Publications by authors named "Naveed Sattar"

942 Publications

Response by Lee et al to Letter Regarding Article, "Effect of Empagliflozin on Left Ventricular Volumes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure With Reduced Ejection Fraction (SUGAR-DM-HF)".

Circulation 2021 Jul 19;144(3):e40. Epub 2021 Jul 19.

Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.M.Y.L., J.J.V.M., P.S.J., M.C.P., N.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055067DOI Listing
July 2021

Association of sarcopenia with incident osteoporosis: a prospective study of 168,682 UK biobank participants.

J Cachexia Sarcopenia Muscle 2021 Jul 15. Epub 2021 Jul 15.

British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Sarcopenia often co-occurs with osteoporosis in cross-sectional studies. However, this association has rarely been studied in prospective studies. This study aimed to investigate the association between sarcopenia categories-along with its individual components-and incident osteoporosis in both middle-aged and older men and women from the UK Biobank study.

Methods: A total of 168,682 participants (48.8% women, aged 37 to 70 years at baseline) were included in this prospective study. Categories of sarcopenia (pre-sarcopenia and sarcopenia), and its individual components, were defined according to the EWGSOP2 criteria (2019). Associations with incident osteoporosis by sex were investigated using Cox-proportional hazard models adjusted for socio-demographic, lifestyle and health-related factors, and morbidity count. Associations between categories of sarcopenia and incident osteoporosis were also investigated by age-groups and subtype of osteoporosis (with and without pathological fractures).

Results: After a median follow-up of 7.4 years, 6296 participants were diagnosed with osteoporosis. When the analyses were adjusted for a range of relevant confounding factors, pre-sarcopenia was associated with 1.3-times higher risk of osteoporosis in men (HR: 1.30 [95% CI: 1.03 to 1.63]) but not in women, and sarcopenia was associated with 1.66-times increased osteoporosis risk in women (HR: 1.66 [95% CI: 1.33 to 2.08]) but not in men compared with people without sarcopenia or pre-sarcopenia. A similar magnitude of associations was found in osteoporosis without pathological fractures but weaker for those with pathological fractures. Within the individual components, low muscle mass (HR : 1.36 [95% CI: 1.22 to 1.51] and HR : 3.07 [95% CI: 1.68 to 5.59]), followed by slow gait speed (HR : 1.30 [95% CI: 1.17 to 1.45] and HR : 1.70 [95% CI: 1.43 to 2.02]), were associated with a higher risk of incident osteoporosis in both sexes. Low grip strength was associated with a higher risk of incident osteoporosis in men (HR: 1.38 [95% CI: 1.15 to 1.65]), but not in women. No significant interaction between the exposures and incident osteoporosis by age groups were identified.

Conclusions: Our findings demonstrated that pre-sarcopenic men and sarcopenic women had a higher risk of developing osteoporosis even after adjustment for a large range of potential confounders. Considering that sarcopenia could be prevented, health interventions to improve physical capability may delay or prevent the onset of osteoporosis.
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http://dx.doi.org/10.1002/jcsm.12757DOI Listing
July 2021

Rising Rates and Widening Socioeconomic Disparities in Diabetic Ketoacidosis in Type 1 Diabetes in Scotland: A Nationwide Retrospective Cohort Observational Study.

Diabetes Care 2021 Jul 8. Epub 2021 Jul 8.

Royal Infirmary of Edinburgh, National Health Service Lothian, Edinburgh, U.K.

Objective: Whether advances in the management of type 1 diabetes are reducing rates of diabetic ketoacidosis (DKA) is unclear. We investigated time trends in DKA rates in a national cohort of individuals with type 1 diabetes monitored for 14 years, overall and by socioeconomic characteristics.

Research Design And Methods: All individuals in Scotland with type 1 diabetes who were alive and at least 1 year old between 1 January 2004 and 31 December 2018 were identified using the national register ( = 37,939). DKA deaths and hospital admissions were obtained through linkage to Scottish national death and morbidity records. Bayesian regression was used to test for DKA time trends and association with risk markers, including socioeconomic deprivation.

Results: There were 30,427 DKA admissions and 472 DKA deaths observed over 393,223 person-years at risk. DKA event rates increased over the study period (incidence rate ratio [IRR] per year 1.058 [95% credibility interval 1.054-1.061]). Males had lower rates than females (IRR male-to-female 0.814 [0.776-0.855]). DKA incidence rose in all age-groups other than 10- to 19-year-olds, in whom rates were the highest, but fell over the study. There was a large socioeconomic differential (IRR least-to-most deprived quintile 0.446 [0.406-0.490]), which increased during follow-up. Insulin pump use or completion of structured education were associated with lower DKA rates, and antidepressant and methadone prescription were associated with higher DKA rates.

Conclusions: DKA incidence has risen since 2004, except in 10- to 19-year-olds. Of particular concern are the strong and widening socioeconomic disparities in DKA outcomes. Efforts to prevent DKA, especially in vulnerable groups, require strengthening.
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http://dx.doi.org/10.2337/dc21-0689DOI Listing
July 2021

Remote history of VTE is associated with severe COVID-19 in middle and older age: UK Biobank cohort study.

J Thromb Haemost 2021 Jul 9. Epub 2021 Jul 9.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Background: Venous thromboembolism (VTE) is a common, life-threatening complication of COVID-19 infection. COVID-19 risk-prediction models include a history of VTE. However, it is unclear whether remote history (>9 years previously) of VTE also confers increased risk of COVID-19.

Objectives: To investigate possible association between VTE and COVID-19 severity, independent of other risk factors.

Methods: Cohort study of UK Biobank participants recruited between 2006 and 2010. Baseline data, including history of VTE, were linked to COVID-19 test results, COVID-19-related hospital admissions, and COVID-19 deaths. The risk of COVID-19 hospitalization or death was compared for participants with a remote history VTE versus without. Poisson regression models were run univariately then adjusted stepwise for sociodemographic, lifestyle, and comorbid covariates.

Results: After adjustment for sociodemographic and lifestyle confounders and comorbid conditions, remote history of VTE was associated with nonfatal community (RR 1.61, 95% CI 1.02-2.54, p = .039), nonfatal hospitalized (RR 1.52, 95% CI 1.06-2.17, p = .024) and severe (hospitalized or fatal) (RR 1.40, 95% CI 1.04-1.89, p = .025) COVID-19. Associations with remote history of VTE were stronger among men (severe COVID-19: RR 1.68, 95% CI 1.14-2.42, p = .009) than for women (severe COVID-19: RR 1.07, 95% CI 0.66-1.74, p = .786).

Conclusion: Our findings support inclusion of remote history of VTE in COVID-19 risk-prediction scores, and consideration of sex-specific risk scores.
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http://dx.doi.org/10.1111/jth.15452DOI Listing
July 2021

Sex Differences in Cardiac Troponin I and T and the Prediction of Cardiovascular Events in the General Population.

Clin Chem 2021 Jul 8. Epub 2021 Jul 8.

Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.

Background: Cardiac troponin concentrations differ in women and men, but how this influences risk prediction and whether a sex-specific approach is required is unclear. We evaluated whether sex influences the predictive ability of cardiac troponin I and T for cardiovascular events in the general population.

Methods: High-sensitivity cardiac troponin (hs-cTn) I and T were measured in the Generation Scotland Scottish Family Health Study of randomly selected volunteers drawn from the general population between 2006 and 2011. Cox-regression models evaluated associations between hs-cTnI and hs-cTnT and the primary outcome of cardiovascular death, myocardial infarction, or stroke.

Results: In 19 501 (58% women, mean age 47 years) participants, the primary outcome occurred in 2.7% (306/11 375) of women and 5.1% (411/8126) of men during the median follow-up period of 7.9 (IQR , 7.1-9.2) years. Cardiac troponin I and T concentrations were lower in women than men (P < 0.001 for both), and both were more strongly associated with cardiovascular events in women than men. For example, at a hs-cTnI concentration of 10 ng/L, the hazard ratio relative to the limit of blank was 9.7 (95% CI 7.6-12.4) and 5.6 (95% CI 4.7-6.6) for women and men, respectively. The hazard ratio for hs-cTnT at a concentration of 10 ng/L relative to the limit of blank was 3.7 (95% CI 3.1-4.3) and 2.2 (95% CI 2.0-2.5) for women and men, respectively.

Conclusions: Cardiac troponin concentrations differ in women and men and are stronger predictors of cardiovascular events in women. Sex-specific approaches are required to provide equivalent risk prediction.
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http://dx.doi.org/10.1093/clinchem/hvab109DOI Listing
July 2021

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes.

N Engl J Med 2021 Jun 28. Epub 2021 Jun 28.

From the Population Health Research Institute, Hamilton Health Sciences (H.C.G., C.R., L.H., L.D.), and McMaster University (H.C.G.) - both in Hamilton, ON, Canada; the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (N.S.); the Dallas Diabetes Research Center at Medical City, Dallas (J.R.); AdventHealth Translational Research Institute, Orlando, FL (R.P.); Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.); National Heart Centre Singapore and Duke-National University of Singapore, Singapore (C.S.P.L.); Sanofi, Bridgewater, NJ (N.S.K.); the Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy (S.D.P.); and the Division of Cardiology, University of Washington, Seattle (K.B.).

Background: Four glucagon-like peptide-1 (GLP-1) receptor agonists that are structurally similar to human GLP-1 have been shown to reduce the risk of adverse cardiovascular events among persons with type 2 diabetes. The effect of an exendin-based GLP-1 receptor agonist, efpeglenatide, on cardiovascular and renal outcomes in patients with type 2 diabetes who are also at high risk for adverse cardiovascular events is uncertain.

Methods: In this randomized, placebo-controlled trial conducted at 344 sites across 28 countries, we evaluated efpeglenatide in participants with type 2 diabetes and either a history of cardiovascular disease or current kidney disease (defined as an estimated glomerular filtration rate of 25.0 to 59.9 ml per minute per 1.73 m of body-surface area) plus at least one other cardiovascular risk factor. Participants were randomly assigned in a 1:1:1 ratio to receive weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg or placebo. Randomization was stratified according to use of sodium-glucose cotransporter 2 inhibitors. The primary outcome was the first major adverse cardiovascular event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes).

Results: A total of 4076 participants were enrolled; 2717 were assigned to receive efpeglenatide and 1359 to receive placebo. During a median follow-up of 1.81 years, an incident MACE occurred in 189 participants (7.0%) assigned to receive efpeglenatide (3.9 events per 100 person-years) and 125 participants (9.2%) assigned to receive placebo (5.3 events per 100 person-years) (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P<0.001 for noninferiority; P = 0.007 for superiority). A composite renal outcome event (a decrease in kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (hazard ratio, 0.68; 95% CI, 0.57 to 0.79; P<0.001). Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than with placebo.

Conclusions: In this trial involving participants with type 2 diabetes who had either a history of cardiovascular disease or current kidney disease plus at least one other cardiovascular risk factor, the risk of cardiovascular events was lower among those who received weekly subcutaneous injections of efpeglenatide at a dose of 4 or 6 mg than among those who received placebo. (Funded by Sanofi; AMPLITUDE-O ClinicalTrials.gov number, NCT03496298.).
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http://dx.doi.org/10.1056/NEJMoa2108269DOI Listing
June 2021

Impact of nutraceuticals on markers of systemic inflammation: Potential relevance to cardiovascular diseases - A position paper from the International Lipid Expert Panel (ILEP).

Prog Cardiovasc Dis 2021 Jun 27. Epub 2021 Jun 27.

Department of Hypertension, Medical University of Lodz (MUL), Lodz, Poland; Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland. Electronic address:

Inflammation is a marker of arterial disease stemming from cholesterol-dependent to -independent molecular mechanisms. In recent years, the role of inflammation in atherogenesis has been underpinned by pharmacological approaches targeting systemic inflammation that have led to a significant reduction in cardiovascular disease (CVD) risk. Although the use of nutraceuticals to prevent CVD has largely focused on lipid-lowering (e.g, red-yeast rice and omega-3 fatty acids), there is growing interest and need, especially now in the time of coronavirus pandemic, in the use of nutraceuticals to reduce inflammatory markers, and potentially the inflammatory CVD burden, however, there is still not enough evidence to confirm this. Indeed, diet is an important lifestyle determinant of health and can influence both systemic and vascular inflammation, to varying extents, according to the individual nutraceutical constituents. Thus, the aim of this Position Paper is to provide the first attempt at recommendations on the use of nutraceuticals with effective anti-inflammatory properties.
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http://dx.doi.org/10.1016/j.pcad.2021.06.010DOI Listing
June 2021

Ethnic differences in guideline-indicated statin initiation for people with type 2 diabetes in UK primary care, 2006-2019: A cohort study.

PLoS Med 2021 Jun 29;18(6):e1003672. Epub 2021 Jun 29.

University College London, London, United Kingdom.

Background: Type 2 diabetes is 2-3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes.

Methods And Findings: Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people (n/N [%]: 605/1,142 [53%] and 18,803/27,511 [68%], respectively; age- and gender-adjusted HR 0.67 [95% CI 0.60 to 0.76], p < 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 [95% CI 0.69 to 0.85], p < 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 [95% CI 0.68, 0.85], p < 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 [62%] and 18,803/27,511 [68%], respectively; fully adjusted HR 0.91 [95% CI 0.85 to 0.98], p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data.

Conclusions: In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.
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http://dx.doi.org/10.1371/journal.pmed.1003672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241069PMC
June 2021

Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

Eur Heart J 2021 Jun 29. Epub 2021 Jun 29.

Baylor University Medical Center, 3500 Gaston Ave, Dallas, TX 75246, USA.

Aims: The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.

Methods And Results: Of 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%.

Conclusions: There were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.
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http://dx.doi.org/10.1093/eurheartj/ehab360DOI Listing
June 2021

Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: A Cohort Study of Nearly 500,000 Individuals.

Circulation 2021 Jun 25. Epub 2021 Jun 25.

Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.

Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A simple AAA risk score was derived and compared to current guidelines used for ultrasound screening of AAA. UK Biobank participants without previous AAA were split into a derivation cohort (n=401,820, 54.6% women, mean age 56.4 years, 95.5% white race) and validation cohort (n=83,816). Incident AAA was defined as first hospital inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modelled. Discrimination of the risk score was compared to a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines. In the derivation cohort there were 1,570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and cholesterol lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the validation cohort, over ten years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI 0.678, 0.733). The C-index of the risk score as a continuous variable was 0.856 (95%CI 0.837-0.878). In the validation cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk score yielded sensitivity 82.1% and specificity 70.7%, while also improving the net reclassification index (NRI) compared to the USPSTF model +0.176 (95%CI 0.120, 0.232). A combined model, whereby risk scoring was combined with the USPSTF model, also improved prediction compared to USPSTF alone (NRI +0.101, 95%CI 0.055, 0.147). In an asymptomatic general population, a risk score based on patient age, height, weight and medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation of risk scores to detect asymptomatic AAA is needed.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.053022DOI Listing
June 2021

Association of statin use in older people primary prevention group with risk of cardiovascular events and mortality: a systematic review and meta-analysis of observational studies.

BMC Med 2021 Jun 22;19(1):139. Epub 2021 Jun 22.

Head Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz (MUL), Lodz, Poland.

Background: Current evidence from randomized controlled trials on statins for primary prevention of cardiovascular disease (CVD) in older people, especially those aged > 75 years, is still lacking. We conducted a systematic review and meta-analysis of observational studies to extend the current evidence about the association of statin use in older people primary prevention group with risk of CVD and mortality.

Methods: PubMed, Scopus, and Embase were searched from inception until March 18, 2021. We included observational studies (cohort or nested case-control) that compared statin use vs non-use for primary prevention of CVD in older people aged ≥ 65 years; provided that each of them reported the risk estimate on at least one of the following primary outcomes: all cause-mortality, CVD death, myocardial infarction (MI), and stroke. Risk estimates of each relevant outcome were pooled as a hazard ratio (HR) with a 95% confidence interval (CI) using the random-effects meta-analysis model. The quality of the evidence was rated using the GRADE approach.

Results: Ten observational studies (9 cohorts and one case-control study; n = 815,667) fulfilled our criteria. The overall combined estimate suggested that statin therapy was associated with a significantly lower risk of all-cause mortality (HR: 0.86 [95% CI 0.79 to 0.93]), CVD death (HR: 0.80 [95% CI 0.78 to 0.81]), and stroke (HR: 0.85 [95% CI 0.76 to 0.94]) and a non-significant association with risk of MI (HR 0.74 [95% CI 0.53 to 1.02]). The beneficial association of statins with the risk of all-cause mortality remained significant even at higher ages (> 75 years old; HR 0.88 [95% CI 0.81 to 0.96]) and in both men (HR: 0.75 [95% CI: 0.74 to 0.76]) and women (HR 0.85 [95% CI 0.72 to 0.99]). However, this association with the risk of all-cause mortality remained significant only in those with diabetes mellitus (DM) (HR 0.82 [95% CI 0.68 to 0.98]) but not in those without DM. The level of evidence of all the primary outcomes was rated as "very low."

Conclusions: Statin therapy in older people (aged ≥ 65 years) without CVD was associated with a 14%, 20%, and 15% lower risk of all-cause mortality, CVD death, and stroke, respectively. The beneficial association with the risk of all-cause mortality remained significant even at higher ages (> 75 years old), in both men and women, and in individuals with DM, but not in those without DM. These observational findings support the need for trials to test the benefits of statins in those above 75 years of age.
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http://dx.doi.org/10.1186/s12916-021-02009-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218529PMC
June 2021

Are people with metabolically healthy obesity really healthy? A prospective cohort study of 381,363 UK Biobank participants.

Diabetologia 2021 Jun 10. Epub 2021 Jun 10.

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Aims/hypothesis: People with obesity and a normal metabolic profile are sometimes referred to as having 'metabolically healthy obesity' (MHO). However, whether this group of individuals are actually 'healthy' is uncertain. This study aims to examine the associations of MHO with a wide range of obesity-related outcomes.

Methods: This is a population-based prospective cohort study of 381,363 UK Biobank participants with a median follow-up of 11.2 years. MHO was defined as having a BMI ≥ 30 kg/m and at least four of the six metabolically healthy criteria. Outcomes included incident diabetes and incident and fatal atherosclerotic CVD (ASCVD), heart failure (HF) and respiratory diseases.

Results: Compared with people who were not obese at baseline, those with MHO had higher incident HF (HR 1.60; 95% CI 1.45, 1.75) and respiratory disease (HR 1.20; 95% CI 1.16, 1.25) rates, but not higher ASCVD. The associations of MHO were generally weaker for fatal outcomes and only significant for all-cause (HR 1.12; 95% CI 1.04, 1.21) and HF mortality rates (HR 1.44; 95% CI 1.09, 1.89). However, when compared with people who were metabolically healthy without obesity, participants with MHO had higher rates of incident diabetes (HR 4.32; 95% CI 3.83, 4.89), ASCVD (HR 1.18; 95% CI 1.10, 1.27), HF (HR 1.76; 95% CI 1.61, 1.92), respiratory diseases (HR 1.28; 95% CI 1.24, 1.33) and all-cause mortality (HR 1.22; 95% CI 1.14, 1.31). The results with a 5 year landmark analysis were similar.

Conclusions/interpretation: Weight management should be recommended to all people with obesity, irrespective of their metabolic status, to lower risk of diabetes, ASCVD, HF and respiratory diseases. The term 'MHO' should be avoided as it is misleading and different strategies for risk stratification should be explored.
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http://dx.doi.org/10.1007/s00125-021-05484-6DOI Listing
June 2021

Development and validation of a cardiovascular risk prediction model in type 1 diabetes.

Diabetologia 2021 Jun 9. Epub 2021 Jun 9.

Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.

Aims/hypothesis: We aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes.

Methods: A cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., ≥10%) using the model with the percentage eligible for statins using current guidelines by age.

Results: The age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer-Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic from 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and ≥ 60 years, respectively (all p values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those ≥40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD ≥10% in 10 years.

Conclusions/interpretation: A prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention, the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.
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http://dx.doi.org/10.1007/s00125-021-05478-4DOI Listing
June 2021

Meal-induced inflammation: postprandial insights from the Personalised REsponses to DIetary Composition Trial (PREDICT) study in 1000 participants.

Am J Clin Nutr 2021 Jun 8. Epub 2021 Jun 8.

Department of Nutritional Sciences, King's College London, London, United Kingdom.

Background: Meal-induced metabolic changes trigger an acute inflammatory response, contributing to chronic inflammation and associated diseases.

Objectives: We aimed to characterize variability in postprandial inflammatory responses using traditional (IL-6) and novel [glycoprotein acetylation (GlycA)] biomarkers of inflammation and dissect their biological determinants with a focus on postprandial glycemia and lipemia.

Methods: Postprandial (0-6 h) glucose, triglyceride (TG), IL-6, and GlycA responses were measured at multiple intervals after sequential mixed-nutrient meals (0 h and 4 h) in 1002 healthy adults aged 18-65 y from the PREDICT (Personalised REsponses to DIetary Composition Trial) 1 study, a single-arm dietary intervention study. Measures of habitual diet, blood biochemistry, gut microbiome composition, and visceral fat mass (VFM) were also collected.

Results: The postprandial changes in GlycA and IL-6 concentrations were highly variable between individuals. Participants eliciting an increase in GlycA and IL-6 (60% and 94% of the total participants, respectively) had mean 6-h increases of 11% and 190%, respectively. Peak postprandial TG and glucose concentrations were significantly associated with 6-h GlycA (r = 0.83 and r = 0.24, respectively; both P < 0.001) but not with 6-h IL-6 (both P > 0.26). A random forest model revealed the maximum TG concentration was the strongest postprandial TG predictor of postprandial GlycA and structural equation modeling revealed that VFM and fasting TG were most strongly associated with fasting and postprandial GlycA. Network Mendelian randomization demonstrated a causal link between VFM and fasting GlycA, mediated (28%) by fasting TG. Individuals eliciting enhanced GlycA responses had higher predicted cardiovascular disease risk (using the atherosclerotic disease risk score) than the rest of the cohort.

Conclusions: The variable postprandial increases in GlycA and their associations with TG metabolism highlight the importance of modulating TG in concert with obesity to reduce GlycA and associated low-grade inflammation-related diseases.This trial was registered at clinicaltrials.gov as NCT03479866.
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http://dx.doi.org/10.1093/ajcn/nqab132DOI Listing
June 2021

Effect of the phosphodiesterase 4 inhibitor apremilast on cardiometabolic outcomes in psoriatic disease-results of the IMAPA study.

Rheumatology (Oxford) 2021 Jun 7. Epub 2021 Jun 7.

Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, UK.

Objectives: Studies have suggested phosphodiesterase 4 (PDE4) inhibition may be associated with weight loss and other cardiometabolic benefits. We evaluated the effect of the PDE4 inhibitor apremilast on body weight and composition, glucose homeostasis, lipid profiles, and vascular function in psoriatic disease, and whether weight change correlated with therapeutic response.

Methods: We conducted a prospective, open label study (Immune Metabolic Associations in Psoriatic Arthritis, IMAPA) of adults receiving apremilast 30 mg as part of routine care for psoriatic arthritis and/or psoriasis. Cardiometabolic, anthropometric, and disease activity assessments were performed at baseline (pre-apremilast) and at months 1, 3, and 6 of apremilast treatment in 60 patients. A subgroup underwent further assessment of endothelial function, body composition, and adipocyte morphology.

Results: In patients (median age 54.5 years, 63% women, median BMI 33.2 kg/m2) apremilast was associated with a mean weight loss of 2.2 kg (95% CI 1.4-3.0 kg, p< 0.001) and mean BMI decrease of 0.8 kg/m2 (95% CI 0.5-1.2 kg/m2, p< 0.001) after 6 months treatment. Body composition analysis demonstrated a reduction in total abdominal fat (mean decrease 0.52 L, 95% CI 0.08-0.96L, p= 0.022), principally subcutaneous adipose tissue (mean decrease 0.37 L, 95% CI 0.05-0.68L, p= 0.022). There was no change in adipocyte diameter, HbA1c, lipid, GLP-1, or vascular function. Psoriatic disease activity improved with apremilast, although this was not correlated with weight change.

Conclusion: Following apremilast treatment, we observed weight loss, principally abdominal subcutaneous fat, and improvement in psoriatic disease activity. The latter was independent of weight change, suggesting apremilast likely acts through direct immunological mechanisms.
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http://dx.doi.org/10.1093/rheumatology/keab474DOI Listing
June 2021

Levothyroxine Treatment and Cardiovascular Outcomes in Older People With Subclinical Hypothyroidism: Pooled Individual Results of Two Randomised Controlled Trials.

Front Endocrinol (Lausanne) 2021 20;12:674841. Epub 2021 May 20.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.

Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).

Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.

Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.

Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.

Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age.

Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+).
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http://dx.doi.org/10.3389/fendo.2021.674841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173189PMC
May 2021

Type 2 Diabetes, Metabolic Traits, and Risk of Heart Failure: A Mendelian Randomization Study.

Diabetes Care 2021 Jun 4. Epub 2021 Jun 4.

Medical Research Council Population Health Research Unit, University of Oxford, Oxford, U.K.

Objective: The aim of this study was to use Mendelian randomization (MR) techniques to estimate the causal relationships between genetic liability to type 2 diabetes (T2D), glycemic traits, and risk of heart failure (HF).

Research Design And Methods: Summary-level data were obtained from genome-wide association studies of T2D, insulin resistance (IR), glycated hemoglobin, fasting insulin and glucose, and HF. MR was conducted using the inverse-variance weighted method. Sensitivity analyses included the MR-Egger method, weighted median and mode methods, and multivariable MR conditioning on potential mediators.

Results: Genetic liability to T2D was causally related to higher risk of HF (odds ratio [OR] 1.13 per 1-log unit higher risk of T2D; 95% CI 1.11-1.14; < 0.001); however, sensitivity analysis revealed evidence of directional pleiotropy. The relationship between T2D and HF was attenuated when adjusted for coronary disease, BMI, LDL cholesterol, and blood pressure in multivariable MR. Genetically instrumented higher IR was associated with higher risk of HF (OR 1.19 per 1-log unit higher risk of IR; 95% CI 1.00-1.41; = 0.041). There were no notable associations identified between fasting insulin, glucose, or glycated hemoglobin and risk of HF. Genetic liability to HF was causally linked to higher risk of T2D (OR 1.49; 95% CI 1.01-2.19; = 0.042), although again with evidence of pleiotropy.

Conclusions: These findings suggest a possible causal role of T2D and IR in HF etiology, although the presence of both bidirectional effects and directional pleiotropy highlights potential sources of bias that must be considered.
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http://dx.doi.org/10.2337/dc20-2518DOI Listing
June 2021

Cohort profile: National Diabetes Audit for England and Wales.

Diabet Med 2021 Jun 1:e14616. Epub 2021 Jun 1.

Diabetes UK, London, UK.

The National Diabetes Audit (NDA) collates and analyses data on the quality and variation in clinical care and outcomes for people with diabetes. It also provides opportunities to assess trends, determinants, and outcomes of diabetes to help guide clinical and public health priorities.

Cohort: Between 1 January 2003 and 31 March 2020, a total of 5,280,885 people diagnosed with diabetes were included in at least one NDA data collection. To this date, median follow-up was 12 and 8 years for people with type 1 diabetes and type 2 diabetes respectively. Comparisons with the 2019/20 Quality and Outcomes Framework show it included 98% of adults in England and Wales with diagnosed type 1 and type 2 diabetes. Data include demographic characteristics (age, sex, ethnicity, age at diagnosis, deprivation), risk factors (HbA , blood pressure, cholesterol, body mass index, smoking status) diabetic and cardiovascular complications and deaths.

Secondary Analysis: Secondary analyses have included comparisons of HbA and blood pressure measurements in cohorts with similar characteristics to the Epidemiology of Diabetes Interventions and Complications study and the UK Prospective Diabetes Study; COVID-19 related mortality in people with type 1 and type 2 diabetes and incidence of type 2 diabetes following admission to intensive care units.

Future Plans: Commissioned NDA reports will continue to inform service development in England and Wales. The same data, with or without linkages to other external datasets, are also a rich resource for clinically orientated research.
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http://dx.doi.org/10.1111/dme.14616DOI Listing
June 2021

Comparison between data-driven clusters and models based on clinical features to predict outcomes in type 2 diabetes: nationwide observational study.

Diabetologia 2021 May 31. Epub 2021 May 31.

Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

Aims/hypothesis: Research using data-driven cluster analysis has proposed five novel subgroups of diabetes based on six measured variables in individuals with newly diagnosed diabetes. Our aim was (1) to validate the existence of differing clusters within type 2 diabetes, and (2) to compare the cluster method with an alternative strategy based on traditional methods to predict diabetes outcomes.

Methods: We used data from the Swedish National Diabetes Register and included 114,231 individuals with newly diagnosed type 2 diabetes. k-means clustering was used to identify clusters based on nine continuous variables (age at diagnosis, HbA, BMI, systolic and diastolic BP, LDL- and HDL-cholesterol, triacylglycerol and eGFR). The elbow method was used to determine the optimal number of clusters and Cox regression models were used to evaluate mortality risk and risk of CVD events. The prediction models were compared using concordance statistics.

Results: The elbow plot, with values of k ranging from 1 to 10, showed a smooth curve without any clear cut-off points, making the optimal value of k unclear. The appearance of the plot was very similar to the elbow plot made from a simulated dataset consisting only of one cluster. In prediction models for mortality, concordance was 0.63 (95% CI 0.63, 0.64) for two clusters, 0.66 (95% CI 0.65, 0.66) for four clusters, 0.77 (95% CI 0.76, 0.77) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with smoothing splines. In prediction models for CVD events, the concordance was 0.64 (95% CI 0.63, 0.65) for two clusters, 0.66 (95% CI 0.65, 0.67) for four clusters, 0.77 (95% CI 0.77, 0.78) for the ordinary Cox model and 0.78 (95% CI 0.77, 0.78) for the Cox model with splines for all variables.

Conclusions/interpretation: This nationwide observational study found no evidence supporting the existence of a specific number of distinct clusters within type 2 diabetes. The results from this study suggest that a prediction model approach using simple clinical features to predict risk of diabetes complications would be more useful than a cluster sub-stratification.
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http://dx.doi.org/10.1007/s00125-021-05485-5DOI Listing
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Trajectories in HbA1c and other risk factors among adults with type 1 diabetes by age at onset.

BMJ Open Diabetes Res Care 2021 05;9(1)

Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg, Västra Götaland, Sweden

Introduction: In type 1 diabetes, potential loss of life-years is greatest in those who are youngest at the time of onset. Using data from a nationwide cohort of patients with type 1 diabetes, we aimed to study risk factor trajectories by age at diagnosis.

Research Design And Methods: We stratified 30 005 patients with type 1 diabetes aged 18-75 years into categories based on age at onset: 0-10, 11-15, 16-20, 21-25, and 26-30 years. HbA1c, albuminuria, estimated glomerular filtration rate (eGFR), body mass index (BMI), low-denisty lipoprotein (LDL)-cholesterol, systolic blood pressure (SBP), and diastolic blood pressure trends were analyzed using mixed models. Variable importance for baseline HbA1c was analyzed using conditional random forest and gradient boosting machine approaches.

Results: Individuals aged ≥16 years at onset displayed a relatively low mean HbA1c level (~55-57 mmol/mol) that gradually increased. In contrast, individuals diagnosed at ≤15 years old entered adulthood with a mean HbA1c of approximately 70 mmol/mol. For all groups, HbA1c levels stabilized at a mean of approximately 65 mmol/mol by about 40 years old. In patients who were young at the time of onset, albuminuria appeared at an earlier age, suggesting a more rapid decrease in eGFR, while there were no distinct differences in BMI, SBP, and LDL-cholesterol trajectories between groups. Low education, higher age, and poor risk factor control were associated with higher HbA1c levels.

Conclusions: Young age at the diabetes onset plays a substantial role in subsequent glycemic control and the presence of albuminuria, where patients with early onset may accrue a substantial glycemic load during this period.
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http://dx.doi.org/10.1136/bmjdrc-2021-002187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169495PMC
May 2021

Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT).

Diabetologia 2021 May 31. Epub 2021 May 31.

Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.

Aims/hypothesis: Our aim was to evaluate the safety and efficacy of a planned therapeutic withdrawal of all antihypertensive and diuretic medications, on commencing a formula low-energy diet replacement, targeting remission of type 2 diabetes.

Methods: Post hoc analysis of changes in BP, antihypertensive medication prescriptions and symptoms during the initial total diet replacement phase was performed in the intervention arm of the Diabetes Remission Clinical Trial (n = 143) and in the subset (n = 69) who discontinued antihypertensive medications at the start of total diet replacement. The Counterweight-Plus total diet replacement provided about 3470 kJ/day (830 kcal) with automatic reductions in all nutrients, including sodium, to achieve marked negative energy balance and rapid weight loss over 12-20 weeks, with regular BP monitoring and an antihypertensive reintroduction protocol based on current clinical guidelines.

Results: Of 143 intervention group participants who commenced total diet replacement, 78 (55%) were on treatment for hypertension at baseline. The overall mean BP fell significantly from the start of total diet replacement (week 1) and was significantly lower at week 20, after total diet replacement finished, and also at 12 and 24 months. Of the 78 participants previously on treatment for hypertension, 65 (83%) stopped all antihypertensive and diuretic medications as per protocol, and four (5%) stopped some drugs. These 69 participants experienced no immediate (within the first week) change in BP, but their mean BP fell significantly from 9 weeks. No excessive rises in BP were recorded in individuals, but antihypertensive medications were reintroduced during total diet replacement to manage raised BP for 19/69 (27.5%) participants, mostly within the first 3-7 weeks, despite some weight loss. Reintroduction of antihypertensive medications was necessary for 5/19 participants previously on one drug, and for 14/19 previously on two or more drugs. Of the 69 who stopped antihypertensives, 19 (28%) remained off medications at 24 months. Among the 53 participants who achieved sustained remissions of diabetes at 24 months (with a mean weight loss of 11.4 kg), 31 had been previously treated for hypertension. Twenty-seven stopped medication at baseline, and 15/27 required reintroduction of antihypertensive medications. Mild to moderate dizziness, suggesting some postural hypotension, was reported during total diet replacement by 51 participants, 15 of whom had recorded dizziness at baseline prior to starting total diet replacement, with nine of these on antihypertensive or diuretic medications.

Conclusions/interpretation: Replacing antihypertensive medications with a 3470 kJ/day (830 kcal) diet to induce weight loss reduces BP substantially and may increase mild dizziness. It is safe to stop antihypertensives, but BP should be monitored regularly, particularly for those taking two or more antihypertensives, as over two-thirds will require reintroduction of some medications. Long-term support to maintain weight loss is vital.

Trial Registration: ISRCTN registry, number 03267836.
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http://dx.doi.org/10.1007/s00125-021-05471-xDOI Listing
May 2021

Targeted metabolomic profiling and prediction of cardiovascular events: a prospective study of patients with psoriatic arthritis and psoriasis.

Ann Rheum Dis 2021 May 28. Epub 2021 May 28.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada

Objective: In patients with psoriatic disease (PsD), we sought serum metabolites associated with cardiovascular (CV) events and investigated whether they could improve CV risk prediction beyond traditional risk factors and the Framingham Risk Score (FRS).

Methods: Nuclear magnetic resonance metabolomics identified biomarkers for incident CV events in patients with PsD. The association of each metabolite with incident CV events was analysed using Cox proportional hazards regression models first adjusted for age and sex, and subsequently for traditional CV risk factors. Variable selection was performed using penalisation with boosting after adjusting for age and sex, and the FRS.

Results: Among 977 patients with PsD, 70 patients had incident CV events. In Cox regression models adjusted for CV risk factors, alanine, tyrosine, degree of unsaturation of fatty acids and high-density lipoprotein particles were associated with decreased CV risk. Glycoprotein acetyls, apolipoprotein B and cholesterol remnants were associated with increased CV risk. The age-adjusted and sex-adjusted expanded model with 13 metabolites significantly improved prediction of CV events beyond the model with age and sex alone, with an area under the receiver operator characteristic curve (AUC) of 79.9 versus 72.6, respectively (p=0.02). Compared with the FRS alone (AUC=73.9), the FRS-adjusted expanded model with 11 metabolites (AUC=75.0, p=0.72) did not improve CV risk discrimination.

Conclusions: We identify novel metabolites associated with the development of CV events in patients with PsD. Further study of their underlying causal role may clarify important pathways leading to CV events in this population.
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http://dx.doi.org/10.1136/annrheumdis-2021-220168DOI Listing
May 2021

Ramadan fasting: recommendations for patients with cardiovascular disease.

Heart 2021 May 14. Epub 2021 May 14.

Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, UK

Ramadan fasting is observed by most of the 1.8 billion Muslims around the world. It lasts for 1 month per the lunar calendar year and is the abstention from any food and drink from dawn to sunset. While recommendations on 'safe' fasting exist for patients with some chronic conditions, such as diabetes mellitus, guidance for patients with cardiovascular disease is lacking. We reviewed the literature to help healthcare professionals educate, discuss and manage patients with cardiovascular conditions, who are considering fasting. Studies on the safety of Ramadan fasting in patients with cardiac disease are sparse, observational, of small sample size and have short follow-up. Using expert consensus and a recognised framework, we risk stratified patients into 'low or moderate risk', for example, stable angina or non-severe heart failure; 'high risk', for example, poorly controlled arrhythmias or recent myocardial infarction; and 'very high risk', for example, advanced heart failure. The 'low-moderate risk' group may fast, provided their medications and clinical conditions allow. The 'high' or 'very high risk' groups should not fast and may consider safe alternatives such as non-consecutive fasts or fasting shorter days, for example, during winter. All patients who are fasting should be educated before Ramadan on their risk and management (including the risk of dehydration, fluid overload and terminating the fast if they become unwell) and reviewed after Ramadan to reassess their risk status and condition. Further studies to clarify the benefits and risks of fasting on the cardiovascular system in patients with different cardiovascular conditions should help refine these recommendations.
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http://dx.doi.org/10.1136/heartjnl-2021-319273DOI Listing
May 2021

Severe COVID-19 in people with type 1 and type 2 diabetes in Sweden: A nationwide retrospective cohort study.

Lancet Reg Health Eur 2021 May 30;4:100105. Epub 2021 Apr 30.

Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sweden.

Background: Whether infection with SARS-CoV-2 leads to excess risk of requiring hospitalization or intensive care in persons with diabetes has not been reported, nor have risk factors in diabetes associated with increased risk for these outcomes.

Methods: We included 44,639 and 411,976 adult patients with type 1 and type 2 diabetes alive on Jan 1, 2020, and compared them to controls matched for age, sex, and county of residence (n=204,919 and 1,948,900). Age- and sex-standardized rates for COVID-19 related hospitalizations, admissions to intensive care and death, were estimated and hazard ratios were calculated using Cox regression analyses.

Findings: There were 10,486 hospitalizations and 1,416 admissions into intensive care. A total of 1,175 patients with diabetes and 1,820 matched controls died from COVID-19, of these 53•2% had been hospitalized and 10•7% had been in intensive care. Patients with type 2 diabetes, compared to controls, displayed an age- and sex-adjusted hazard ratio (HR) of 2•22, 95%CI 2•13-2•32) of being hospitalized for COVID-19, which decreased to HR 1•40, 95%CI 1•34-1•47) after further adjustment for sociodemographic factors, pharmacological treatment and comorbidities, had higher risk for admission to ICU due to COVID-19 (age- and sex-adjusted HR 2•49, 95%CI 2•22-2•79, decreasing to 1•42, 95%CI 1•25-1•62 after adjustment, and increased risk for death due to COVID-19 (age- and sex-adjusted HR 2•19, 95%CI 2•03-2•36, complete adjustment 1•50, 95%CI 1•39-1•63). Age- and sex-adjusted HR for COVID-19 hospitalization for type 1 diabetes was 2•10, 95%CI 1•72-2•57), decreasing to 1•25, 95%CI 0•3097-1•62) after adjustment• Patients with diabetes type 1 were twice as likely to require intensive care for COVID-19, however, not after adjustment (HR 1•49, 95%CI 0•75-2•92), and more likely to die (HR 2•90, 95% CI 1•6554-5•47) from COVID-19, but not independently of other factors (HR 1•38, 95% CI 0•64-2•99). Among patients with diabetes, elevated glycated hemoglobin levels were associated with higher risk for most outcomes.

Interpretation: In this nationwide study, type 2 diabetes was independently associated with increased risk of hospitalization, admission to intensive care and death for COVID-19. There were few admissions into intensive care and deaths in type 1 diabetes, and although hazards were significantly raised for all three outcomes, there was no independent risk persisting after adjustment for confounding factors.
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http://dx.doi.org/10.1016/j.lanepe.2021.100105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086507PMC
May 2021

Genome-wide association study of cardiac troponin I in the general population.

Hum Mol Genet 2021 May 7. Epub 2021 May 7.

Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes is unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI and HF development in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
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http://dx.doi.org/10.1093/hmg/ddab124DOI Listing
May 2021

More Evidence for 5-a-Day for Fruit and Vegetables and a Greater Need for Translating Dietary Research Evidence to Practice.

Circulation 2021 Apr 26;143(17):1655-1658. Epub 2021 Apr 26.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, United Kingdom (N.G.F.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053293DOI Listing
April 2021

Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England.

Lancet Diabetes Endocrinol 2021 05 30;9(5):293-303. Epub 2021 Mar 30.

National Diabetes Audit Programme, NHS England & Improvement, London, UK; NHS England and NHS Improvement, London, UK; Department of Diabetes and Endocrinology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK; Division of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.

Background: In patients with type 2 diabetes, hyperglycaemia is an independent risk factor for COVID-19-related mortality. Associations between pre-infection prescription for glucose-lowering drugs and COVID-19-related mortality in people with type 2 diabetes have been postulated but only investigated in small studies and limited to a few agents. We investigated whether there are associations between prescription of different classes of glucose-lowering drugs and risk of COVID-19-related mortality in people with type 2 diabetes.

Methods: This was a nationwide observational cohort study done with data from the National Diabetes Audit for people with type 2 diabetes and registered with a general practice in England since 2003. Cox regression was used to estimate the hazard ratio (HR) of COVID-19-related mortality in people prescribed each class of glucose-lowering drug, with covariate adjustment with a propensity score to address confounding by demographic, socioeconomic, and clinical factors.

Findings: Among the 2 851 465 people with type 2 diabetes included in our analyses, 13 479 (0·5%) COVID-19-related deaths occurred during the study period (Feb 16 to Aug 31, 2020), corresponding to a rate of 8·9 per 1000 person-years (95% CI 8·7-9·0). The adjusted HR associated with recorded versus no recorded prescription was 0·77 (95% CI 0·73-0·81) for metformin and 1·42 (1·35-1·49) for insulin. Adjusted HRs for prescription of other individual classes of glucose-lowering treatment were as follows: 0·75 (0·48-1·17) for meglitinides, 0·82 (0·74-0·91) for SGLT2 inhibitors, 0·94 (0·82-1·07) for thiazolidinediones, 0·94 (0·89-0·99) for sulfonylureas, 0·94 (0·83-1·07) for GLP-1 receptor agonists, 1·07 (1·01-1·13) for DPP-4 inhibitors, and 1·26 (0·76-2·09) for α-glucosidase inhibitors.

Interpretation: Our results provide evidence of associations between prescription of some glucose-lowering drugs and COVID-19-related mortality, although the differences in risk are small and these findings are likely to be due to confounding by indication, in view of the use of different drug classes at different stages of type 2 diabetes disease progression. In the context of the COVID-19 pandemic, there is no clear indication to change prescribing of glucose-lowering drugs in people with type 2 diabetes.

Funding: None.
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http://dx.doi.org/10.1016/S2213-8587(21)00050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009618PMC
May 2021

Can biomarkers help find the 'sweet spot' for treating patients with diabetes?

Eur J Heart Fail 2021 Jun 13;23(6):1037-1039. Epub 2021 Apr 13.

Massachusetts General Hospital, Harvard Medical School, and Baim Institute for Clinical Research, Boston, MA, USA.

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http://dx.doi.org/10.1002/ejhf.2175DOI Listing
June 2021