.06 (95% CI 3.15–5.23, p = 3 × 10−27) for chronic kidney disease, 5.4 (95% CI 4.9–5.8, p = 1 × 10−354) for neurological disease, 3.61 (95% CI 2.60–5.00, p = 2 × 10−14) for chronic liver disease, and 2.66 (95% CI 1.86–3.79, p = 7 × 10−8) for immune deficiency or suppression. Seventy-eight percent of cases and 52% of controls had at least one listed condition (51% of cases and 11% of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past 9 months and with at least one hospital admission in the past 5 years (rate ratios 3.10 [95% CI 2.59–3.71] and 2.75 [95% CI 2.53–2.99], respectively) even after adjusting for the listed conditions. In those without listed conditions, significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses, and prescriptions provided an additional 1.07 bits (C-statistic 0.804). A limitation of this study is that records from primary care were not available. Conclusions We have shown that, along with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over., Paul McKeigue and co-workers study comorbidities and medical treatments as risk factors for severe COVID-19 in Scotland., Author summary Why was this study done? Most people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not become seriously ill: risk of severe or fatal disease is associated with older age, male sex, and conditions designated by public health agencies, including asthma, diabetes, and heart disease. Studies reported so far have focused on these “listed conditions” but have not examined medical records systematically to identify possible risk factors for severe coronavirus disease 2019 (COVID-19). The objectives of this study were to identify risk factors for severe COVID-19 and to lay the basis for risk stratification based on electronic health records. What did the researchers do and find? Using Scotland’s capability for linking electronic health records, we report the first systematic study of the relationship of severe or fatal COVID-19 to preexisting health conditions and other risk factors. Residents in care homes were 21 times more likely to develop severe disease than people of the same age and sex not living in care homes. The conditions associated with increased risk include not only those already designated by public health agencies—asthma, diabetes, heart disease, disabling neurological disease, kidney disease—but other diagnoses that are associated with frailty and poor health such as strokes and a history of falls. In those without any listed conditions, use of prescribed drugs acting on the digestive system or nervous system is associated with increased risk of severe COVID-19. What do these findings mean? The risk to younger individuals without any recent history of hospital admission or use of prescription drugs is very low. This study lays a basis for calculating a risk score based on electronic health records for every individual in the population and using it to advise those at high risk of severe disease to shield themselves when there is a COVID-19 epidemic in their locality.

SummaryThe classic Susceptible-Infected-Recovered model formulated by Kermack and McKendrick [1] assumes that all individuals in the population are equally susceptible to infection. From fitting such a model to the trajectory of mortality from COVID-19 in 11 European countries up to 4 May 2020 Flaxman et al. concluded that “major non-pharmaceutical interventions – and lockdowns in particular – have had a large effect on reducing transmission” [2]. We show that relaxing the assumption of homogeneity to allow for individual variation in susceptibility or connectivity gives a model that has better fit to the data and more accurate 14-day forward prediction of mortality. Allowing for heterogeneity reduces the estimate of “counterfactual” deaths that would have occurred if there had been no interventions from 3.2 million to 262,000, implying that most of the slowing and reversal of COVID-19 mortality is explained by the build-up of herd immunity. The estimate of the herd immunity threshold depends on the value specified for the infection fatality ratio (IFR): a value of 0.3% for the IFR gives 15% for the average herd immunity threshold.

BackgroundChildren are relatively protected from novel coronavirus infection (COVID-19). The reasons for this protection are not well understood but differences in the immune response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) have been implicated. If such differences are due to differential exposure to non-SARS-CoV-2 infectious agents, adults who are close contacts of children may partly share in this protection. Such a protective effect would have important implications for the lives of children, not least in terms of schooling.MethodsUsing a Scotland-wide record-linkage based occupational cohort comprising healthcare workers and members of their households, we examined whether sharing a household with young children (aged 0 to 11) attenuated the risk of hospitalisation with COVID-19, and/or testing positive for COVID-19 infection of any severity (any case of Covid-19). All healthcare workers directly employed by the National health Service (NHS) in Scotland, or contracted to provide general practice services, were included. Outcome and covariate data were obtained via linkage to Scotland-wide microbiology, drug prescribing, hospitalisation and death data.Results241,266 adults did not share a household with young children; 41,198, 23,783 and 3,850 shared a household with 1, 2 and 3 or more young children respectively. The risk of hospitalisation with COVID-19 was lower in those with one child and lower still in those with two or more children, adjusting for age the hazard ratio (HR) was 0.83 per child (95% CI 0.70-0.99). On additionally adjusting for sex, socioeconomic deprivation, occupation, professional role, staff/non-staff status, the number of adults and adolescents in each household, and comorbidity, the HR was 0.89 per child (95% CI 0.74-1.06). An association of the same magnitude, but more precisely estimated, was obtained for any case of COVID-19 (fully adjusted model, HR per child 0.89; 95% CI 0.84-0.95).ConclusionIncreased household exposure to young children was associated with an attenuated risk of testing positive for SARS-CoV-2 and appeared to also be associated with an attenuated risk of COVID-19 disease severe enough to require hospitalisation.

ObjectivesTo investigate the relation of severe COVID-19 to prior drug prescribing.DesignMatched case-control study (REACT-SCOT) based on record linkage to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days.SettingScottish population.Main outcome measureSevere COVID-19, defined by entry to critical care or fatal outcome.ParticipantsAll 4272 cases of severe COVID-19 in Scotland since the start of the epidemic, with 36948 controls matched for age, sex and primary care practice.ResultsSevere COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in care homes, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.7, 13.2), and was not accounted for by treatment of conditions designated as conferring increased risk. Of 17 drug classes postulated at the start of the epidemic to be “medications compromising COVID”, all were associated with increased risk of severe COVID-19. The largest effect was for antipsychotic agents: rate ratio 4.14 (3.39, 5.07). Other drug classes with large effects included proton pump inhibitors (rate rato 2.19 (1.70, 2.80) for >= 2 defined daily doses/day), opioids (3.62 (2.65, 4.94) for >= 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates, and were stronger with recent than with non-recent exposure.ConclusionsSevere COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression or dyskinesia, have anticholinergic effects or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Although the evidence for causality is not conclusive, these results support existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy as a potential means of reducing COVID-19 risk.RegistrationENCEPP number EUPAS35558What is already known on this topicTwo previous studies have examined the relationship of severe COVID-19 to drugs for the cardiovascular system. This is the first systematic study of the relationship of severe COVID-19 to prior drug prescribing.What this study addsSevere COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression or dyskinesia, have anticholinergic effects or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. These results support earlier warnings that these drug classes that these drugs might increase susceptibility to COVID-19, and reinforce existing guidance on reducing overprescribing of these drug classes.

Aims/hypothesis Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. Methods We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. Results HbA1c decreased after CSII initiation, with a median within-person change of −5.5 mmol/mol (IQR −12.0, 0.0) (−0.5% [IQR −1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median −21.0 mmol/mol (−30.0, −11.0) (−1.9% [−2.7, −1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: −19.0 mmol/mol (−27.6, −6.5) (−1.7% [−2.5, −0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). Conclusions/interpretation CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control. Graphical abstract

Digital, Background Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial. Methods REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1–5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85–1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79–0·95; p=0·0018). Interpretation Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated., Ciencias Médicas y de la Salud

OBJECTIVE In 2019, the European Society of Cardiology led and released new guidelines for diabetes cardiovascular risk management, reflecting recent evidence of cardiovascular disease (CVD) reduction with sodium–glucose cotransporter 2 inhibitors (SGLT-2is) and some glucagon-like peptide 1 receptor agonists (GLP-1RAs) in type 2 diabetes (T2D). A key recommendation is that all those with T2D who are (antihyperglycemic) drug naïve or on metformin monotherapy should be CVD risk stratified and an SGLT-2i or a GLP-1RA initiated in all those at high or very high risk, irrespective of glycated hemoglobin. We assessed the impact of these guidelines in Scotland were they introduced as is. RESEARCH DESIGN AND METHODS Using a nationwide diabetes register in Scotland, we did a cross-sectional analysis, using variables in our register for risk stratification at 1 January 2019. We were conservative in our definitions, assuming the absence of a risk factor where data were not available. The risk classifications were applied to people who were drug naïve or on metformin monotherapy and the anticipated prescribing change calculated. RESULTS Of the 265,774 people with T2D in Scotland, 53,194 (20.0% of those with T2D) were drug naïve, and 56,906 (21.4%) were on metformin monotherapy. Of these, 74.5% and 72.4%, respectively, were estimated as at least high risk given the guideline risk definitions. CONCLUSIONS Thus, 80,830 (30.4%) of all those with T2D (n = 265,774) would start one of these drug classes according to table 7 and figure 3 of the guideline. The sizeable impact on drug budgets, enhanced clinical monitoring, and the trade-off with reduced CVD-related health care costs will need careful consideration.

The REWIND trial showed that relative to placebo (PL), once weekly dulaglutide (DU) 1.5 mg reduced the incidence of a major adverse cardiovascular (CV) event (MACE; nonfatal myocardial infarction, nonfatal stroke, or CV death) in patients with T2D with and without established CV disease (hazard ratio (HR) 0.88, 95% CI [0.79, 0.99]; p=0.026). DU also significantly reduced A1C, body weight (BW), and systolic blood pressure (SBP) (Table). In this post-hoc assessment, a mediation analysis was used to estimate the degree to which the effect of DU on these risk factors could statistically account for its effect on MACE. Data were analyzed from 9901 patients who had 1257 first MACE events over 5.4 median yrs of observation. Those risk factors for which the updated mean on follow-up was significantly related to MACE were added to a separate Cox model that included DU allocation, the baseline [BL] value of the measurement and the updated mean of the variable as time dependent covariates. Only A1C satisfied this condition (Table), suggesting that BW and SBP did not mediate the effect of DU on MACE in this study population. The effect size of DU on the MACE outcome was attenuated by 36.1% after accounting for its effect on A1C (Table). In conclusion, the results suggest most of the CV benefit of DU on MACE is not attributable to the A1C, BW, or SBP-lowering effects of DU. Disclosure H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. C. Hasenour: Employee; Self; Eli Lilly and Company. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K. Branch: Consultant; Self; Bayer AG. Research Support; Self; Bayer AG, Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.

Introduction: End-stage kidney disease (ESKD) is a life-threatening but preventable complication to diabetes and early detection of high-risk persons is essential. Our aim was to develop a prediction model for ESKD in type 1 diabetes (T1D). Materials and Methods: Detailed clinical- and lifestyle data from 5,460 Danish adults with T1D was linked to ESKD events and death recorded in the national registries. Median follow-up time was 10.4 years (Q1-Q3: 5.1-14.7), during which 303 (5.5%) developed ESKD and 764 (14.0%) died of non-ESKD related causes. To account for the competing risk of death, rate models for the two events (ESKD and death) were estimated separately using Poisson regression analysis, censoring for the other event, and subsequently combined to give the cumulative incidence function for ESKD. External validation of the model is ongoing. Results: The rate model for ESKD included age, male sex, diabetes duration, eGFR, albuminuria, urine albumin-to-creatinine ratio, systolic BP, HbA1c, haemoglobin, previous cardiovascular disease and retinopathy status. Model discrimination was excellent for up to 10-year risk of ESKD with C-statistics between 0.883 and 0.911 (Figure 1). Calibration was adequate for predicting up to 5-year risk of ESKD (P ≥ 0.166). Conclusion: This tool for ESKD risk assessment could be an essential support for the decision on initiation of preventive treatment in persons with T1D. However, external validation is needed. Disclosure D. Vistisen: Stock/Shareholder; Self; Novo Nordisk A/S. G.S. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. A. Hulman: None. S. McGurnaghan: None. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. J. Henriksen: None. R.W. Thomsen: None. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S.

Aims: In REMOVAL (NCT01483560), metformin attenuated decline in estimated glomerular filtration rate (eGFR) using the creatinine-based Modified Diet in Renal Disease (MDRD) equation in adults with T1D. We now report the effects of metformin vs. placebo on: (i) eGFR by CKD-EPI; and (ii) microalbuminuria (albumin: creatinine ratio, ACR). Methods: In 428 participants (mean age 55 years; HbA1c 8.0%; BP 130/72mmHg; eGFR 92 ml/min/1.73m2, 69% on ACE inhibitors/ARBs), CKD-EPI was derived separately from creatinine and cystatin C (annual). ACR was measured on annual first morning void. Treatment effects were compared by ANCOVA for continuous data (adjusted for baseline) and Cox Regression for incident microalbuminuria. Results: Mean baseline eGFR by CKD-EPI was 90 ml/min/1.73m2 by creatinine and 96 ml/min/1.73m2 by cystatin C. Decline in eGFR over 3 years was attenuated by metformin vs. placebo when CKD-EPI was derived from creatinine and cystatin C. There was no effect on ACR but confidence intervals were wide (Table). Conclusions: Deriving eGFR from other biomarkers/equations does not alter the conclusion that metformin has a potentially beneficial effect on eGFR in T1D; its effect on ACR requires further study. Disclosure J.G. Timmons: None. N. Greenlaw: None. C.D. Stehouwer: None. M. Brouwers: None. N. Chaturvedi: Consultant; Self; AstraZeneca. A.D. Hughes: Advisory Panel; Spouse/Partner; AstraZeneca. I. Hramiak: Consultant; Self; Medtronic, Novo Nordisk Inc. Research Support; Self; Eli Lilly and Company, PHRI Population Health Research Institute, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim (Canada) Ltd., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, Bristol-Myers Squibb, Insulet Corporation. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. P. Welsh: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Roche Diagnostics. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. P. Rossing: Advisory Panel; Self; Sanofi. Consultant; Self; Astellas Pharma Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Eli Lilly and Company. Stock/Shareholder; Self; Novo Nordisk A/S. J.R. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Advanced Clinical Intelligence, IQVIA. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Merck KGaA, Novo Nordisk A/S.

In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk. Disclosure J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. Funding Eli Lilly and Company

SummaryAlthough population-wide lockdowns have been successful in slowing the COVID-19 epidemic, there is a consensus among disease modellers that keeping the load on critical care services within manageable limits will require an adaptive social distancing strategy, alternating cycles of relaxation and reimposition until a vaccine is available. An alternative strategy that has been tentatively proposed is to shield the elderly and others at high risk of severe disease, while allowing immunity to build up in those at low risk until the entire population is protected. We examine the performance required from a classifier that uses information from medical records to assign risk status for a such a stratify-and-shield policy to be effective in limiting mortality when social distancing is relaxed.We show that under plausible assumptions about the level of immunity required for population-level immunity, the proportion shielded is constrained to be no more than 15% of the population. Under varying assumptions about the infection fatality ratio (from 0.1% to 0.4%) and the performance of the classifier (3 to 4.5 bits of information for discrimination), we calculate the expected number of deaths in the unshielded group. We show that with likely values of the performance of a classifier that uses information from age, sex and medical records, at least 80% of those who would die if unshielded would be allocated to the high-risk shielded group comprising 15% of the population. Although the proportion of deaths that would be prevented by effective shielding does not vary much with the infection fatality ratio, the absolute number of deaths in the unshielded varies from less than 10,000 if the infection fatality rate is 0.1% to more than 50,000 if the infection fatality rate is as high as 0.4%.For projecting the effect of an optimally applied stratify-and-shield policy, studies now under way should help to resolve key uncertainties: the extent to which infection confers immunity, the prevalence of immunity, the infection fatality ratio, and the performance of a classifier constructed using information from medical records. It is time to give serious consideration to a stratify-and-shield policy that could bring the COVID-19 epidemic to an end in a matter of months while restoring economic activity, avoiding overload of critical care services and limiting mortality.

Aim\ud To compare costs for three groups of people with type 2 diabetes, those at high risk of future cardiovascular disease, those without cardiovascular disease and those with established cardiovascular disease, and to also compare costs incurred by people with type 2 diabetes with an incident cardiovascular disease event with those who remain incident event‐free over a 3‐year period.\ud \ud Methods\ud Data about people with type 2 diabetes in Scotland were obtained from the Scottish Care Information Diabetes registry. Data linkage was used to retrieve information on healthcare utilization, care home use and deaths. Productivity effects were estimated for those of non‐pensionable age. We estimated costs over 12 months (prevalent cardiovascular disease) and 3 years from incident cardiovascular disease event.\ud \ud Results\ud Mean annual cost per person with established cardiovascular disease was £6900, £3300 for a person at high risk of future cardiovascular disease, and £2500 for a person without cardiovascular disease and not at high risk. In year 1, the cost of an incident cardiovascular disease event was £16 700 compared with £2100 for people without an incident event. Over 2 years, the cumulative costs were £21 500 and £4200, and by year 3, £25 000 and £5900, respectively.\ud \ud Conclusions\ud Cardiovascular disease in people with type 2 diabetes places a significant financial burden on healthcare and the wider economy. Our results emphasize the financial consequences of cardiovascular disease prevention strategies.

Aims To describe the association between socio-economic status and mortality in a nation-wide cohort of people with type 1 diabetes in Scotland and to compare patterns over time and with the general population. Methods A retrospective cohort study was performed using data for people with type 1 diabetes from a population-based register linked to mortality records. Socio-economic status was derived from quintiles of an area-based measure: the Scottish Index of Multiple Deprivation. Sex-specific directly age-standardized mortality rates for each Scottish Index of Multiple Deprivation quintile and rate ratios comparing the most vs least deprived quintile were calculated for two time periods: 2006-2010 and 2011-2015. Data for the population without type 1 diabetes between 2011 and 2015 were available for comparison. Results Data for 3802 deaths among 33 547 people with type 1 diabetes were available. The age-standardized mortality rate per 1000 person-years decreased over time (from 2006-2010 to 2011-2015) for men and women with type 1 diabetes: 24.8 to 20.2 and 22.5 to 17.6, respectively. Mortality in populations with and without type 1 diabetes was generally higher for men than women and was inversely associated with socio-economic status. Rate ratios for the most vs least deprived groups increased over time among people with type 1 diabetes (men: 2.49 to 2.81; women: 1.92 to 2.86) and were higher than among populations without type 1 diabetes in 2011-2015 (men: 2.06; women: 1.66). Conclusions Socio-economic deprivation was associated with a steeper mortality gradient in people with type 1 diabetes than in the population without type 1 diabetes in Scotland. Age-standardized mortality has decreased over time but socio-economic inequalities may be increasing.

Cardiovascular diabetology 19, 14 (2020). doi:10.1186/s12933-020-0991-1, Published by BioMed Central, London

Background: The risks of, and risk factors for, COVID-19 disease associated with diabetes are poorly quantified brbrMethods: We identified as cases all th

Supplemental Digital Content is available in the text., Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain.METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials.FUNDING: Novartis Pharma AG.

Background: Although COVID-19 vaccines have been shown to have high efficacy in the general population, it has not been established whether this applies to vulnerable groups. The objective of this study was to estimate the efficacy of vaccination in reducing the risk of severe COVID-19 among those designated as clinically extremely vulnerable in Scotland. Methods: In a matched case-control design (REACT-SCOT), all 111295 cases of COVID-19 in Scotland diagnosed from 1 December 2020 to 16 March 2021 were matched for age, sex and primary care practice to 1093449 controls from the general population. This was linked to national data on vaccinations and those designated as clinically extremely vulnerable and thus eligible for shielding support. Severe COVID-19 was defined as cases with entry to critical care or fatal outcome. Rate ratios associated with vaccination within risk groups were estimated by conditional logistic regression. Results: The rate ratio for severe COVID-19 associated with vaccination at least 14 days before was 0.29 (95% CI 0.22 to 0.37) in those eligible for shielding, compared with 0.29 (95% CI 0.25 to 0.34) in those ineligible for shielding. The rate ratio for hospitalized or fatal COVID-19 was 0.39 (95% CI 0.33 to 0.46) in those eligible and 0.37 (95% CI 0.33 to 0.41) in those not eligible for shielding. Examined by specific shielding conditions, the rate ratio for hospitalized or fatal COVID-19 ranged from 0.33 (95% CI 0.21 to 0.51) in those with specific cancers to 0.74 (95% CI 0.36 to 1.51) in solid organ transplant recipients, and 0.53 (95% CI 0.33 to 0.84) in others on immunosuppressants (excluding solid organ transplant recipients). Conclusions: These results are reassuring with respect to efficacy in clinically vulnerable individuals including immunocompromised individuals, but studies in larger populations are needed to estimate efficacy in solid organ transplant recipients.

Summary Background Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. Objectives To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome‐wide association study. Methods A genome‐wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e‐health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e‐health records. Results There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single‐nucleotide polymorphism rs80028505 (Chr6p21·31) in MAPK14 reached genome‐wide significance with a lowest P‐value of 2·45 × 10−8. The narrow‐sense heritability of this phenotype is 0·06. Conclusions We suggest that MAPK14 is associated with DFUs., What's already known about this topic? Around 25% of people with diabetes will develop foot ulceration in their lifetime.Diabetic foot ulcers (DFUs) account for 85% of all lower‐limb amputations in the U.K.There are multiple risk factors for DFUs, the strongest initiating factor being peripheral sensory neuropathy.The genetics of DFUs are poorly understood. What does this study add? This genome‐wide association study suggests that a skin‐related gene, MAPK14, is associated with DFUs in individuals with evidence of neuropathy.The narrow‐sense heritability of this disorder, in individuals with evidence of neuropathy, is 0·06. What is the translational message? Genetic variants in MAPK14 are strongly linked with DFUs.Further study is needed to confirm the gene's role, followed by clinical trials that should bring significant benefits to patients with DFUs. Linked Comment: Lainer. Br J Dermatol 2017; 177:1482–1483. Plain language summary available online Respond to this article

OBJECTIVE To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40–89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors. RESULTS A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality. CONCLUSIONS Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.

Purpose To demonstrate a modelling approach that controls for time-invariant allocation bias in estimation of associations of outcome with drug exposure. Methods We show that in a model that includes terms for both ever-exposure versus never-exposure and cumulative exposure, the parameter for ever-exposure represents the effect of time-invariant allocation bias, and the parameter for cumulative exposure represents the effect of the drug after adjustment for this unmeasured confounding. This assumes no stepwise effect of the drug on the event rate, no reverse causation, and no unmeasured time-varying confounders. We demonstrated this by modelling the effect of statins on cardiovascular disease, for which the true effect has been well characterised in randomised trials, using time-updated Cox regression models in a national cohort of Type 2 diabetes patients. Results The crude hazard ratio associated with ever-use of statins was 1.13 in a standard cohort analysis comparing exposed with unexposed person-time intervals. When ever-never use and cumulative exposure are modelled jointly, the effect of statins can be estimated from the cumulative exposure parameter (hazard ratio 0.97 per year of exposure, 95% CI 0.97 to 0.98). The ever-exposed term (hazard ratio 1.20, 1.16 to 1.23) in this model can be interpreted as estimating the allocation bias. Conclusions Where stepwise effects on the risk of adverse events are unlikely, as for instance for effects on risk of cancer, joint modelling of ever-never and cumulative exposure can be used to study the effects of multiple drugs and to distinguish causal effects from confounding by allocation.

Aims/hypothesis The aim of this study was to assess the role of socioeconomic status (SES) in the associations between type 2 diabetes and life expectancy in a complete national population. Methods An observational population-based cohort study was performed using the Scottish Care Information – Diabetes database. Age-specific life expectancy (stratified by SES) was calculated for all individuals with type 2 diabetes in the age range 40–89 during the period 2012–2014, and for the remaining population of Scotland aged 40–89 without type 2 diabetes. Differences in life expectancy between the two groups were calculated. Results Results were based on 272,597 individuals with type 2 diabetes and 2.75 million people without type 2 diabetes (total for 2013, the middle calendar year of the study period). With the exception of deprived men aged 80–89, life expectancy in people with type 2 diabetes was significantly reduced (relative to the type 2 diabetes-free population) at all ages and levels of SES. Differences in life expectancy ranged from −5.5 years (95% CI −6.2, −4.8) for women aged 40–44 in the second most-deprived quintile of SES, to 0.1 years (95% CI −0.2, 0.4) for men aged 85–89 in the most-deprived quintile of SES. Observed life-expectancy deficits in those with type 2 diabetes were generally greater in women than in men. Conclusions/interpretation Type 2 diabetes is associated with reduced life expectancy at almost all ages and levels of SES. Elimination of life-expectancy deficits in individuals with type 2 diabetes will require prevention and management strategies targeted at all social strata (not just deprived groups). Electronic supplementary material The online version of this article (10.1007/s00125-017-4478-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to substantially reduce low-density lipoprotein cholesterol (LDL-C). Demonstrating whether efficacy and safety are maintained over a long duration of exposure is vital for clinical decision-making. The COMBO II trial compared the efficacy and safety of alirocumab versus ezetimibe over 2 years. A prespecified first analysis was reported at 52 weeks. Here we report the final end-of-study data (on-treatment) and evaluate post hoc the safety profile with longer versus shorter duration of alirocumab exposure. Patients (n = 720) on maximally tolerated statin dose were treated with alirocumab (75/150 mg every 2 weeks) or ezetimibe (10 mg/day). Overall mean adherence for both treatment groups during the first and second year was >97%. At 2 years, LDL-C was reduced by 49% (alirocumab) versus 17% (ezetimibe; p

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.