A cross-sectional time series of cardiometabolic health education format preferences across sociodemographic groups.

AIMS: Health education is integral to cardiometabolic disease (CMD) management. This study aimed to assess whether and how education preferences have changed over time, and whether trends differ by sociodemographic characteristics (education status, age, ethnicity, and sex). METHODS: A cross-sectional questionnaire was deployed across five counties in the East Midlands, UK between 2017 and 2022 to adults with CMD (type 2 diabetes, cardiovascular disease or cerebrovascular disease). Respondent demographic data were collected alongside health education preferences. Statistical analyses ascertained whether demographic characteristics influenced preferences. The distribution of preferences over time was charted to identify trends. RESULTS: A total of 4301 eligible responses were collected. Face-to-face one-to-one education was preferred (first choice for 75.1% of participants) but popularity waned over the five-year period. Trends were similar amongst demographic groups. Online education showed a U-shaped trend: In 2017, 44% of respondents ranked it as acceptable, peaking at 53% in 2019, but declining again, to below base line, 43%, by 2022. This modality was more popular with participants aged younger than 65 years, but popularity in people older than 65 years increased over the study period. The popularity of printed information also declined over time across all demographic groups except those of South Asian ethnicity, for whom it remained static. CONCLUSIONS: The overwhelming preference for face-to-face one-to-one health education from a doctor or nurse highlights the importance of preserving access to this modality, even in the face of current NHS pressures and trends towards digitalisation. Trends are changing, and should continue to be monitored, including between different sociodemographic groups.

Greater hepatic lipid saturation is associated with impaired glycaemic regulation in men with metabolic dysfunction-associated steatotic liver disease but is not altered by 6 weeks of exercise training.

AIMS: To examine the impact of impaired glycaemic regulation (IGR) and exercise training on hepatic lipid composition in men with metabolic dysfunction-associated steatotic liver disease (MASLD). MATERIALS AND METHODS: In Part A (cross-sectional design), 40 men with MASLD (liver proton density fat fraction [PDFF] ≥5.56%) were recruited to one of two groups: (1) normal glycaemic regulation (NGR) group (glycated haemoglobin [HbA1c] < 42 mmol∙mol-1 [<6.0%]; n = 14) or (2) IGR group (HbA1c ≥ 42 mmol∙mol-1 [≥6.0%]; n = 26). In Part B (randomized controlled trial design), participants in the IGR group were randomized to one of two 6-week interventions: (1) exercise training (EX; 70%-75% maximum heart rate; four sessions/week; n = 13) or (2) non-exercise control (CON; n = 13). Saturated (SI; primary outcome), unsaturated (UI) and polyunsaturated (PUI) hepatic lipid indices were determined using proton magnetic resonance spectroscopy. Additional secondary outcomes included liver PDFF, HbA1c, fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA-IR), peak oxygen uptake (VO2 peak), and plasma cytokeratin-18 (CK18) M65, among others. RESULTS: In Part A, hepatic SI was higher and hepatic UI was lower in the IGR versus the NGR group (p = 0.038), and this hepatic lipid profile was associated with higher HbA1c levels, FPG levels, HOMA-IR and plasma CK18 M65 levels (rs ≥0.320). In Part B, hepatic lipid composition and liver PDFF were unchanged after EX versus CON (p ≥ 0.257), while FPG was reduced and VO2 peak was increased (p ≤ 0.030). ΔVO2 peak was inversely associated with Δhepatic SI (r = -0.433) and positively associated with Δhepatic UI and Δhepatic PUI (r ≥ 0.433). CONCLUSIONS: Impaired glycaemic regulation in MASLD is characterized by greater hepatic lipid saturation; however, this composition is not altered by 6 weeks of moderate-intensity exercise training.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Footwear fit as a causal factor in diabetes-related foot ulceration: A systematic review.

AIMS: Incorrectly fitting footwear (IFF) poses a risk of trauma to at-risk feet with diabetes. The aim of this systematic review was to summarise and assess the evidence that IFF is a statistically significant cause of ulceration. METHODS: We searched PubMed, Scopus, Web of Science and Google Scholar for English-language peer-reviewed studies reporting the number or percentage of people with diabetes-related foot ulceration (DFU) attributed to wearing IFF and included a physical examination of the footwear worn. Two independent reviewers assessed the risk of bias using the Newcastle-Ottawa scale. RESULTS: 4318 results were retrieved excluding duplicates with 45 studies shortlisted. Ten studies met the inclusion criteria with most rated as fair (n = 6) or good (n = 3). There is some evidence that DFU is significantly associated with IFF, but this is limited: only 3 of 10 included studies found a statistically significant percentage of those with DFU were wearing IFF or inappropriate footwear which included fastening, material, type or fit (15.0%-93.3%). Risk of bias in these three studies ranged from 'fair' to 'poor'. IFF definitions were often unreported or heterogeneous. Only one study reported IFF-related ulcer sites: 70% were at plantar hallux/toes and 10% at plantar metatarsal heads. CONCLUSIONS: There is some evidence that IFF is a cause of DFU, but further research is needed, which defines IFF, and methodically records footwear assessment, ulcer location and physical activity. Researchers need to uncover why IFF is worn and if this is due to economic factors, a need for footwear education or other reasons.

Characterization of Turner Syndrome-associated diabetes mellitus.

CONTEXT: Diabetes mellitus (DM) risk factors in Turner Syndrome (TS) may include autoimmunity, obesity, beta-cell dysfunction, genetic predisposition and insulin resistance (IR). OBJECTIVE: Evaluate glucose tolerance and DM risk factors in adults with TS. DESIGN: A single centre study with two phases. To determine the prevalence of DM and to assess diabetes risk markers comparing women with TS with and without impaired glucose tolerance (IGT). SETTING: Tertiary referral center, University College Hospitals. PATIENTS: 106 Women with TS (age range 18-70 years) undergoing annual health surveillance. INTERVENTIONS: Participants underwent oral glucose tolerance tests (OGTT), with additional samples for autoimmunity and genetic analysis. MAIN OUTCOME MEASURE: Glucose tolerance, insulin, autoimmune and single nucleotide polymorphism (SNP) profile. RESULTS: OGTT screening showed that those without a previous DM diagnosis, 72.7% had normal glucose tolerance, 19.5% had IGT, and 7.6% were newly diagnosed with DM. OGTT identified more cases of DM than HbAc1 sampling alone. Women with IGT or DM were older, with higher body mass index and IR. No association was found between autoimmune markers GAD, IA-2 and ZnT8, risk karyotypes or selected SNPs and DM. In DM cases, GAD positivity was associated with requirement for insulin therapy. The median age of onset of the diagnosis of DM was 36 years (range 11-56). CONCLUSIONS: In the spectrum of DM subtypes, TS-associated DM lies between type 1 and type 2 DM with features of both. Key factors include weight and IR. Assessing C-peptide or GAD antibodies may aid future insulin requirement.

Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.

BACKGROUND: More women than men have heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program. METHODS: In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes. RESULTS: Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).

Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.

BACKGROUND: In the Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) program, semaglutide improved heart failure (HF)-related symptoms, physical limitations, and exercise function, and reduced bodyweight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Whether semaglutide improves functional status, as assessed by NYHA functional class, is unknown. OBJECTIVES: The goal of this study was to examine the effects of semaglutide on change in NYHA functional class over time. We also investigated the effects of semaglutide on HF-related symptoms, physical limitations, and bodyweight and other trial endpoints across baseline NYHA functional class categories. METHODS: This was a prespecified analysis of pooled data from 2 international, double-blind, randomized trials (STEP-HFpEF and STEP-HFpEF type 2 diabetes [STEP-HFpEF DM], comprising the STEP-HFpEF program), which collectively randomized 1,145 participants with obesity-related HFpEF to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The outcome of interest for this analysis was the change in NYHA functional class (baseline to 52 weeks). We also investigated the effects of semaglutide on the dual primary, confirmatory secondary, and selected exploratory endpoints according to baseline NYHA functional class. RESULTS: More semaglutide-treated than placebo-treated patients had an improvement in NYHA functional class (32.6% vs 21.5%, respectively; OR: 2.20 [95% CI: 1.62-2.99; P < 0.001]) and fewer semaglutide-treated patients experienced deterioration in NYHA functional class (2.09% vs 5.24%, respectively; OR: 0.36 [95% CI: 0.19-0.70; P = 0.003]) at 52 weeks. Semaglutide (vs placebo) improved the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CCS) across NYHA functional class categories; this was especially pronounced in those in NYHA functional classes III/IV (10.5 points [95% CI: 6.6-14.4 points]) vs NYHA functional class II (6.0 points [95% CI: 3.4-8.6 points]) (P interaction = 0.06). By contrast, the degree of reduction in bodyweight was similar with semaglutide vs placebo regardless of baseline NYHA functional class category (NYHA functional class II, -8.4% [95% CI: -9.4% to -7.3%]; NYHA functional classes III/IV, -8.3% [95% CI: -9.9% to -6.8%]; P interaction = 0.96). Semaglutide consistently improved 6-minute walking distance (6MWD), the hierarchical composite endpoint (death, HF events, differences in KCCQ-CSS, and 6MWD changes), and reduced C-reactive protein and N-terminal prohormone of brain natriuretic peptide across NYHA functional class categories (all P interactions = NS). CONCLUSIONS: In patients with obesity-related HFpEF, fewer semaglutide-treated than placebo-treated patients had a deterioration, and more had an improvement, in NYHA functional class at 52 weeks. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories. Semaglutide-mediated improvements in health status were especially large in patients with NYHA functional classes III/IV. (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure and Obesity; NCT04788511) (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes; NCT04916470).

Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. AREAS COVERED: Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. EXPERT OPINION: We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

BACKGROUND: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP. METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP. RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21). CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Sarcopenia prevalence using handgrip strength or chair stand performance in adults living with type 2 diabetes mellitus.

BACKGROUND: The updated European Working Group on Sarcopenia in Older People (EWGSOP2) recommends handgrip strength (HGS) and the chair stand test (CST) to assess muscle strength, with the CST being a convenient proxy for lower limb strength. However, adiposity may differentially influence these strength criteria and produce discrepant sarcopenia prevalence. OBJECTIVE: To determine the prevalence of sarcopenia using HGS or the CST, and to investigate the associations between these strength criteria and adiposity in adults with type 2 diabetes mellitus. METHODS: The EWGSOP2 definition was used to assess the prevalence of probable (low muscle strength), confirmed (plus low muscle mass) and severe (plus poor physical performance) sarcopenia. Linear regression models were used to study the association between different measures of muscle strength and adiposity. RESULTS: We used data from 732 adults with type 2 diabetes mellitus (35.7% female, aged 64 ± 8 years, body mass index 30.7 ± 5.0 kg/m2). Using the CST compared with HGS produced a higher prevalence of probable (31.7% vs. 7.1%), confirmed (5.6% vs. 1.6%) and severe (1.0% vs. 0.3%) sarcopenia, with poor agreement between strength criteria to identify probable sarcopenia. CST performance, but not HGS, was significantly associated with all measures of adiposity in unadjusted and adjusted models. CONCLUSIONS: Higher levels of adiposity may impact CST performance, but not HGS, resulting in a higher prevalence of sarcopenia in adults with type 2 diabetes mellitus. Consideration should be paid to the most appropriate measure of muscle function in this population.

Recommended measurement instruments for genitourinary symptoms associated with menopause: the COMMA (Core outcomes in menopause) consortium.

OBJECTIVE: The aim of the study is to identify appropriate definitions and patient-reported outcome measures (PROMs) for each of the eight core outcomes previously selected for genitourinary symptoms associated with menopause: pain with sex, vulvovaginal dryness, vulvovaginal discomfort or irritation, discomfort or pain when urinating, change in most bothersome symptom, distress, bother or interference of genitourinary symptoms, satisfaction with treatment, and side effects. METHODS: We conducted a systematic review to identify possible definitions and PROMs, including their measurement properties. Identified definitions and relevant PROMs with acceptable measurement properties were entered into an international consensus process involving 28 participants from 10 countries to achieve final recommendations for each core outcome. RESULTS: A total of 87 publications reporting on 34 PROMs were identified from 21,207 publications screened. Of these 34 PROMs, 29 were not considered to sufficiently map onto the core outcomes, and 26 of these also had insufficient measurement properties. Therefore, only five PROMs corresponding to two core outcomes were considered for recommendation. We recommend the PROMIS Scale v2.0 - Sexual Function and Satisfaction: Vaginal Discomfort with Sexual Activity to measure the outcome of "pain with sexual activity" and the Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire to measure "distress, bother or interference" from genitourinary symptoms. Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events in study participants, which is a requirement of Good Clinical Practice. CONCLUSIONS: Suitable PROMs and definitions were identified to measure three of eight core outcomes. Because of the lack of existing measures, which align with the core outcomes and have evidence of high-quality measurement properties, future work will focus on developing or validating PROMs for the remaining five core outcomes.

Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial.

Background: An effective prescribing pathway for liraglutide 3 mg, an approved obesity pharmacotherapy, may improve treatment access. This trial compared a targeted prescribing pathway for liraglutide 3 mg with multiple stopping rules in specialist weight management services (SWMS) to standard SWMS care. Methods: This phase four, two-year, multicentre, open-label, parallel-group, real-world randomized clinical trial (ClinicalTrials.gov: NCT03036800) enrolled adults with BMI ≥35 kg/m2 plus prediabetes, type 2 diabetes, hypertension or sleep apnoea from five SWMS in Ireland and UK. Participants were randomly allocated (2:1, stratified by centre and BMI) to SWMS care plus a targeted prescribing pathway for once daily subcutaneous liraglutide 3 mg (intervention) with stopping rules at 16 (≥5% weight loss, WL), 32 (≥10% WL) and 52 weeks (≥15% WL) or to SWMS care alone (control) through an online randomization service. The primary outcome was WL ≥15% at 52 weeks, assessed by complete cases analysis. All randomized participants were included in safety analysis. Findings: From November 28, 2017 to February 28, 2020, 434 participants were screened, and 392 randomized (260 intervention; 132 control), while 294 (201 intervention; 93 control) included in the 52 weeks complete case analysis. More intervention than control participants achieved WL ≥15% at 52 weeks [51/201 (25.4%) vs 6/93 (6.5%); odds ratio 5.18; 95% CI 2.09, 12.88; p < 0.0001]. More adverse events occurred in the intervention (238/260, 91.5%; two deaths) than control (89/132, 67.4%; no deaths) group. Interpretation: A targeted prescribing pathway for liraglutide 3 mg helps more people achieve ≥15% WL at 52 weeks than standard care alone. Funding: Novo Nordisk A/S.

Fertility and pregnancy outcomes in women with Turner syndrome: A single centre experience.

OBJECTIVE: Many women with Turner syndrome (TS) will consider fertility options and pregnancy. We wished to examine the fertility and pregnancy outcomes in women with TS undergoing oocyte donation (OD) treatment or spontaneous pregnancy in a large single-centre cohort. General population reference data or data from those with idiopathic premature ovarian insufficiency were used as comparators. DESIGN: A retrospective single-centre cross-sectional study. PATIENTS AND MEASUREMENTS: Seventy-four women with TS underwent OD treatment with a total of 105 pregnancies, and 31 women with TS had 71 spontaneous conceptions. Fertility outcomes included clinical pregnancy and live birth rate. Pregnancy outcomes included miscarriage rate, prevalence of hypertension, gestational diabetes, lower segment caesarean section (LSCS), small for gestational age (SGA), prematurity and vertical transmission of TS. RESULTS: In those with TS, OD pregnancies were associated with increased rates of LSCS and SGA compared to spontaneous pregnancies; LSCS (OR: 4.19, 95% CI: 1.6-10.8, p = .003) and SGA (OR: 2.92, 95% CI: 1.02-8.38, p = .04). There were no recorded cardiac events but 5 (17.2%) cases of vertical transmissions of TS in daughters were identified. OD in those with TS was associated with a lower live birth rate per cycle started (OR: 0.53, 95% CI: 0.34-0.84, p = .008) and a higher rate of miscarriage compared to women with POI (40% vs. 26.2%, p = .04). CONCLUSIONS: We show that pregnancy in women with TS, whether OD or spontaneously conceived, carries obstetric risks, and therefore, women with TS, considering pregnancy, should receive comprehensive pre-pregnancy counselling and optimal obstetric care.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Association of ethnicity and socioeconomic status with health outcomes in women with gestational diabetes: Clinical practice research datalink cohort study.

AIMS: To investigate in women with prior gestational diabetes mellitus (GDM), differences by ethnicity and socioeconomic status in the incidence of recurrent GDM, type 2 diabetes (T2D), hypertension, and depression. METHODS: This was a retrospective cohort study including 10,868 women diagnosed with GDM in the Clinical Practice Research Datalink (CPRD GOLD) between January 01, 2000 and November 05, 2018. Linked data were obtained for Hospital Episode Statistics and the Index of Multiple Deprivation. We estimated incidence rates and hazard ratios, by ethnicity and socioeconomic status. RESULTS: During a follow-up of 58,479 person years (mean (SD): 5.38 (3.67) years), the crude incidence was 9.67 (95 % confidence interval: 9.30-10.00) per 100 person years for recurrent GDM, 3.86 (3.70-4.02) for depression, 2.15 (2.03-2.27) for T2D and 0.89 (0.81-0.97) for hypertension. South Asian ethnicity was associated with an increased risk of T2D compared to White (adjusted hazard ratio: 1.65; 1.34-2.05) and Black ethnicity was associated with a greater risk of hypertension (2.93; 1.93-4.46). Black and South Asian ethnicity were associated with a reduced risk of depression compared to White: 0.23 (0.13-0.39) and 0.37 (0.29-0.46), respectively. Incidence rates were higher for all conditions with increasing deprivation level. CONCLUSIONS: The risk of health complications in women with a prior history of GDM differs by ethnicity and socio-economic status, suggesting the opportunity for targeted assessment in the years following pregnancy. These findings may inform future guidelines on screening for health outcomes in women with GDM.

Early-Onset Type 2 Diabetes and Tirzepatide Treatment: A Post Hoc Analysis From the SURPASS Clinical Trial Program.

OBJECTIVE: We evaluated baseline characteristics of participants with early-onset type 2 diabetes (T2D) from the SURPASS program and tirzepatide's effects on glycemic control, body weight (BW), and cardiometabolic markers. RESEARCH DESIGN AND METHODS: This post hoc analysis compared baseline characteristics and changes in mean HbA1c, BW, waist circumference (WC), lipids, and blood pressure (BP) in 3,792 participants with early-onset versus later-onset T2D at week 40 (A Study of Tirzepatide [LY3298176] in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone [SURPASS-1] and A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes [SURPASS-2]) or week 52 (A Study of Tirzepatide [LY3298176] Versus Insulin Degludec in Participants With Type 2 Diabetes [SURPASS-3]). Analyses were performed by study on data from participants while on assigned treatment without rescue medication in case of persistent hyperglycemia. RESULTS: At baseline in SURPASS-2, participants with early-onset versus later-onset T2D were younger with longer diabetes duration (9 vs. 7 years, P < 0.001) higher glycemic levels (8.5% vs. 8.2%, P < 0.001), higher BW (97 vs. 93 kg, P < 0.001) and BMI (35 vs. 34 kg/m2, P < 0.001), and a similarly abnormal lipid profile (e.g., triglycerides 167 vs. 156 mg/dL). At week 40, similar improvements in HbA1c (-2.6% vs. -2.4%), BW (-14 vs. -13 kg), WC (-10 vs. -10 cm), triglycerides (-26% vs. -24%), HDL (7% vs. 7%), and systolic BP (-6 vs. -7 mmHg) were observed in both subgroups with tirzepatide. CONCLUSIONS: Despite younger age, participants with early-onset T2D from the SURPASS program had higher glycemic levels and worse overall metabolic health at baseline versus those with later-onset T2D. In this post hoc analysis, similar improvements in HbA1c, BW, and cardiometabolic markers were observed with tirzepatide, irrespective of age at T2D diagnosis. Future studies are needed to determine long-term outcomes of tirzepatide in early-onset T2D.

Recommended measurement instruments for menopausal vasomotor symptoms: the COMMA (Core Outcomes in Menopause) consortium.

OBJECTIVE: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects. METHODS: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome. RESULTS: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice. CONCLUSIONS: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes.

Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).