Association Between Accelerometer-Assessed Physical Activity and Severity of COVID-19 in UK Biobank.

Funder: UKRI Science and Technology Facilities CouncilOBJECTIVE: To quantify the association between accelerometer-assessed physical activity and coronavirus disease 2019 (COVID-19) outcomes. METHODS: Data from 82,253 UK Biobank participants with accelerometer data (measured 2013-2015), complete covariate data, and linked COVID-19 data from March 16, 2020, to March 16, 2021, were included. Two outcomes were investigated: severe COVID-19 (positive test result from in-hospital setting or COVID-19 as primary cause of death) and nonsevere COVID-19 (positive test result from community setting). Logistic regressions were used to assess associations with moderate to vigorous physical activity (MVPA), total activity, and intensity gradient. A higher intensity gradient indicates a higher proportion of vigorous activity. RESULTS: Average MVPA was 48.1 (32.7) min/d. Physical activity was associated with lower odds of severe COVID-19 (adjusted odds ratio per standard deviation increase: MVPA, 0.75 [95% CI, 0.67 to 0.85]; total, 0.83 [0.74 to 0.92]; intensity, 0.77 [0.70 to 0.86]), with stronger associations in women (MVPA, 0.63 [0.52 to 0.77]; total, 0.76 [0.64 to 0.90]; intensity, 0.63 [0.53 to 0.74]) than in men (MVPA, 0.84 [0.73 to 0.97]; total, 0.88 [0.77 to 1.01]; intensity, 0.88 [0.77 to 1.00]). In contrast, when mutually adjusted, total activity was associated with higher odds of a nonsevere infection (1.10 [1.04 to 1.16]), whereas the intensity gradient was associated with lower odds (0.91 [0.86 to 0.97]). CONCLUSION: Odds of severe COVID-19 were approximately 25% lower per standard deviation (∼30 min/d) MVPA. A greater proportion of vigorous activity was associated with lower odds of severe and nonsevere infections. The association between total activity and higher odds of a nonsevere infection may be through greater community engagement and thus more exposure to the virus. Results support calls for public health messaging highlighting the potential of MVPA for reducing the odds of severe COVID-19

Patterns of multimorbidity and risk of severe SARS-CoV-2 infection: an observational study in the U.K.

Funder: National Institute for Health Research; Grant(s): Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014), NIHR Applied Research Collaboration East Midlands (ARC EM), NIHR Leicester Biomedical Research CentreBackgroundPre-existing comorbidities have been linked to SARS-CoV-2 infection but evidence is sparse on the importance and pattern of multimorbidity (2 or more conditions) and severity of infection indicated by hospitalisation or mortality. We aimed to use a multimorbidity index developed specifically for COVID-19 to investigate the association between multimorbidity and risk of severe SARS-CoV-2 infection.MethodsWe used data from the UK Biobank linked to laboratory confirmed test results for SARS-CoV-2 infection and mortality data from Public Health England between March 16 and July 26, 2020. By reviewing the current literature on COVID-19 we derived a multimorbidity index including: (1) angina; (2) asthma; (3) atrial fibrillation; (4) cancer; (5) chronic kidney disease; (6) chronic obstructive pulmonary disease; (7) diabetes mellitus; (8) heart failure; (9) hypertension; (10) myocardial infarction; (11) peripheral vascular disease; (12) stroke. Adjusted logistic regression models were used to assess the association between multimorbidity and risk of severe SARS-CoV-2 infection (hospitalisation/death). Potential effect modifiers of the association were assessed: age, sex, ethnicity, deprivation, smoking status, body mass index, air pollution, 25-hydroxyvitamin D, cardiorespiratory fitness, high sensitivity C-reactive protein.ResultsAmong 360,283 participants, the median age was 68 [range 48-85] years, most were White (94.5%), and 1706 had severe SARS-CoV-2 infection. The prevalence of multimorbidity was more than double in those with severe SARS-CoV-2 infection (25%) compared to those without (11%), and clusters of several multimorbidities were more common in those with severe SARS-CoV-2 infection. The most common clusters with severe SARS-CoV-2 infection were stroke with hypertension (79% of those with stroke had hypertension); diabetes and hypertension (72%); and chronic kidney disease and hypertension (68%). Multimorbidity was independently associated with a greater risk of severe SARS-CoV-2 infection (adjusted odds ratio 1.91 [95% confidence interval 1.70, 2.15] compared to no multimorbidity). The risk remained consistent across potential effect modifiers, except for greater risk among older age. The highest risk of severe infection was strongly evidenced in those with CKD and diabetes (4.93 [95% CI 3.36, 7.22]).ConclusionThe multimorbidity index may help identify individuals at higher risk for severe COVID-19 outcomes and provide guidance for tailoring effective treatment

Uses and limitations of the restricted mean survival time: illustrative examples from cardiovascular outcomes and mortality trials in type 2 diabetes

The Restricted Mean Survival Time (RMST) has been advocated as an alternative, or supplement, to the hazard ratio (HR) for reporting the effect of an intervention in a randomized clinical trial. The RMST difference allows quantifying the postponement of an outcome over a specified (restricted) time interval and corresponds to the difference between the areas under the two survival curves for the intervention and the control arm.In this article, we present examples of its uses in a research and a clinical context. First, we show how the RMST difference can answer research questions about the efficacy of different treatments. We present estimates for the effects of pharmacological or strategy-driven glucose-lowering interventions for adults with type 2 diabetes from 36 trials and 9 follow-up studies reporting cardiovascular outcomes and mortality. We show how these measures can be used to mitigate uncertainty about the efficacy of intensive glucose control. Second, we demonstrate how the RMST difference can be used in the setting of a clinical consultation to guide the decision to start or discontinue a treatment.We then discuss the advantages of the RMST over the absolute risk difference, the number needed to treat, and the median survival difference. We argue that the RMST difference is both easily interpretable and flexible in its application to different settings. Lastly, we highlight its major limitations, including difficulties in comparing studies of heterogeneous designs and in inferring the long-term effects of treatments using trials of short duration, and summarize the available statistical software for calculating the RMST.</div

Cardiovascular effects of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: The P value and beyond

Despite growing awareness of the dangers of a dichotomous interpretation of trial results based on the ‘statistical significance’ of a treatment effect, the uptake of new approaches has been slow in diabetes medicine. We showcase a number of ways to interpret the evidence for a treatment effect applied to the cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2is): the P value function (or confidence curves), which depicts the treatment effect across the whole spectrum of confidence levels; the counternull value, which is the hazard ratio (i.e. treatment effect size) supported by the same amount of evidence as the null value (i.e. no treatment effect); and the S value, which quantifies the strength of the evidence against the null hypothesis in terms of the number of coin tosses yielding the same side. We show how this approach identifies potential treatment effects, highlights similarities among trials straddling the threshold of statistical significance, and quantifies differences in the strength of the evidence from trials reporting statistically significant results. For example, while REWIND, CANVAS and CREDENCE failed to reach statistical significance at the .05 level for all-cause mortality, their counternull values indicate that reduced death rates by 19%, 24% and 31%, respectively, are supported by the same amount of evidence as that indicating no treatment effect. Moreover, similarities among results emerge in trials of GLP-1RAs (REWIND, EXSCEL and LEADER) lying closely around the threshold of ‘statistical significance’. Lastly, several S values, such as for the primary outcome in HARMONY Outcomes (S value 10.9) and all-cause death in EMPAREG-OUTCOME (S value 15.0), stand out compared with values for other outcomes and other trials, suggesting much larger differences in the evidence between these studies and several others that cluster around the .05 significance threshold. P value functions, counternull values and S values should complement the standard reporting of the treatment effect to help interpret clinical trials and make decisions among competing glucose-lowering medications

Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

Aims While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. Materials and Methods A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. Results The median duration of follow-up was 7.7 years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (−0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c Discussion Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects.</p

Efficacy of Low- and Very-Low-Energy Diets in people with Type 2 Diabetes Mellitus: A systematic review and meta-analysis of interventional studies.

AIMS: To systematically review and quantify the weight loss achieved by Low- and Very-Low-Energy Diets in people with type 2 diabetes mellitus. MATERIALS AND METHODS: Studies reporting the effects of diet-only interventions up to 1600kcal/day in people with type 2 diabetes mellitus were searched in MEDLINE, EMBASE, CINAHL until July 2018. Changes in the primary (body weight and body mass index) and secondary (HbA1c, blood lipids) outcomes according to energy restriction and duration of diet were modelled using restricted cubic splines. RESULTS: Forty-four studies (3817 participants) were included. The overall quality of the evidence was moderate and limited to short-term interventions up to four months. Baseline mean weight and body mass index were 92.1kg and 36.6kg/m2 . Very-Low-Energy Diets of 400kcal/day led to 5.4% weight loss at two weeks, increasing to 17.9% at three months. More modest reductions of 7.3% were observed on Low-Energy Diets of 1200kcal/day and 2.0% on 1600kcal/day after three months. No clear patterns emerged for secondary outcomes. Publication bias was significant for primary outcomes. CONCLUSIONS: High-quality studies are required to support evidence-based Low- and Very-Low Energy prescription in people with type 2 diabetes. Available evidence would suggest variable reduction of body weight, ranging from 2% to 18%, after three months of Low- and Very-Low-Energy Diets

Use of Metformin and Cardiovascular Effects of New Classes of Glucose-Lowering Agents: A Meta-analysis of Cardiovascular Outcome Trials in Type 2 Diabetes

Over the last two decades, the large majority of clinical guidelines on the treatment of hyperglycaemia in subjects with type 2 diabetes have suggested metformin as the first-line glucose-lowering treatment alongside lifestyle changes to reach personalized glycemictargets. Recently, the European Society of Cardiology (ESC) recommended using glucagon-like peptide 1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors(SGLT-2is) as first line glucose-lowering therapy in subjects with type 2 diabetes at high or very high risk of cardiovascular disease (CVD), ahead of metformin treatment, to reduce cardiovascular events

Ethnic minorities and COVID-19: examining whether excess risk is mediated through deprivation

Background: people from South Asian and black minority ethnic groups are disproportionately affected by the COVID-19 pandemic. It is unknown whether deprivation mediates this excess ethnic risk.Methods: we used UK Biobank with linked COVID-19 outcomes occurring between 16th March 2020 and 24th August 2020. A four-way decomposition mediation analysis was used to model the extent to which the excess risk of testing positive, severe disease and mortality for COVID-19 in South Asian and black individuals, relative to white individuals, would be eliminated if levels of high material deprivation were reduced within the population.Results: we included 15 044 (53.0% women) South Asian and black and 392 786 (55.2% women) white individuals. There were 151 (1.0%) positive tests, 91 (0.6%) severe cases and 31 (0.2%) deaths due to COVID-19 in South Asian and black individuals compared with 1471 (0.4%), 895 (0.2%) and 313 (0.1%), respectively, in white individuals. Compared with white individuals, the relative risk of testing positive for COVID-19, developing severe disease and COVID-19 mortality in South Asian and black individuals were 2.73 (95% CI: 2.26, 3.19), 2.96 (2.31, 3.61) and 4.04 (2.54, 5.55), respectively. A hypothetical intervention moving the 25% most deprived in the population out of deprivation was modelled to eliminate between 40 and 50% of the excess risk of all COVID-19 outcomes in South Asian and black populations, whereas moving the 50% most deprived out of deprivation would eliminate over 80% of the excess risk of COVID-19 outcomes.Conclusions: the excess risk of COVID-19 outcomes in South Asian and black communities could be substantially reduced with population level policies targeting material deprivation

Efficacy and tolerability of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: A systematic review and network meta‐analysis

Aim: To compare the efficacy and tolerability of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with type 2 diabetes.Materials and methods: Electronic databases were searched from inception to 24th April 2019 for randomised controlled trials reporting change in glycated haemoglobin (HbA1c) at approximately 24 and/or 52 weeks for SGLT-2is and/or GLP-1RAs (classified as short- and long-acting). Bayesian network meta-analyses were conducted to compare within and between SGLT-2i and GLP-1RA classes for cardiometabolic efficacy and adverse events (PROSPERO registration number: CRD42018091306). Results: 64 trials (53 trials of 24 weeks; 7 trials of 52 weeks; 4 trials of both 24 and 52 weeks), comprising of 31,384 participants were identified. Compared to placebo, all treatments improved HbA1c. Long-acting GLP-1RAs reduced HbA1c compared to short-acting GLP-1RAs and SGLT-2 is, with semaglutide showing greater reduction compared to placebo (24 weeks: -1.49% (95% credible interval [CrI]: -1.76, -1.22), 52 weeks: -1.38% (-2.05, -0.71)) and all other treatments. Long-acting GLP-1RAs showed benefits in body weight and waist circumference reduction, while SGLT-2 is reduced blood pressure. SGLT-2is showed increased odds of genital infection in comparison to long-acting GLP-1RAs (odds ratio (95% CrI): 5.26 (1.45, 25.00)), while GLP-1RAs showed increased odds of diarrhoea in comparison to SGLT-2is (short-acting GLP-1RAs: 1.65 (1.09, 2.49), long-acting GLP-1RAs: 2.23 (1.51, 3.28)). No other differences were found between SGLT-2is and GLP-1RAs in adverse events. Conclusion: Long-acting GLP-1RAs showed superiority in reducing HbA1c levels, body weight and waist circumference. SGLT-2 is showed reductions in blood pressure levels. This review provide essential evidence to guide treatment recommendations in the management of type 2 diabetes<br

Ethnic minorities and COVID-19: Examining whether excess risk is mediated through deprivation.

BackgroundPeople from South Asian and black minority ethnic groups are disproportionately affected by the COVID-19 pandemic. It is unknown whether deprivation mediates this excess ethnic risk.MethodsWe used UK Biobank with linked COVID-19 outcomes occurring between 16th March 2020 and 24th August 2020. A four-way decomposition mediation analysis was used to model the extent to which the excess risk of testing positive, severe disease and mortality for COVID-19 in South Asian and black individuals, relative to white individuals, would be eliminated if levels of high material deprivation were reduced within the population.Results15,044 (53.0% women) South Asian and black and 392,786 (55.2% women) white individuals were included. There were 151 (1.0%) positive tests, 91 (0.6%) severe cases and 31 (0.2%) deaths due to COVID-19 in South Asian and black individuals compared to 1,471 (0.4%), 895 (0.2%) and 313 (0.1%), respectively, in white individuals. Compared to white individuals, the relative risk of testing positive for COVID-19, developing severe disease and COVID-19 mortality in South Asian and black individuals were 2.73 (95% CI: 2.26, 3.19), 2.96 (2.31, 3.61) and 4.04 (2.54, 5.55), respectively. A hypothetical intervention moving the 25% most deprived in the population out of deprivation was modelled to eliminate between 40-50% of the excess risk of all COVID-19 outcomes in South Asian and black populations, whereas moving the 50% most deprived out of deprivation would eliminate over 80% of the excess risk of COVID-19 outcomes.ConclusionsThe excess risk of COVID-19 outcomes in South Asian and black communities could be substantially reduced with population level policies targeting material deprivation