Glucagon-like-peptide 1 receptor agonism and attempted suicide: A Mendelian randomisation study to assess a potential causal association.

Glucagon-like-peptide 1 receptor agonists (GLP-1RA) have transformed type 2 diabetes (T2D) and obesity management. Multiple regulatory agencies are investigating reported associations between GLP1-RA and increased suicide attempts (SA), but observational data may be prone to confounding. Randomised control trials (RCT) of GLP-1RA were largely undertaken in people at lower risk of SA. Real-world data suggest semaglutide use associates with reduced suicidal ideation and depression but was under-powered to statistically assess risk of SA. Mendelian randomisation (MR) leverages genetic instrument(s) to infer potential causal association between an exposure and an outcome. We undertook MR using missense variants in the gene encoding GLP1R that improve glycemia, lower T2D risk and/or lower BMI, to investigate potential causal association between GLP-1RA and SA. In people of European ancestry, MR did not find evidence genetically proxied GLP1RA increased SA in a general population cohort: (rs10305492, exposure: HbA1c, odds ratio [OR] and 95% confidence interval [CI]: 1.38, 0.41-4.62, p = .60), (rs10305492, exposure: FG, OR 1.27, 0.52-3.13, p = .60) and (rs1042044, exposure BMI, OR 0.30, 0.06-1.48) with concordant results in a multi-ancestry SA case-control cohort. In conclusion, we did not find MR evidence that increased GLP-1RA impacts SA. This awaits confirmation with RCT and real-world data.

Analyses of potential causal contributors to increased waist/hip ratio-associated cardiometabolic disease: A combined and sex-stratified Mendelian randomization study.

BACKGROUND: Increased waist/hip ratio (WHR) contributes to type 2 diabetes, fatty liver, dyslipidaemia, hypertension and coronary artery disease, with potential sex-differential effects. Postulated mediators include increased lipid flux, branched-chain amino acids, glycine and glycoprotein acetyl, but their relative contributions and sex-specific impact on WHR-associated cardiometabolic disease (CMD) are not established. METHODS: We therefore undertook combined and sex-stratified Mendelian randomization (MR) to assess the relative causal contributions of these mediators to WHR-associated CMD using summary statistics from the largest genome-wide association studies in European ancestries. RESULTS: In sex-combined MR analyses, increased WHR significantly reduces high-density lipoprotein (beta = -0.416, SE = 0.029, p = 2.87E-47), increases triglyceride (beta = 0.431, SE = 0.029, p = 1.87E-50), type 2 diabetes (odds ratio = 2.747, SE = 0.09, p = 26E-23), coronary artery disease (odds ratio = 1.478, SE = 0.045, p = 6.96E-18), alanine transaminase (beta = 0.062, SE = 0.004, p = 6.88E-67), and systolic (beta = 0.134, SE = 0.022, p = 7.81E-10) and diastolic blood pressure (beta = 0.162, SE = 0.026, p = 5.38E-10). Adjustment for the mediators attenuated WHR's effects, but the associations remained significant with concordant results in females. In males, a similar pattern was seen, except after adjusting for the effect of the ratio of monounsaturated fatty acid to total free fatty acid, the potential causal effect of WHR was no longer significant: high-density lipoprotein (beta = -0.117, SE = 0.069, p = .09) and triglyceride (beta = 0.051, SE = 0.068, p = .459). CONCLUSIONS: MR suggests WHR increases the risk of CMD independent of these mediators, with the exception of dyslipidaemia in males, which is largely driven by the monounsaturated fatty acid to total free fatty acid ratio.

Erythritol as a Potential Causal Contributor to Cardiometabolic Disease: A Mendelian Randomization Study.

People with type 2 diabetes frequently use low-calorie sweeteners to manage glycemia and reduce caloric intake. Use of erythritol, a low-calorie sweetener, has increased recently. Higher circulating concentration associates with major cardiac events and metabolic disease in observational data, prompting some concern. As observational data may be prone to confounding and reverse causality, we undertook bidirectional Mendelian randomization (MR) to investigate potential causal associations between erythritol and coronary artery disease (CAD), BMI, waist-hip-ratio (WHR), and glycemic and renal traits in cohorts of European ancestry. Analyses were undertaken using instruments comprising genome-wide significant variants from three cohorts with erythritol measurement. Across instruments, we did not find supportive evidence that increased erythritol increases CAD (b = -0.033 ± 0.02, P = 0.14; b = 0.46 ± 0.37, P = 0.23). MR indicates erythritol may decrease BMI (b = -0.04 ± 0.018, P = 0.03; b = -0.04 ± 0.0085, P = 1.23 × 10-5; b = -0.083 ± 0.092, P = 0.036), with potential evidence from one instrument of increased BMI adjusted for WHR (b = 0.046 ± 0.022, P = 0.035). No evidence of causal association was found with other traits. In conclusion, we did not find supportive evidence from MR that erythritol increases cardiometabolic disease. These findings await confirmation in well-designed prospective studies.

Beyond apples and pears: sex-specific genetics of body fat percentage.

Introduction: Biological sex influences both overall adiposity and fat distribution. Further, testosterone and sex hormone binding globulin (SHBG) influence adiposity and metabolic function, with differential effects of testosterone in men and women. Here, we aimed to perform sex-stratified genome-wide association studies (GWAS) of body fat percentage (BFPAdj) (adjusting for testosterone and sex hormone binding globulin (SHBG)) to increase statistical power. Methods: GWAS were performed in white British individuals from the UK Biobank (157,937 males and 154,337 females). To avoid collider bias, loci associated with SHBG or testosterone were excluded. We investigated association of BFPAdj loci with high density cholesterol (HDL), triglyceride (TG), type 2 diabetes (T2D), coronary artery disease (CAD), and MRI-derived abdominal subcutaneous adipose tissue (ASAT), visceral adipose tissue (VAT) and gluteofemoral adipose tissue (GFAT) using publicly available data from large GWAS. We also performed 2-sample Mendelian Randomization (MR) using identified BFPAdj variants as instruments to investigate causal effect of BFPAdj on HDL, TG, T2D and CAD in males and females separately. Results: We identified 195 and 174 loci explaining 3.35% and 2.60% of the variation in BFPAdj in males and females, respectively at genome-wide significance (GWS, p<5x10-8). Although the direction of effect at these loci was generally concordant in males and females, only 38 loci were common to both sexes at GWS. Seven loci in males and ten loci in females have not been associated with any adiposity/cardiometabolic traits previously. BFPAdj loci generally did not associate with cardiometabolic traits; several had paradoxically beneficial cardiometabolic effects with favourable fat distribution. MR analyses did not find convincing supportive evidence that increased BFPAdj has deleterious cardiometabolic effects in either sex with highly significant heterogeneity. Conclusions: There was limited genetic overlap between BFPAdj in males and females at GWS. BFPAdj loci generally did not have adverse cardiometabolic effects which may reflect the effects of favourable fat distribution and cardiometabolic risk modulation by testosterone and SHBG.

Biology and Clinical Use of Glucagon-Like Peptide-1 Receptor Agonists in Vascular Protection.

Glucagon-like peptide-1 receptor agonists (GLP1RA) are incretin agents initially designed for the treatment of type 2 diabetes mellitus but because of pleiotropic actions are now used to reduce cardiovascular disease in people with type 2 diabetes mellitus and in some instances as approved treatments for obesity. In this review we highlight the biology and pharmacology of GLP1RA. We review the evidence for clinical benefit on major adverse cardiovascular outcomes in addition to modulation of cardiometabolic risk factors including reductions in weight, blood pressure, improvement in lipid profiles, and effects on kidney function. Guidance is provided on indications and potential adverse effects to consider. Finally, we describe the evolving landscape of GLP1RA and including novel glucagon-like peptide-1-based dual/polyagonist therapies that are being evaluated for weight loss, type 2 diabetes mellitus, and cardiorenal benefit.

Investigating the association between fasting insulin, erythrocytosis and HbA1c through Mendelian randomization and observational analyses.

Background: Insulin resistance (IR) with associated compensatory hyperinsulinemia (HI) are early abnormalities in the etiology of prediabetes (preT2D) and type 2 diabetes (T2D). IR and HI also associate with increased erythrocytosis. Hemoglobin A1c (HbA1c) is commonly used to diagnose and monitor preT2D and T2D, but can be influenced by erythrocytosis independent of glycemia. Methods: We undertook bidirectional Mendelian randomization (MR) in individuals of European ancestry to investigate potential causal associations between increased fasting insulin adjusted for BMI (FI), erythrocytosis and its non-glycemic impact on HbA1c. We investigated the association between the triglyceride-glucose index (TGI), a surrogate measure of IR and HI, and glycation gap (difference between measured HbA1c and predicted HbA1c derived from linear regression of fasting glucose) in people with normoglycemia and preT2D. Results: Inverse variance weighted MR (IVWMR) suggested that increased FI increases hemoglobin (Hb, b=0.54 ± 0.09, p=2.7 x 10-10), red cell count (RCC, b=0.54 ± 0.12, p=5.38x10-6) and reticulocyte (RETIC, b=0.70 ± 0.15, p=2.18x10-6). Multivariable MR indicated that increased FI did not impact HbA1c (b=0.23 ± 0.16, p=0.162) but reduced HbA1c after adjustment for T2D (b=0.31 ± 0.13, p=0.016). Increased Hb (b=0.03 ± 0.01, p=0.02), RCC (b=0.02 ± 0.01, p=0.04) and RETIC (b=0.03 ± 0.01, p=0.002) might modestly increase FI. In the observational cohort, increased TGI associated with decreased glycation gap, (i.e., measured HbA1c was lower than expected based on fasting glucose, (b=-0.09 ± 0.009, p<0.0001)) in people with preT2D but not in those with normoglycemia (b=0.02 ± 0.007, p<0.0001). Conclusions: MR suggests increased FI increases erythrocytosis and might potentially decrease HbA1c by non-glycemic effects. Increased TGI, a surrogate measure of increased FI, associates with lower-than-expected HbA1c in people with preT2D. These findings merit confirmatory studies to evaluate their clinical significance.

Association Between Obesity and Chronic Kidney Disease: Multivariable Mendelian Randomization Analysis and Observational Data From a Bariatric Surgery Cohort.

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission rates plateau with 20-25% WL after bariatric surgery (BS), but further WL increases normoglycemia and normotension. We undertook bidirectional inverse variance weighted Mendelian randomization (IVWMR) to investigate potential independent causal associations between increased BMI and estimated glomerular filtration rate (eGFR) in CKD (CKDeGFR) (<60 mL/min/1.73 m2) and microalbuminuria (MA). In 5,337 BS patients, we assessed whether WL influences >50% decline in eGFR (primary outcome) or CKD hospitalization (secondary outcome), using <20% WL as a comparator. IVWMR results suggest that increased BMI increases CKDeGFR (b = 0.13, P = 1.64 × 10-4; odds ratio [OR] 1.14 [95% CI 1.07, 1.23]) and MA (b = 0.25; P = 2.14 × 10-4; OR 1.29 [1.13, 1.48]). After adjusting for hypertension and fasting glucose, increased BMI did not significantly increase CKDeGFR (b = -0.02; P = 0.72; OR 0.98 [0.87, 1.1]) or MA (b = 0.19; P = 0.08; OR 1.21 [0.98, 1.51]). Post-BS WL significantly reduced the primary outcome with 30 to <40% WL (hazard ratio [HR] 0.53 [95% CI 0.32, 0.87]) but not 20 to <30% WL (HR 0.72 [0.44, 1.2]) and ≥40% WL (HR 0.73 [0.41, 1.30]). For CKD hospitalization, progressive reduction was seen with increased WL, which was significant for 30 to <40% WL (HR 0.37 [0.17, 0.82]) and ≥40% WL (HR 0.24 [0.07, 0.89]) but not 20 to <30% WL (HR 0.60 [0.29, 1.23]). The data suggest that obesity is likely not an independent cause of CKD. WL thresholds previously associated with normotension and normoglycemia, likely causal mediators, may reduce CKD after BS.

Investigating the effects of antipsychotics on brain insulin action: Study protocol for a multi-modality magnetic resonance imaging (MRI) study in healthy controls.

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2-6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.

Telephone-based cognitive behavioural therapy for patients with postoperative bariatric surgery to manage COVID-19 pandemic-related mental health issues and distress (TELE-BARICARE): a protocol for a randomised controlled trial.

INTRODUCTION: Bariatric surgery is currently the most effective treatment for obesity, and is performed yearly in over 8000 patients in Canada. Over 50% of those who live with obesity also have a history of mental health disorder. The COVID-19 pandemic has made it difficult for people living with obesity to manage their weight even after undergoing bariatric surgery, which combined with pandemic-related increases in mental health distress, has the potential to adversely impact obesity outcomes such as weight loss and quality of life. Reviews of virtual mental health interventions during COVID-19 have not identified any interventions that specifically address psychological distress or disordered eating in patients with obesity, including those who have had bariatric surgery. METHODS AND ANALYSIS: A randomised controlled trial will be conducted with 140 patients across four Ontario Bariatric Centres of Excellence to examine the efficacy of a telephone-based cognitive behavioural therapy intervention versus a control intervention (online COVID-19 self-help resources) in postoperative bariatric patients experiencing disordered eating and/or psychological distress. Patients will be randomised 1:1 to either group. Changes in the Binge Eating Scale and the Patient Health Questionnaire 9-Item Scale will be examined between groups across time (primary outcomes). Qualitative exit interviews will be conducted, and data will be used to inform future adaptations of the intervention to meet patients' diverse needs during and post-pandemic. ETHICS AND DISSEMINATION: This study has received ethics approvals from the following: Clinical Trials Ontario (3957) and the University Health Network Research Ethics Committee (22-5145), the Board of Record. All participants will provide written informed consent prior to enrolling in the study. Results will be made available to patients with bariatric surgery, the funders, the supporting organisations and other researchers via publication in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT05258578.

Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality.

Mendelian randomization (MR) suggests that postprandial hyperinsulinemia (unadjusted for plasma glucose) increases BMI, but its impact on cardiometabolic disease, a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution i.e., increased centripetal and/or reduced femoro-gluteal adiposity, is causally associated with and better predicts cardiometabolic disease than BMI. We therefore undertook bidirectional MR to assess the effect of corrected insulin response (CIR) (insulin 30 min after a glucose challenge adjusted for plasma glucose) on BMI, waist-to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), HDL, liver fat, hypertension (HTN), and coronary artery disease (CAD) in people of European descent. Inverse variance-weighted MR suggests a potential causal association between increased CIR and increased BMI (b = 0.048 ± 0.02, P = 0.03), increased leg fat (b = 0.029 ± 0.012, P = 0.01), reduced T2D (b = -0.73 ± 0.15, P = 6 × 10-7, odds ratio [OR] 0.48 [95% CI 0.36-0.64]), reduced TG (b = -0.07 ± 0.02, P = 0.003), and increased HDL (b = 0.04 ± 0.01, P = 0.006) with some evidence of horizontal pleiotropy. CIR had neutral effects on WHR (b = 0.009 ± 0.02, P = 0.69), liver fat (b = -0.08 ± 0.04, P = 0.06), HTN (b = -0.001 ± 0.004, P = 0.7, OR 1.00 [95% CI 0.99-1.01]), and CAD (b = -0.002 ± 0.002, P = 0.48, OR 0.99 [95% CI 0.81-1.21]). T2D decreased CIR (b -0.22 ± 0.04, P = 1.3 × 10-7), with no evidence that BMI, TG, HDL, liver fat, HTN, and CAD modulate CIR. In conclusion, we did not find evidence that increased CIR increases cardiometabolic disease. It might increase BMI with favorable fat distribution, reduce T2D, and improve lipids.

The Impact of Telephone-Based Cognitive Behavioral Therapy on Mental Health Distress and Disordered Eating Among Bariatric Surgery Patients During COVID-19: Preliminary Results from a Multisite Randomized Controlled Trial.

BACKGROUND: Patients undergoing bariatric surgery have high rates of psychiatric comorbidity, which may increase their vulnerability to COVID-19-related mental health distress. Exacerbation of mental health distress and disordered eating could have significant negative effects on long-term weight management and quality of life for these patients if untreated. OBJECTIVE: To determine the efficacy of a telephone-based cognitive behavioral therapy (Tele-CBT) intervention in improving depressive, anxiety, and disordered eating symptoms during COVID-19. METHODS: Participants were recruited as part of a larger randomized controlled trial study (clinicaltrials.gov ID: NCT03315247) between March 2020 and March 2021 and randomized 1:1 to receive Tele-CBT or standard bariatric care. Outcomes of Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Emotional Eating Scale (EES), and Binge Eating Scale (BES) were measured at baseline, immediately post-intervention, and 3 months post-intervention. Linear mixed models were used to test the effect of intervention group, time, and group-by-time interaction for each outcome. RESULTS: Eighty-one patients were included in the intention-to-treat analysis. Mean (SD) age of participants was 47.68 (9.36) years and 80.2% were female. There were significant group-by-time interactions for all outcomes and significant differences between groups across time. There were significant decreases in mean GAD-7 (p = 0.001), PHQ-9 (p < 0.001), EES-Total (p = 0.001), EES-Anger (p = 0.003), EES-Anxiety (p < 0.001), EES-Depression (p < 0.001), and BES (p = 0.002) scores for the Tele-CBT group at post-intervention and follow-up when compared to baseline and the control group. CONCLUSION: Tele-CBT is a feasible and effective treatment for improving psychological distress and disordered eating among post-operative bariatric surgery patients during the COVID-19 pandemic.

Central diabetes insipidus and partial anterior pituitary dysfunction in acute myeloid leukemia.

Summary: Central diabetes insipidus (CDI) is a rare manifestation of acute myeloid leukemia (AML) with unclear etiology. When present, CDI in AML has most often been described in patients with chromosome 3 or 7 aberrations and no abnormalities on brain imaging. In this case, we present a woman with newly diagnosed AML t(12;14)(p12;q13) found to have diabetes insipidus (DI) with partial anterior pituitary dysfunction and abnormal brain imaging. While in hospital, the patient developed an elevated serum sodium of 151 mmol/L with a serum osmolality of 323 mmol/kg and urine osmolality of 154 mmol/kg. On history, she reported polyuria and polydipsia for 5 months preceding hospitalization. Based on her clinical symptoms and biochemistry, she was diagnosed with DI and treated using intravenous desmopressin with good effect; sodium improved to 144 mmol/L with a serum osmolality of 302 mmol/kg and urine osmolality of 501 mmol/kg. An MRI of the brain done for the assessment of neurologic involvement revealed symmetric high-T2 signal within the hypothalamus extending into the mamillary bodies bilaterally, a partially empty sella, and loss of the pituitary bright spot. A pituitary panel was completed which suggested partial anterior pituitary dysfunction. The patient's robust improvement with low-dose desmopressin therapy along with her imaging findings indicated a central rather than nephrogenic cause for her DI. Given the time course of her presentation with respect to her AML diagnosis, MRI findings, and investigations excluding other causes, her CDI and partial anterior pituitary dysfunction were suspected to be secondary to hypothalamic leukemic infiltration. Learning points: Leukemic infiltration of the pituitary gland is a rare cause of central diabetes insipidus (CDI) in patients with acute myeloid leukemia (AML). Patients with AML and CDI may compensate for polyuria and prevent hypernatremia with increased water intake. AML-associated CDI can require long-term desmopressin treatment, independent of AML response to treatment.

Hypothalamic miR-1983 Targets Insulin Receptor ß and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin.

MicroRNAs (miRNAs) expressed in the hypothalamus are capable of regulating energy balance and peripheral metabolism by inhibiting translation of target messenger RNAs (mRNAs). Hypothalamic insulin resistance is known to precede that in the periphery, thus a critical unanswered question is whether central insulin resistance creates a specific hypothalamic miRNA signature that can be identified and targeted. Here we show that miR-1983, a unique miRNA, is upregulated in vitro in 2 insulin-resistant immortalized hypothalamic neuronal neuropeptide Y-expressing models, and in vivo in hyperinsulinemic mice, with a concomitant decrease of insulin receptor ß subunit protein, a target of miR-1983. Importantly, we demonstrate that miR-1983 is detectable in human blood serum and that its levels significantly correlate with blood insulin and the homeostatic model assessment of insulin resistance. Levels of miR-1983 are normalized with metformin exposure in mouse hypothalamic neuronal cell culture. Our findings provide evidence for miR-1983 as a unique biomarker of cellular insulin resistance, and a potential therapeutic target for prevention of human metabolic disease.

Obesity and Cardiovascular Disease: The Emerging Role of Inflammation.

Obesity is a growing public health challenge across the globe. It is associated with increased morbidity and mortality. Cardiovascular disease (CVD) is the leading cause of mortality for people with obesity. Current strategies to reduce CVD are largely focused on addressing traditional risk factors such as dyslipidemia, type 2 diabetes (T2D) and hypertension. Although this approach is proven to reduce CVD, substantial residual risk remains for people with obesity. This necessitates a better understanding of the etiology of CVD in people with obesity and alternate therapeutic approaches. Reducing inflammation may be one such strategy. A wealth of animal and human data indicates that obesity is associated with adipose tissue and systemic inflammation. Inflammation is a known contributor to CVD in humans and can be successfully targeted to reduce CVD. Here we will review the etiology and pathogenesis of inflammation in obesity associated metabolic disease as well as CVD. We will review to what extent these associations are causal based on human genetic studies and pharmacological studies. The available data suggests that anti-inflammatory treatments can be used to reduce CVD, but off-target effects such as increased infection have precluded its broad therapeutic application to date. The role of anti-inflammatory therapies in improving glycaemia and metabolic parameters is less established. A number of clinical trials are currently ongoing which are evaluating anti-inflammatory agents to lower CVD. These studies will further clarify whether anti-inflammatory agents can safely reduce CVD.

Cardiorenal outcomes in eligible patients referred for bariatric surgery.

OBJECTIVE: Bariatric surgery is associated with reduced atherosclerotic cardiovascular disease (CVD) and heart failure hospitalization in people with type 2 diabetes (T2D) and those with prior CVD. Most patients undergoing bariatric surgery do not have T2D or CVD. Many otherwise eligible patients do not have surgery because of self-exclusion. Clinical outcomes in these groups are less established. METHODS: This study retrospectively assessed cardiorenal outcomes in 8,568 patients after acceptance of referral for surgery. RESULTS: A total of 63.8% patients did not undergo surgery. After multivariate adjustment for sex, age, BMI, income quintile, distance from hospital, hypertension, T2D, and CVD, hazard ratios (HR) for the primary (incident myocardial infarction, stroke, heart failure hospitalization, and death; HR = 0.52, 95% CI: 0.4-0.66) and secondary CVD outcomes (primary outcomes and coronary/carotid revascularization; HR = 0.53, 95% CI: 0.42-0.67) were lower in the surgery cohort. This reduction was seen in those with (primary: HR = 0.45, 95% CI: 0.32-0.63, secondary: HR = 0.47, 95% CI: 0.34-0.65) and without T2D (primary: HR = 0.61, 95% CI: 0.42-0.88, secondary: HR = 0.53, 95% CI: 0.42-0.67). Reduced kidney disease (HR = 0.46, 95% CI: 0.22-0.92) but increased liver disease hospitalization (HR = 2.5, 95% CI: 1.45-4.27) was observed with surgery. CONCLUSIONS: Non-progression to surgery associates with increased CVD despite low baseline prevalence of CVD. The cardiorenal benefits of bariatric surgery warrant confirmation in a well-powered randomized clinical trial.

Obesity as a multisystem disease: Trends in obesity rates and obesity-related complications.

Obesity is a chronic multisystem disease associated with increased morbidity and mortality. The increasing prevalence of obesity makes it a major healthcare challenge across both developed and developing countries. Traditional measures such as body mass index do not always identify individuals at increased risk of comorbidities, yet continue to be used in deciding who qualifies for weight loss treatment. A better understanding of how obesity is associated with comorbidities, in particular non-metabolic conditions, is needed to identify individuals at risk in order to prioritize treatment. For metabolic disorders such as type 2 diabetes (T2D), weight loss can prevent T2D in individuals with prediabetes. It can improve and reverse T2D if weight loss is achieved early in the course of the disease. However, access to effective weight loss treatments is a significant barrier to improved health for people with obesity. In the present paper, we review the rising prevalence of obesity and why it should be classed as a multisystem disease. We will discuss potential mechanisms underlying its association with various comorbidities and how these respond to treatment, with a particular focus on cardiometabolic disease, malignancy and mental health.

Genetically determined lean mass and dietary response.

Weight loss attenuates many obesity-related co-morbidities, but is difficult to sustain with dietary change. Dietary adherence, not macronutrient composition, is a better predictor of weight loss. Weight loss-induced endocrine changes promote food intake and increase energy efficiency, contributing to the difficulty with dietary adherence and weight regain. Macronutrient preference is partly genetically determined, suggesting that personalized dietary interventions might be more successful. In this issue, Li et al. report that a genetic risk score comprising the cumulative weighted effects of variants previously associated with increased lean mass is associated with increased satiety and weight loss 6 months after initiating a low- but not a high-fat diet. The effects were attenuated by 2 years. These findings suggest that genetic variants may influence response to specific diet. Further studies are necessary to assess whether genetically determined lean mass is causally associated with dietary response. Significant progress has recently been made in identifying additional genetic determinants of lean mass, which will enable such investigations and potentially inform future nutritional studies.