Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation and (Morbid) Obesity or Low Body Weight: a Systematic Review and Meta-Analysis.

PURPOSE: Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Therefore, a critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum is needed. METHODS AND RESULTS: After searching Medline, this systematic review discusses the impact of body weight on the risk-benefit profile of NOACs versus VKAs. The meta-analysis demonstrated that NOAC use in obese and class III obese AF patients (body mass index (BMI) ≥ 30 and ≥ 40 kg/m2, respectively) was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96] and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00] and RR 0.74, 95%CI [0.57-0.95], respectively) and similar mortality risks (RR 0.92, 95%CI [0.73-1.15] and RR 1.17, 95%CI [0.83-1.64], respectively) compared to VKAs. In AF patients ≤ 60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), but similar mortality risks (RR 0.68, 95%CI [0.42-1.10]), were observed for NOAC- versus VKA-treated patients. CONCLUSION: The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight. However, more data are needed on underweight AF patients (BMI < 18.5 kg/m2) and on differences between NOACs in these patients.

Oral Anticoagulant Use in Patients with Morbid Obesity: A Systematic Review and Meta-Analysis.

OBJECTIVES: Obesity is associated with increased risks of atrial fibrillation (AF) and venous thromboembolism (VTE) for which anticoagulation is commonly used. However, data on the efficacy and safety of oral anticoagulants in patients with morbid obesity are limited. METHODS: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) for AF or VTE in patients with morbid obesity. RESULTS: We included three randomized controlled trials (5 studies) and 18 observational studies in adult patients with a body weight ≥120 kg, body mass index ≥40 kg/m2, or classified as morbid obesity who received DOACs or VKAs for AF or VTE (N = 77,687). The primary efficacy outcome was stroke/systemic embolism or recurrent VTE, and the primary safety outcome was major bleeding. DOACs were associated with a pooled incidence rate of stroke/systemic embolism of 1.16 per 100 person-years, compared to 1.18 with VKAs. The incidence of recurrent VTE on DOACs was 3.83 per 100 person-years, compared to 6.81 on VKAs. In both VTE and AF populations, DOACs were associated with lower risks of major bleeding compared to VKAs. However, all observational studies had moderate to serious risks of bias. CONCLUSION: Patients with morbid obesity on DOACs had similar risks of stroke/systemic embolism, lower rates of recurrent VTE, and major bleeding events compared to those on VKAs. However, the certainty of evidence was low given that studies were mostly observational with high risk of confounding.

Efficacy and safety of direct oral anticoagulant in morbidly obese patients with atrial fibrillation: systematic review and meta-analysis.

AIMS: We conducted a systematic review and meta-analysis on three outcomes. We assessed the efficacy and safety of direct oral anticoagulants (DOAC) compared to vitamin K antagonists (VKA) in morbidly obese patients with atrial fibrillation (AF). We compared the efficacy and safety of DOAC in obese patients and non-obese patients with AF. Finally, we updated the current knowledge of outcomes of AF patients with obesity compared with normal-weight patients regardless of anticoagulation type. METHODS AND RESULTS: Using PubMed and Embase, we searched for literature published from inception to August 2020 for studies conducted in morbidly obese patients with AF who used DOACs and/or VKA for stroke or systemic embolism (stroke/SE) prevention that report efficacy and/or safety data. GRADE assessment was performed to determine the quality of the meta-analysis results. Direct oral anticoagulant was not statistically different from VKA in reducing stroke/SE with relative risk (RR) of 0.85 [95% confidence interval (CI): 0.56-1.29; very low certainty evidence]. Major bleeding risk was lower in the DOAC groups with RR of 0.62 (95% CI: 0.48-0.80; low certainty evidence). Obese patients with AF who used DOACs had lower risk of stroke/SE and similar major bleeding risk compared to non-obese patients with RR of 0.77 (95% CI: 0.70-0.84; low certainty evidence) and 1.02 (95% CI: 0.94-1.09; low certainty evidence), respectively. Obese patients with AF who used any type of anticoagulant had lower risk of stroke/SE compared to normal-weight patients with RR of 0.62 (95% CI: 0.57-0.69; low certainty evidence). CONCLUSION: The use of DOACs in morbidly obese patients may be reasonable if needed, and more dedicated studies are needed to make a more robust recommendation.

A pilot study about the development and characterization of a Roux en Y gastric bypass model in obese Yucatan minipigs.

Performing the Roux-en-Y gastric bypass (RYGBP) in obese Yucatan minipigs provides an opportunity to explore the mechanisms behind the effects of this surgery in controlled environmental and nutritional conditions. We hypothesized that RYGBP in these minipigs would induce changes at multiple levels, as in obese humans. We sought to characterize RYGBP in a diet-induced obese minipig model, compared with a pair-fed sham group. After inducing obesity with an ad libitum high-fat/high-sugar diet, we performed RYGBP (n = 7) or sham surgery (n = 6). Oral glucose tolerance tests (OGTT) were performed before and after surgery. Histological analyses were conducted to compare the alimentary limb at sacrifice with tissue sampled during RYGBP surgery. One death occurred in the RYGBP group at postoperative day (POD) 3. Before sacrifice, weight loss was the same across groups. GLP-1 secretion (OGTT) was significantly higher at 15, 30 and 60 min at POD 7, and at 30 and 60 min at POD 30 in the RYGBP group. Incremental insulin area under the curve increased significantly after RYGBP (p = 0.02). RYGBP induced extensive remodeling of the alimentary limb. Results show that RYGBP can be safely performed in obese minipigs, and changes mimic those observed in humans.

Increases in body mass index and cardiovascular risk factors during methadone maintenance treatment.

OBJECTIVE: This study describes changes in weight and cardiovascular risk factors over time among individuals enrolled in methadone maintenance treatment for opioid use disorder. Demographic and clinical predictors of weight gain were also evaluated. DESIGN: This study was a retrospective chart review evaluating data over a period of 3 years. SETTING: Medical records of individuals enrolled in an academic research outpatient methadone maintenance treatment program were reviewed. PATIENTS: Seventy-four individuals who were admitted and retained in methadone maintenance treatment for at least 3 consecutive years were included. OUTCOME MEASURES: Annual weight was assessed by calculating body mass index (BMI). Changes over time in cardiovascular risk factors of hypertension, diabetes, and hypercholesterolemia were also assessed. RESULTS: The percentage of patients categorized as overweight, obese, or morbidly obese BMI increased from 42 percent (n = 31) at admission to 76 percent (n = 56), 82 percent (n = 61), and 88 percent (n = 65) at 1, 2, and 3 years post-admission, respectively. Hypertension, diabetes, and hypercholesterolemia also tended to increase following admission. BMI increases tended to be greater for those with a higher dose of methadone, as well as for females and Black/African American individuals. No other predictors of weight gain were identified. CONCLUSIONS: These data indicate that methadone maintenance treatment is associated with clinically meaningful weight gain and increases in cardiovascular risk factors. Given the importance of methadone maintenance for treatment of opioid use disorder, future research should examine additional predictors and potential mechanisms of weight gain among methadone patients and develop tailored interventions including nutritional knowledge and lifestyle recommendations.

Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite.

BACKGROUND: World-wide obesity has risen to alarming levels. We present experimental support for a new and very challenging hypothesis linking obesity, voracity, and growth hormone (GH) deficiency, to the consumption of elevated amounts of the amino-acid glutamate (GLU). Supraphysiological doses of GLU are toxic for neuronal cells. METHODS: Human data were obtained from 807,592 German conscripts born between 1974 and 1978, and from 1,432,368 women of the German birth statistics (deutsche Perinatalerhebung) 1995-1997. The effects of orally administered monosodium glutamate (MSG) were investigated in 30 pregnant Wistar rats and their offspring. Pregnant animals either received no extra MSG, or 2.5 g MSG, or 5 g MSG per day, up to the end of the weaning period. In all, 2.5 g, respectively 5 g, MSG accounted for some 10%, respectively 20%, of dry weight of the average daily food ration. After weaning, MSG feeding was continued in the offspring. FINDINGS: Morbid obesity associates with short stature. Average stature of conscripts progressively declines when body mass index increases above 38 kg/m2. Also morbidly obese young women are shorter than average though to a lesser extent than conscripts. Oral administration of MSG to pregnant rats affects birth weight of the offspring. Maternal feeding with 5 g MSG per day results in severe birth weight reduction (P<0.01). Weight increments remain subnormal when MSG feeding to the mothers is maintained during weaning (P < 0.01). GH serum levels are affected in animals that received MSG during prenatal life via maternal feeding. Animals that are kept on high MSG diet (5 g MSG per day) continue to show serum GH levels that are as low or even lower than those of MSG injected animals (P < 0.05), both at day 30 and at day 90 of life. Animals that were kept on medium MSG diet (2.5 g MSG per day) showed low serum GH levels at day 30 of life (P < 0.01), but seemed to partially recover before day 90. Almost identical results were observed in IGF-1 serum levels. Oral MSG resulted in dose dependent voracity. The animals fed 5 g MSG per day increased water uptake by threefold (P < 0.01), and food uptake by almost two-fold (P < 0.01). The influence of MSG is in general more marked in males than in females. INTERPRETATION: GLU is a widely used nutritional substance that potentially exhibits significant neuronal toxicity. Voracity, and impaired GH secretion are the two major characteristics of parenterally administered GLU-induced neuronal damage. GLU maintains its toxicity in animals even when administered orally. Males appear to be more sensitive than females. The present study for the first time demonstrates, that a widely used nutritional monosubstance--the flavouring agent MSG--at concentrations that only slightly surpass those found in everyday human food, exhibits significant potential for damaging the hypothalamic regulation of appetite, and thereby determines the propensity of world-wide obesity. We suggest to reconsider the recommended daily allowances of amino acids and nutritional protein, and to abstain from the popular protein-rich diets, and particularly from adding the flavouring agents MSG.

Nonpharmacologic and pharmacologic management of weight gain.

Obesity increases the risk of several serious health problems, including heart disease, type II diabetes mellitus, hypertension, and osteoarthritis. Patients taking certain psychotropic medications may gain a significant amount of weight (as much as a 5% increase in body weight within 1 to 2 months), placing them at risk for obesity. Body weight monitoring and prudent drug selection are the best approaches to preventing weight gain in patients taking psychotropic drugs. When weight gain (> 5% of initial body weight) is unavoidable, intervention counseling should begin. Nonpharmacologic measures for managing weight gain include a balanced deficit diet of 1000 calories and higher, depending on the patient's weight; 30 to 60 minutes of physical activity daily; and behavioral training to restrain excess caloric intake. Each of these measures requires a considerable commitment on the part of the patient and works best with support from the physician and weight-loss support groups. Drug therapy for weight loss is available (at present, sibutramine is the only approved appetite suppressant in the United States); however, for most patients already being treated with a psychotropic agent, the risks (such as drug interactions, adverse events, compliance problems) of adding an antiobesity agent probably outweigh the benefits. Surgical intervention for obesity should be reserved for morbidly obese patients whose disease is intractable to medical therapy.

Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying ß-cell dysfunction.

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic ß-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic ß-cells to secrete insulin.

Lethal obesity associated with sodium valproate in a brain-injured patient.

A 34-year-old man developed posttraumatic epilepsy and a disinhibited orbitofrontal syndrome following severe head trauma at age 22. After an 11-year prison term marked by repeated impulsive aggression, he was transferred to a state psychiatric hospital. Replacement of phenytoin by valproic acid resulted in a 100-lb weight gain, exacerbation of sleep apnea, and right heart failure. Despite replacement of valproate with topiramate, he died of a cardiorespiratory arrest during a seizure. This case illustrates the potential risks associated with valproate therapy in the obese brain-damaged population.

Obesity in schizophrenic outpatients receiving antipsychotics in Taiwan.

This investigation estimates and compares, for the first time, the distribution of body mass index (BMI: kg/m(2)) and the prevalence of obesity among Chinese outpatients with schizophrenia treated with antipsychotics. The BMI of 201 outpatients with schizophrenia-spectrum disorders was studied via a cross-sectional naturalistic study. This investigation also compared the BMI of the subjects with a Taiwanese reference population. This investigation found no significant difference in the prevalence of obesity between male and female subjects. The prevalence of obesity among male and female patients in this investigation was, respectively, 2.74- and 2.51-fold greater than the Taiwanese reference population, and the prevalence of severe obesity among male and female patients was 4.66- and 3.53-fold greater than that in the Taiwanese reference population, respectively. The rate of severe obesity was especially high in patients treated with olanzapine. Atypical antipsychotics other than olanzapine did not seem to be more closely associated with obesity or severe obesity compared to typical antipsychotics.