Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

AIMS: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. METHODS AND RESULTS: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). CONCLUSIONS: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

Putting More Weight on Obesity Trials in Heart Failure.

PURPOSE OF REVIEW: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. RECENT FINDINGS: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum.

Natriuretic Peptides and Prognosis in Patients with Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: Prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well known. METHODS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years follow-up for hospitalizations for HF (HHF), cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. RESULTS: Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. Incidence rate per 1000 patient-years for HHF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4 and 40.1; P<0.001) and without (1.8, 3.1, 6.0 and 19.1; P<0.001) HF, with significantly higher risk in patients with HF compared to those without (with HF: quartile 3 HR 9.28 [1.15, 75.05]; P=0.04; without HF: quartile-4 HR 4.86, [2.08, 11.35]; P<0.001). Similar higher risk for kidney events was seen in HF patients (with HF: quartile-4 HR 6.94, [2.66, 18.08]; P=0.001; without HF: quartile-4th HR 4.85 [3.02, 7.80]; P=0.001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general regardless of history of HF, however presence of a clinical diagnosis of HF at baseline was associated with incrementally higher risk particularly in higher NT-proBNP quartiles.

Insulin-like growth factor binding protein-7 concentrations in chronic heart failure: Results from the EMPEROR programme.

AIMS: Insulin-like growth factor binding protein-7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio-renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio-renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. METHODS AND RESULTS: IGFBP7 was measured in 1125 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher-risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28-3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61-13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 (p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. CONCLUSION: Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence-associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio-renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time.

Genetic evidence for distinct biological mechanisms that link adiposity to type 2 diabetes: towards precision medicine.

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We employed MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites and Magnetic Resonance Imaging-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size, enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data.

AIMS: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. METHODS: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS < 20) and average level (42-48 mmol/mol). RESULTS: An increased infection risk (IRR > 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. CONCLUSIONS: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal.

Ongoing burden and recent trends in severe hospitalised hypoglycaemia events in people with type 1 and type 2 diabetes in Scotland: A nationwide cohort study 2016-2022.

AIMS: We examined severe hospitalised hypoglycaemia (SHH) rates in people with type 1 and type 2 diabetes in Scotland during 2016-2022, stratifying by sociodemographics. METHODS: Using the Scottish National diabetes register (SCI-Diabetes), we identified people with type 1 and type 2 diabetes alive anytime during 2016-2022. SHH events were determined through linkage to hospital admission and death registry data. We calculated annual SHH rates overall and by age, sex, and socioeconomic status. Summary estimates of time and stratum effects were obtained by fitting adjusted generalised additive models using R package mgcv. RESULTS: Rates for those under 20 with type 1 diabetes reached their minimum at the 2020-2021 transition, 30% below the study period average. A gradual decline over time also occurred among 20-49-year-olds with type 1 diabetes. Overall, females had 15% higher rates than males with type 2 diabetes (rate ratio 1.15, 95% CI 1.08-1.22). People in the most versus least deprived quintile experienced 2.58 times higher rates (95% CI 2.27-2.93) in type 1 diabetes and 2.33 times higher (95% CI 2.08-2.62) in type 2 diabetes. CONCLUSIONS: Despite advances in care, SHH remains a significant problem in diabetes. Future efforts must address the large socioeconomic disparities in SHH risks.

Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.

PURPOSE OF REVIEW: Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. RECENT FINDINGS: High-dose once weekly injectable semaglutide (2.4 mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.

Carbohydrate antigen 125 concentrations across the ejection fraction spectrum in chronic heart failure: The EMPEROR programme.

AIM: Vascular congestion may lead to an increase of carbohydrate antigen 125 (CA-125). The role of CA-125 as a biomarker of congestion or for prognosis across the full ejection fraction (EF) spectrum of chronic heart failure (HF) remains unknown. METHODS AND RESULTS: Serum CA-125 was measured in 1111 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Congestive signs and symptoms were evaluated across CA-125 tertiles. Cox regression was used to study the association with outcomes. The primary outcome was a composite of first HF hospitalization or cardiovascular (CV) death. No significant association was present between baseline CA-125 levels and congestive signs or symptoms. In the overall population, higher CA-125 levels were not associated with an increased risk of primary outcome (tertile 3 vs. tertile 1: hazard ratio [HR] 1.34; 95% confidence interval [CI] 0.91-1.96; p-trend = 0.11). However, higher CA-125 levels were associated with an increased risk of primary outcome in patients with HF and reduced EF (HFrEF; tertile 3 vs. tertile 1: HR 2.25 [95% CI 1.30-3.89]), but not among patients with preserved EF (HFpEF; tertile 3 vs. tertile 1: HR 0.68 [95% CI 0.38-1.21]); interaction-p = 0.02). Patients in the upper CA-125 tertile also showed the steepest estimated glomerular filtration rate decline over time (p-trend = 0.03). The effect of empagliflozin to reduce the risk of CV death or HF hospitalization appeared to be attenuated in those with lower baseline CA-125 levels (interaction-p-trend = 0.09). CONCLUSION: Across the range of EF in patients with chronic HF enrolled in the EMPEROR trials, the majority of whom did not have clinical evidence of congestion, CA-125 concentrations were not significantly associated with congestive signs or symptoms. CA-125 concentrations may predict HF hospitalization/CV death in patients with HFrEF, but not those with HFpEF. CLINICAL TRIAL REGISTRATION: EMPEROR-Reduced (NCT03057977), EMPEROR-Preserved (NCT03057951).

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

AIMS: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes. MATERIALS AND METHODS: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank. RESULTS: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts. CONCLUSIONS: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation.

Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

AIMS/HYPOTHESIS: A precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA). METHODS: We designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events. RESULTS: Model development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications. CONCLUSIONS/INTERPRETATION: Precision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries.

Impact of Residential Social Deprivation on Prediction of Heart Failure in Patients With Type 2 Diabetes: External Validation and Recalibration of the WATCH-DM Score Using Real World Data.

BACKGROUND: Patients with type 2 diabetes are at risk of heart failure hospitalization. As social determinants of health are rarely included in risk models, we validated and recalibrated the WATCH-DM score in a diverse patient-group using their social deprivation index (SDI). METHODS: We identified US Veterans with type 2 diabetes without heart failure that received outpatient care during 2010 at Veterans Affairs medical centers nationwide, linked them to their SDI using residential ZIP codes and grouped them as SDI <20%, 21% to 40%, 41% to 60%, 61% to 80%, and >80% (higher values represent increased deprivation). Accounting for all-cause mortality, we obtained the incidence for heart failure hospitalization at 5 years follow-up; overall and in each SDI group. We evaluated the WATCH-DM score using the C statistic, the Greenwood Nam D'Agostino test χ2 test and calibration plots and further recalibrated the WATCH-DM score for each SDI group using a statistical correction factor. RESULTS: In 1 065 691 studied patients (mean age 67 years, 25% Black and 6% Hispanic patients), the 5-year incidence of heart failure hospitalization was 5.39%. In SDI group 1 (least deprived) and 5 (most deprived), the 5-year heart failure hospitalization was 3.18% and 11%, respectively. The score C statistic was 0.62; WATCH-DM systematically overestimated heart failure risk in SDI groups 1 to 2 (expected/observed ratios, 1.38 and 1.36, respectively) and underestimated the heart failure risk in groups 4 to 5 (expected/observed ratios, 0.95 and 0.80, respectively). Graphical evaluation demonstrated that the recalibration of WATCH-DM using an SDI group-based correction factor improved predictive capabilities as supported by reduction in the χ2 test results (801-27 in SDI groups I; 623-23 in SDI group V). CONCLUSIONS: Including social determinants of health to recalibrate the WATCH-DM score improved risk prediction highlighting the importance of including social determinants in future clinical risk prediction models.

5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study.

BACKGROUND: In DiRECT, a randomised controlled effectiveness trial, weight management intervention after 2 years resulted in mean weight loss of 7·6 kg, with 36% of participants in remission of type 2 diabetes. Of 36 in the intervention group who maintained over 10 kg weight loss at 2 years, 29 (81%) were in remission. Continued low-intensity dietary support was then offered up to 5 years from baseline to intervention participants, aiming to maintain weight loss and gain clinical benefits. This extension study was designed to provide observed outcomes at 5 years. METHODS: The DiRECT trial took place in primary care practices in the UK. Participants were individuals aged 20-65 years who had less than 6 years' duration of type 2 diabetes, a BMI greater than 27 kg/m2, and were not on insulin. The intervention consisted of withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. After sharing the 2-year results with all participants, UK National Health Service data were collected annually until year 5 from remaining intervention participants who received low-intensity dietary support, intervention withdrawals, and the original randomly allocated groups. The primary outcome was remission of type 2 diabetes; having established in the DiRECT trial that sustained weight loss was the dominant driver of remission, this was assumed for the Extension study. The trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2016, 149 participants were randomly assigned to the intervention group and 149 were assigned to the control group in the original DiRECT study. After 2 years, all intervention participants still in the trial (101 [68%] of 149) were approached to receive low-intensity support for a further 3 years. 95 (94%) of 101 were able to continue and consented and were allocated to the DiRECT extension group. 54 participants were allocated to the non-extension group, where intervention was withdrawn. At 5 years, DiRECT extension participants (n=85) lost an average of 6·1 kg, with 11 (13%) of 85 in remission. Compared with the non-extension group, DiRECT extension participants had more visits with HbA1c <48 mmol/mol (<6·5%; 36% vs 17%, p=0·0004), without glucose-lowering medication (62% vs 30%, p<0·0001), and in remission (34% vs 12%, p<0·0001). Original control participants (n=149) had mean weight loss 4·6 kg (n=82), and 5 (5%) of 93 were in remission. Compared with control participants, original intervention participants had more visits with weight more than 5% below baseline (61% vs 29%, p<0·0001), HbA1c below 48 mmol/mol (29% vs 15%, p=0·0002), without antidiabetic medication (51% vs 16%, p<0·0001), and in remission (27% vs 4%, p<0·0001). Of those in remission at year 2, 26% remained in remission at 5 years. Serious adverse events in the original intervention group (4·8 events per 100 patient-years) were under half those in the control group (10·2 per 100 patient-years, p=0·0080). INTERPRETATION: The extended DiRECT intervention was associated with greater aggregated and absolute weight loss, and suggested improved health status over 5 years. FUNDING: Diabetes UK.

Clinical outcomes and adverse events of bariatric surgery in adults with severe obesity in Scotland: the SCOTS observational cohort study.

Background: Bariatric surgery is a common procedure worldwide for the treatment of severe obesity and associated comorbid conditions but there is a lack of evidence as to medium-term safety and effectiveness outcomes in a United Kingdom setting. Objective: To establish the clinical outcomes and adverse events of different bariatric surgical procedures, their impact on quality of life and the effect on comorbidities. Design: Prospective observational cohort study. Setting: National Health Service secondary care and private practice in Scotland, United Kingdom. Participants: Adults (age >16 years) undergoing their first bariatric surgery procedure. Main outcome measures: Change in weight, hospital length of stay, readmission and reoperation rate, mortality, diabetes outcomes (HbA1c, medications), quality of life, anxiety, depression. Data sources: Patient-reported outcome measures, hospital records, national electronic health records (Scottish Morbidity Record 01, Scottish Care Information Diabetes, National Records Scotland, Prescription Information System). Results: Between December 2013 and February 2017, 548 eligible patients were approached and 445 participants were enrolled in the study. Of those, 335 had bariatric surgery and 1 withdrew from the study. Mean age was 46.0 (9.2) years, 74.7% were female and the median body mass index was 46.4 (42.4; 52.0) kg/m2. Weight was available for 128 participants at 3 years: mean change was -19.0% (±14.1) from the operation and -24.2% (±12.8) from the start of the preoperative weight-management programme. One hundred and thirty-nine (41.4%) participants were readmitted to hospital in the same or subsequent 35 months post surgery, 18 (5.4% of the operated cohort) had a reoperation or procedure considered to be related to bariatric surgery gastrointestinal complications or revisions. Fewer than five participants (<2%) died during follow-up. HbA1c was available for 93/182 and diabetes medications for 139/182 participants who had type 2 diabetes prior to surgery; HbA1c mean change was -5.72 (±16.71) (p = 0.001) mmol/mol and 65.5% required no diabetes medications (p < 0.001) at 3 years post surgery. Physical quality of life, available for 101/335 participants, improved in the 3 years post surgery, mean change in Rand 12-item Short Form Survey physical component score 8.32 (±8.95) (p < 0.001); however, there was no change in the prevalence of anxiety or depression. Limitations: Due to low numbers of bariatric surgery procedures in Scotland, recruitment was stopped before achieving the intended 2000 participants and follow-up was reduced from 10 years to 3 years. Conclusions: Bariatric surgery is a safe and effective treatment for obesity. Patients in Scotland, UK, appear to be older and have higher body mass than international comparators, which may be due to the small number of procedures performed. Future work: Intervention studies are required to identify the optimal pre- and post surgery pathway to maximise safety and cost-effectiveness. Study registration: This study is registered as ISRCTN47072588. Funding details: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 10/42/02) and is published in full in Health Technology Assessment; Vol. 28, No. 7. See the NIHR Funding and Awards website for further award information.

Bariatric surgery is performed on the stomach and small bowel to help people living with obesity lose weight. Our research study has looked at who is getting bariatric surgery, if they are having problems afterwards, how much weight they lose and if their medical conditions improve. A total of 444 people who were attending bariatric surgery services in Scotland, UK, agreed to take part and 336 had surgery. One hundred and eighty-nine of them completed a questionnaire before their surgery and 85 of them after 3 years, to tell us about how they were feeling physically and mentally. We looked at their computer hospital records to see how long they spent in hospital, any medical problems and changes to diabetes medicines and tests. One in five people taking part did not have surgery after all; they changed their mind or the hospital teams did not think it would be safe or work well for the patient. Those who had surgery lost 19% of their body weight and those with type 2 diabetes needed less or no medication 3 years after the surgery. The effect of physical symptoms on day-to-day activities improved but mental health did not. Compared to other countries, the people taking part were older, heavier and sicker. They spent longer in hospital after surgery and were more likely to be readmitted to hospital. How many appointments they had or what type of health professional they saw before or after surgery did not change these results. We had hoped to have far more people in this study and be able to answer more questions, but not enough people were getting bariatric surgery in Scotland for us to ask them to take part. Further research is needed to find the best ways to care for people living with obesity who would benefit from bariatric surgery.

Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.

BACKGROUND: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. METHOD: The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. RESULTS: At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30). CONCLUSIONS: People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. CLINICAL TRIAL: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791.

Gout and incidence of 12 cardiovascular diseases: a case-control study including 152 663 individuals with gout and 709 981 matched controls.

BACKGROUND: Gout, a common crystal arthropathy, is associated with increased risk of cardiovascular disease. We aimed to identify how this risk varies by individual cardiovascular disease across a broad spectrum of conditions. METHODS: In this matched case-control study, we used linked primary and secondary electronic health records from the UK Clinical Practice Research Datalink to assemble a cohort of individuals with a first-time diagnosis of gout between Jan 1, 2000 and Dec 31, 2017, who were aged 80 years or younger at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. The control cohort comprised up to five control individuals per patient with gout, matched on age, sex, socioeconomic status, geographical region, and calendar time, randomly selected among individuals free of gout at any time before and during the study period. The cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular diseases and used Cox proportional hazards models to examine differences in people with and without gout, overall and by subgroups of sex, age, socioeconomic status, and year of study inclusion. We further adjusted models for known cardiovascular risk factors (blood pressure, BMI, smoking status, cholesterol, type 2 diabetes, chronic kidney disease, and history of hypertension). FINDINGS: We identified 152 663 individuals with gout (mean age 56·2 years [SD 13·3]; 120 324 [78·8%] men and 32 339 [21·2%] women) and 709 981 matched controls (mean age 56·5 years [13·2]; 561 002 [79·0%] men and 148 979 [21·0%] women). Of these individuals, 31 479 (20·6%) with gout and 106 520 (15·0%) without gout developed cardiovascular disease during a median follow-up of 6·5 years (IQR 3·1-10·5). Patients with gout had higher risk of cardiovascular diseases than matched controls (hazard ratio [HR] 1·58 [95% CI 1·52-1·63]). Excess risk of cardiovascular disease in gout was greater in women than men (women: HR 1·88 [1·75-2·02]; men: HR 1·49 [1·43-1·56]), and, among all age groups, was highest in younger individuals (HR in people aged <45 years: 2·22 [1·92-2·57]). Excess risk was observed across all 12 cardiovascular diseases investigated. Patients with gout had higher BMI than matched controls (mean difference 2·90 kg/m2 [95% CI 2·87-2·93]) and higher prevalence of chronic kidney disease, dyslipidaemia, history of hypertension, obesity, and type 2 diabetes. Adjusting for known cardiovascular risk factors attenuated but did not eliminate the excess risk of cardiovascular disease related to gout (adjusted HR 1·31 [1·27-1·36]). INTERPRETATION: Patients with gout had an excess risk of developing a broad range of cardiovascular diseases that extend beyond atherosclerotic diseases and include heart failure, arrhythmias, valve disease, and thromboembolic diseases. Excess risk was highest in women and younger individuals. These findings suggest that strategies to reduce cardiovascular risk in patients with gout need to evolve and be implemented in clinical practice. FUNDING: Research Foundation Flanders.

Cardiovascular and Kidney Risks in Individuals With Type 2 Diabetes: Contemporary Understanding With Greater Emphasis on Excess Adiposity.

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways-e.g., hemodynamic, cellular overnutrition, and inflammatory-could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium-glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes.

Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization.

BACKGROUND: The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. METHODS: A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28-60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. RESULTS: Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. CONCLUSIONS: In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19.

In our study, we aimed to understand how socioeconomic factors impact recovery from COVID-19 following hospitalisation. We followed 252 patients, collecting health data and utilising advanced imaging techniques. We discovered that individuals from deprived areas experienced more severe health complications, reported worse quality of life, and required more specialist care. However, their clinical outcomes were not significantly different. This underscores that socioeconomic deprivation affects health recovery, underlining the need for tailored care for these individuals. Our findings emphasise the importance of considering socioeconomic factors in recovery plans post-COVID-19, potentially improving healthcare for those in deprived areas.

Epigenetic Contributions to Clinical Risk Prediction of Cardiovascular Disease.

BACKGROUND: Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort. METHODS: Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (ncases≥1274; ncontrols≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed. RESULTS: Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI (P<0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; P=3.7×10-3; 0.3% increase in C-statistic). CONCLUSIONS: EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.

Effectiveness of lifestyle interventions/culturally bespoke programmes in South Asian ethnic groups targeting weight loss for prevention and/or remission of type 2 diabetes: a systematic review and meta-analysis of intervention trials.

BACKGROUND: People from South Asian heritage are at high risk of type 2 diabetes, but there are limited specific strategies to prevent and manage this condition. The aim was to assess the effectiveness of culturally bespoke lifestyle programmes in South Asians that target weight loss for the prevention or remission of type 2 diabetes mellitus (T2DM). METHODS: We performed a systematic review and meta-analysis of intervention trials. PubMed, Scopus, MEDLINE (EBSCOhost), CINAHL, PsycINFO and CENTRAL were searched. Human intervention trials (randomised controlled trials and quasi-experimental) investigating the effect of lifestyle interventions on the prevention and remission of T2DM in South Asians were included. Studies including participants at risk of T2DM (prevention trials) and having the disease (remission trials) with duration ≥12 weeks were eligible. For prevention trials, the primary outcome was change in weight (kg) from baseline; for remission trials, it was decrease in HbA1c to non-diabetic levels (HbA1c ≤ 6.5%) without diabetes medications. Prevention trials were separated into (i) lifestyle modification advice and (ii) lifestyle modification advice including a supervised physical activity programme. RESULTS: Twenty-four trials were eligible (21 prevention trials and 3 remission trials). In T2DM prevention trials involving only lifestyle modification advice, the mean postintervention difference in weight between intervention and control groups was -0.65 kg (95% confidence interval [CI]: -1.04, -0.26; p = 0.01). Lifestyle modification advice including a physical activity programme was associated with greater decreases in weight: -1.13 kg (95% CI: -2.04, -0.21; p = 0.02). Fasting blood glucose levels were slightly lower in intervention groups for both intervention subtypes, although there was no significant change in HbA1c levels or 2-h plasma glucose levels. Diabetes remission trials showed potential acceptability but were limited in number and involved a small sample size, and some did not include a control group. CONCLUSIONS: In South Asians, lifestyle interventions for prevention of T2DM offer only modest impacts on weight and glucose control and will unlikely reduce diabetes incidence. Alternative lifestyle interventions co-designed with members of the communities and aimed at both prevention and remission of T2DM must be urgently considered. Systematic review registration number: PROSPERO CRD42022385174 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=385174.