Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m-2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .

Weight loss in adult male Wistar rats by Roux-en-Y gastric bypass is primarily explained by caloric intake reduction and presurgery body weight.

Diets varying in macronutrient composition, energy density, and/or palatability may cause differences in outcome of bariatric surgery. In the present study, rats feeding a healthy low-fat (LF) diet or an obesogenic high-fat/sucrose diet (HF/S) were either subjected to Roux-en-Y gastric bypass surgery (RYGB) or sham surgery, and weight loss trajectories and various energy balance parameters were assessed. Before RYGB, rats eating an HF/S (n = 14) diet increased body weight relative to rats eating an LF diet (n = 20; P < 0.01). After RYGB, absolute weight loss was larger in HF/S (n = 6) relative to LF feeding (n = 6) rats, and this was associated with reduced cumulative energy intake (EI; P < 0.05) and increased locomotor activity (LA; P < 0.05-0.001), finally leading to similar levels of reduced body fat content in HF/S and LF rats 3 wk after surgery. Regression analysis revealed that variation in RYGB-induced body weight loss was best explained by models including 1) postoperative cumulative EI and preoperative body weight (R2 = 0.87) and 2) postoperative cumulative EI and diet (R2 = 0.79), each without significant contribution of LA. Particularly rats on the LF diet became transiently more hypothermic and circadianally arrhythmic following RYGB (i.e., indicators of surgery-associated malaise) than HF/S feeding rats. Our data suggest that relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery, yet it promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.NEW & NOTEWORTHY Relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery in rats. Relative to feeding an LF diet, continued feeding an HF/S diet promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.

Measuring Small Bowel Length in Bariatric Surgery: An Ex Vivo Laparoscopic Training Experiment.

INTRODUCTION: Determining limb length in gastric bypass procedures is a crucial step to ensure significant weight loss without risking malnutrition. This study investigated the effect of ex vivo training on the skills needed to determine limb lengths. MATERIALS AND METHODS: This was a single-center ex vivo training experiment in a teaching hospital in the Netherlands. We designed a training exercise with marked ropes in a laparoscopic trainer box. All ten surgical residents participated and practiced the skill of estimating limb length. Before and after the two-week period their results on a 150-centimeter limb length task were evaluated. RESULTS: Before training, 10 surgical residents estimated 150 centimeters of small bowel with an absolute deviation of 21% [range 9-30]. After the training experiment, the residents measured with 8% [2-20] deviation (P = .17). The 8 residents who trained sufficiently improved statistically significantly to an absolute deviation of 5% [2-17] (P = .012). Over 70% of the participants felt their skills had improved. CONCLUSIONS: With sufficient training, surgical residents' skills in measuring small bowel length improved when tested in an ex vivo model. Residents became more confident in their laparoscopic measurement skills. This ex vivo training model is a alternative and addition to on-site training.

Balancing Risks and Benefits: Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a new class of drugs that have been proven beneficial in the management of diabetes, chronic kidney disease, and heart failure and in the mitigation of cardiovascular risk. The benefits of SGLT2i therapy have led to the rapid adoption of these drugs in clinical guidelines. Since the introduction of these drugs, concerns have arisen, as diabetic ketoacidosis (DKA) unexpectedly occurred in patients treated with SGLT2i. DKA is an infrequent but serious complication of SGLT2i therapy, and is potentially preventable. The risk factors for the development of SGLT2i-associated DKA are inappropriate dose reductions of insulin, the dietary restriction of carbohydrates, and factors that may increase insulin demand such as excessive alcohol intake and major surgery. Moreover, the risk of SGLT2i-associated DKA is higher in persons with type 1 diabetes. It is crucial that both patients and healthcare providers are aware of the risks of SGLT2i-associated DKA. In an effort to encourage safe prescribing of this effective class of drugs, we present two cases that illustrate the risks of SGLT2i therapy with regard to the development of DKA.

The impact of socioeconomic factors, social determinants, and ethnicity on the utilization of glucose sensor technology among persons with diabetes mellitus: a narrative review.

Continuous glucose monitoring (CGM) usage has been shown to improve disease outcomes in people living with diabetes by facilitating better glycemic management. However, previous research has suggested that access to these devices can be influenced by nonmedical factors such as socioeconomic status and ethnicity. It is critical that equitable access to CGM devices is ensured as people from those groups experience poorer diabetes-related health outcomes. In this narrative review, we provide an overview of the various healthcare systems worldwide and how socioeconomic status, social context, and ethnicity shape device usage and the associated health outcomes. In general, we found that having a lower socioeconomic status and belonging to an ethnic minority group negatively impact CGM usage. While financial means proved to be an important mediator in this process, it was not the sole driver as disparities persisted even after adjustment for factors such as income and insurance status. Recommendations to increase CGM usage for people of a lower socioeconomic status and ethnic minorities include increasing the availability of financial, administrative, and educational support, for both patients and healthcare providers. However, recommendations will vary due to local country-specific circumstances, such as reimbursement criteria and healthcare ecosystems.

The effects of income, education, social factors and ethnicity on the use of glucose sensors by people with diabetes mellitus: a narrative review Over the recent years, glucose sensors have transformed the monitoring of glucose levels in people with diabetes. However, access to these devices has been determined by the healthcare systems and the associated rules and regulations, as well as perceptions from providers and patients about who would benefit most from these devices. In this narrative review, we performed an expansive literature search into what is known about factors that negatively impact the access to glucose sensors, and how these factors might be addressed. From this, we learn that, depending on the healthcare system, financial means form a major driver behind the disparities in glucose sensor use. However, factors such as ethnicity and provider and patient perceptions also can negatively affect one's chances to obtain a glucose sensor. Furthermore, we found that a successful program aimed at resolving the found disparities in glucose sensor use must be multi-faceted, and must include measures aimed at financial support, the use of objective and simple criteria for sensor eligibility, as well as educational support for both patients and providers.

HbA1c and fasting plasma glucose levels are equally related to incident cardiovascular risk in a high CVD risk population without known diabetes.

OBJECTIVES: Type 2 diabetes (T2DM) is associated with increased risk for cardiovascular disease (CVD). Whether screen-detected T2DM, based on fasting plasma glucose (FPG) or on HbA1c, are associated with different risks of incident CVD in high-risk populations and which one is preferable for diabetes screening in these populations, remains unclear. METHODS: A total of 8,274 high-risk CVD participants were included from the UCC-SMART cohort. Participants were divided into groups based on prior T2DM diagnosis, and combinations of elevated/non-elevated FPG and HbA1c (cut-offs at 7 mmol/L and 48 mmol/mol, respectively): Group 0: known T2DM; group 1: elevated FPG/HbA1c; group 2: elevated FPG, non-elevated HbA1c; group 3: non-elevated FPG, elevated HbA1c; group 1 + 2: elevated FPG, regardless of HbA1c; group 1 + 3: elevated HbA1c, regardless of FPG; and group 4 (reference), non-elevated FPG/HbA1c. RESULTS: During a median follow-up of 6.3 years (IQR 3.3-9.8), 712 cardiovascular events occurred. Compared to the reference (group 4), group 0 was at increased risk (HR 1.40; 95 % CI 1.16-1.68), but group 1 (HR 1.16; 95 % CI 0.62-2.18), 2 (HR 1.18; 95 % CI 0.84-1.67), 3 (HR 0.61; 95 % CI 0.15-2.44), 1 + 2 (HR 1.17; 95 % CI 0.86-1.59) and 1 + 3 (HR 1.01; 95 % CI 0.57-1.79) were not. However, spline interpolation showed a linearly increasing risk with increasing HbA1c/FPG, but did not allow for identification of other cut-off points. CONCLUSIONS: Based on current cut-offs, FPG and HbA1c at screening were equally related to incident CVD in high-risk populations without known T2DM. Hence, neither FPG, nor HbA1c, is preferential for diabetes screening in this population with respect to risk of incident CVD.

Effects of endocrine disrupting chemicals and their interactions with genetic risk scores on cardiometabolic traits.

Ubiquitous non-persistent endocrine disrupting chemicals (EDCs) have inconsistent associations with cardiometabolic traits. Additionally, large-scale genome-wide association studies (GWASs) have yielded many genetic risk variants for cardiometabolic traits and diseases. This study aimed to investigate the associations between a wide range of EDC exposures (parabens, bisphenols, and phthalates) and 14 cardiometabolic traits and whether these are moderated by their respective genetic risk scores (GRSs). Data were from 1074 participants aged 18 years or older of the Lifelines Cohort Study, a large population-based biobank. GRSs for 14 cardiometabolic traits were calculated based on genome-wide significant common variants from recent GWASs. The concentrations of 15 EDCs in 24-hour urine were measured by isotope dilution liquid chromatography tandem mass spectrometry technology. The main effects of trait-specific GRSs and each of the EDC exposures and their interaction effects on the 14 cardiometabolic traits were examined in multiple linear regression. The present study confirmed significant main effects for all GRSs on their corresponding cardiometabolic trait. Regarding the main effects of EDC exposures, 26 out of 280 EDC-trait tests were significant with explained variances ranging from 0.43 % (MMP- estimated glomerular filtration rate (eGFR)) to 2.37 % (PrP-waist-hip ratio adjusted body mass index (WHRadjBMI)). We confirmed the association of MiBP and MBzP with WHRadjBMI and body mass index (BMI), and showed that parabens, bisphenol F, and many other phthalate metabolites significantly contributed to the variance of WHRadjBMI, BMI, high-density lipoprotein (HDL), eGFR, fasting glucose (FG), and diastolic blood pressure (DBP). Only one association between BMI and bisphenol F was nominally significantly moderated by the GRS explaining 0.36 % of the variance. However, it did not survive multiple testing correction. We showed that non-persistent EDC exposures exerted effects on BMI, WHRadjBMI, HDL, eGFR, FG, and DBP. However no evidence for a modulating role of GRSs was found.

A genome-wide association study of 24-hour urinary excretion of endocrine disrupting chemicals.

Ubiquitous exposure to environmental endocrine disrupting chemicals (EDCs) instigates a major public health problem, but much remains unknown on the inter-individual differences in metabolism and excretion of EDCs. To examine this we performed a two-stage genome-wide association study (GWAS) for 24-hour urinary excretions of four parabens, two bisphenols, and nine phthalate metabolites. Results showed five genome-wide significant (p-value < 5x10-8) and replicated single nucleotide polymorphisms (SNPs) representing four independent signals that associated with mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Three of the four signals were located on chromosome 10 in a locus harboring the cytochrome P450 (CYP) genes CYP2C9, CYP2C58P, and CYP2C19 (rs117529685, pMECPP = 5.38x10-25; rs117033379, pMECPP = 1.96x10-19; rs4918798, pMECPP = 4.01x10-71; rs7895726, pMEHHP = 1.37x10-15, r2 with rs4918798 = 0.93). The other signal was on chromosome 6 close to the solute carrier (SLC) genes SLC17A1, SLC17A3, SLC17A4, and SCGN (rs1359232, pMECPP = 7.6x10-16). These four SNPs explained a substantial part (8.3 % - 9.2 %) of the variance in MECPP in the replication cohort. Bioinformatics analyses supported a likely causal role of CYP2C9 and SLC17A1 in metabolism and excretion of MECPP and MEHHP. Our results provide biological insights into mechanisms of phthalate metabolism and excretion with a likely causal role for CYP2C9 and SLC17A1.