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1.
Cognitive Effects of Intentional Weight Loss in Elderly Obese Individuals With Mild Cognitive Impairment.
Horie, NC, Serrao, VT, Simon, SS, Gascon, MR, Dos Santos, AX, Zambone, MA, Del Bigio de Freitas, MM, Cunha-Neto, E, Marques, EL, Halpern, A, et al
The Journal of clinical endocrinology and metabolism. 2016;101(3):1104-12
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Plain language summary
Several studies have elucidated that midlife obesity increases the risk of dementia later in life. While the neuroprotective effects of caloric restriction have been widely demonstrated, they have not yet been investigated in patients with mild cognitive impairment (MCI). The aim of this trial was to evaluate the effect of intentional weight loss in elderly adults with mild cognitive impairment (MCI). Eighty participants aged over 60 were randomly allocated to receive either nutritional counselling or medical care alone for 12 months. The findings of this study indicated that intentional weight loss through diet was associated with cognitive improvement in patients with MCI, and this association was strongest in younger adults and APOE4 carriers. As this was the first clinical trial exploring these effects in patients with MCI further research is warranted.
Abstract
CONTEXT Obesity in midlife is a risk factor for dementia, but it is unknown if caloric restriction-induced weight loss could prevent cognitive decline and therefore dementia in elderly patients with cognitive impairment. OBJECTIVE To evaluate the cognitive effect of intentional weight loss in obese elderly patients with mild cognitive impairment (MCI), considering the influence of age, apolipoprotein E (APOE) genotype, physical activity, biochemical markers, and diet. DESIGN Single-center, prospective controlled trial. SETTING Academic medical center. PARTICIPANTS Eighty obese patients with MCI, aged 60 or older (68.1 ± 4.9 y, body mass index [BMI] 35.5 ± 4.4 kg/m(2), 83.7% women, 26.3% APOE allele ϵ4 carriers). INTERVENTION Random allocation to conventional medical care alone (n = 40) or together with nutritional counselling (n = 40) in group meetings aiming to promote weight loss through caloric restriction for 12 months. OUTCOME MEASUREMENTS clinical data, body composition, neuropsychological tests (main outcome), serum biomarkers, APOE genotype, physical performance, dietary recalls. RESULTS Seventy-five patients completed the follow-up. BMI, on average, decreased 1.7 ± 1.8 kg/m(2) (P = .021), and most of the cognitive tests improved, without difference between the groups. In analysis with linear generalized models, the BMI decrease was associated with improvements in verbal memory, verbal fluency, executive function, and global cognition, after adjustment for education, gender, physical activity, and baseline tests. This association was strongest in younger seniors (for memory and fluency) and in APOE allele ϵ4 carriers (for executive function). Changes in homeostasis model assessment-estimated insulin resistance, C-reactive protein, leptin and intake of energy, carbohydrates, and fats were associated with improvement in cognitive tests. CONCLUSIONS Intentional weight loss through diet was associated with cognitive improvement in patients with MCI.
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2.
A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management.
Pi-Sunyer, X, Astrup, A, Fujioka, K, Greenway, F, Halpern, A, Krempf, M, Lau, DC, le Roux, CW, Violante Ortiz, R, Jensen, CB, et al
The New England journal of medicine. 2015;(1):11-22
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Free full text
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Abstract
BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.).
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Brown adipose tissue: what have we learned since its recent identification in human adults.
Halpern, B, Mancini, MC, Halpern, A
Arquivos brasileiros de endocrinologia e metabologia. 2014;(9):889-99
Abstract
Brown adipose tissue, an essential organ for thermoregulation in small and hibernating mammals due to its mitochondrial uncoupling capacity, was until recently considered to be present in humans only in newborns. The identification of brown adipose tissue in adult humans since the development and use of positron emission tomography marked with 18-fluorodeoxyglucose (PET-FDG) has raised a series of doubts and questions about its real importance in our metabolism. In this review, we will discuss what we have learnt since its identification in humans as well as both new and old concepts, some of which have been marginalized for decades, such as diet-induced thermogenesis.
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Improvement of insulin resistance and reduction of cardiovascular risk among obese patients with type 2 diabetes with the duodenojejunal bypass liner.
de Moura, EG, Orso, IR, Martins, BC, Lopes, GS, de Oliveira, SL, Galvão-Neto, Mdos P, Mancini, MC, Santo, MA, Sakai, P, Ramos, AC, et al
Obesity surgery. 2011;(7):941-7
Abstract
BACKGROUND This study aims to evaluate the effectiveness of the duodenojejunal bypass liner (DJBL) in the improvement of insulin resistance and reduction of cardiovascular risk among morbidly obese patients with type 2 diabetes mellitus, using the triglyceride/high-density lipoprotein (HDL) cholesterol ratio, percentage of weight loss, and glycemic control. METHODS We used the TG/HDL ratio with a cutoff value of 3.5 to identify patients with insulin resistance. The value of the initial ratio was compared with the ratio obtained 6 months after implantation to evaluate whether an improvement in insulin resistance occurred. We also evaluated the improvement of glycated hemoglobin levels and the weight loss resulted from the use of the device and correlated that with the improvement of the TG/HDL ratio. RESULTS All patients implanted with the device presented a statistically significant reduction of the HbA1c levels, with most patients (70.3%) obtaining diabetes control with HbA1c levels lower than 7% at the end of the study. All patients also presented a significant weight reduction, with an average loss of 12.6% of their initial weight. We observed an important improvement in insulin resistance and metabolic syndrome, with a significant reduction of the TG/HDL ratio from 5.75 to 4.36 (p < 0.001) and 42.6% of the patients presenting a TG/HDL ratio lower than 3.5 at the end of the study. CONCLUSIONS The DJBL, when used for a period of 6 months, is effective in the control of diabetes, weight loss, improvement of insulin resistance, and decrease of cardiovascular risk among morbidly obese patients with type 2 diabetes mellitus.
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Prospective randomized controlled trial comparing 2 versions of laparoscopic ileal interposition associated with sleeve gastrectomy for patients with type 2 diabetes with BMI 21-34 kg/m(2).
De Paula, AL, Stival, AR, Macedo, A, Ribamar, J, Mancini, M, Halpern, A, Vencio, S
Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2010;(3):296-304
Abstract
BACKGROUND The objective of the present study was to prospectively evaluate the results of 2 versions of laparoscopic ileal interposition (II) and sleeve gastrectomy (SG) for the treatment of patients with type 2 diabetes mellitus and body mass index of 21-34 kg/m(2). METHODS The laparoscopic procedures were prospectively and randomly performed in 38 patients. Of the 38 patients, 18 underwent the first version (II-SG) and 20 underwent the second version in which a diversion of the second portion of the duodenum was applied (II-DSG) and a segment of ileum was interposed into the proximal duodenum. The groups were comparable regarding age (56 and 50 years); gender (13 men and 5 women and 14 men and 6 women); weight (78 and 86 kg); mean BMI (27 and 29 kg/m(2)); duration of type 2 diabetes mellitus (10.1 and 9.2 years); the presence of dyslipidemia (12 and 8 patients), micro- and macroalbuminuria (9 and 9 patients), hypertension (8 and 15 patients), and retinopathy (5 and 8 patients); and the use of antidiabetic medications and the hemoglobin A1c level (8.6% and 8.4%). All patients were followed up for >or=2 years. RESULTS The mean hospital stay was 3.4 days for the II-SG and 3.5 days for the II-DSG group. No patient required reoperation. All patients in both groups achieved lower levels of hemoglobin A1c. In the II-SG group, the mean hemoglobin A1c level was 6.35% (range 4.9-8.1). In the II-DSG group, the mean hemoglobin A1c level was 5.39% (range 4.2-6.5%). The mean BMI decreased in both groups to 22.2 kg/m(2) in the II-SG group and 22.7 kg/m(2) in the II-DSG group. Normal cholesterol levels (<200 mg/dL) were observed in 95% of the II-SG group and 100% of the II-DSG group. The triglycerides were lower than 150 mg/dL in 73% of the II-SG group and 90% of the II-DSG group after 24 months. CONCLUSION Laparoscopic II-SG and II-DSG were safe and effective operations for controlling type 2 diabetes mellitus in a nonobese (BMI 21-34 kg/m(2)) population.
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Combinations of drugs in the Treatment of Obesity.
Halpern, B, Oliveira, ES, Faria, AM, Halpern, A, Melo, ME, Cercato, C, Mancini, MC
Pharmaceuticals (Basel, Switzerland). 2010;(8):2398-2415
Abstract
Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry.
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[Recent progress and novel perspectives on obesity pharmacotherapy].
Faria, AM, Mancini, MC, Melo, ME, Cercato, C, Halpern, A
Arquivos brasileiros de endocrinologia e metabologia. 2010;(6):516-29
Abstract
Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin.
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A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects.
Cercato, C, Roizenblatt, VA, Leança, CC, Segal, A, Lopes Filho, AP, Mancini, MC, Halpern, A
International journal of obesity (2005). 2009;(8):857-65
Abstract
OBJECTIVE To evaluate the efficacy of diethylpropion on a long-term basis, with emphasis in cardiovascular and psychiatric safety aspects. DESIGN Randomized, double-blind, placebo-controlled trial. MEASUREMENTS Following a 2-week screening period, 69 obese healthy adults received a hypocaloric diet and were randomized to diethylpropion 50 mg BID (n=37) or placebo (n=32) for 6 months. After this period, all participants received diethylpropion in an open-label extension for an additional 6 months. The primary outcome was percentage change in body weight. Electrocardiogram (ECG), echocardiography and clinical chemistry were performed at baseline and every 6 months. Psychiatric evaluation and application of Hamilton rating scales for depression and anxiety were also performed by experienced psychiatrists at baseline and every 3 months. RESULTS After 6 months, the diethylpropion group lost an average of 9.8% (s.d. 6.9%) of initial body weight vs 3.2% (3.7%) in the placebo group (P<0.0001). From baseline to month 12, the mean weight loss produced by diethylpropion was 10.6% (8.3%). Participants in the placebo group who were switched to diethylpropion after 6 months lost an average of 7.0% (7.7%) of initial body weight. The difference between groups at month 12 was not significant (P=0.07). No differences in blood pressure, pulse rate, ECG and psychiatric evaluation were observed. Dry mouth and insomnia were the most frequent adverse events. CONCLUSION Diethylpropion plus diet produced sustained and clinically significant weight loss over 1 year. It seems to be safe in relation to cardiovascular and psychiatric aspects in a well-selected population.
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Orlistat in the prevention of diabetes in the obese patient.
Mancini, MC, Halpern, A
Vascular health and risk management. 2008;(2):325-36
Abstract
There has been an increase in the concern about preventing type 2 diabetes mellitus (T2DM), a disease with great and increasing prevalence. The prevalence of obesity, physical inactivity, Western processed diet, important risk factors for the development of T2DM, are also rising. Free fatty acids are increased in obesity and reduce insulin clearance and increase hepatic glucose production. Implementation of a healthy lifestyle has been show to slow the progression of impaired glucose tolerance to T2DM. Orlistat is an inhibitor of lipase activity, with proved efficacy in body weight reduction and long-term management of obesity and more favorable effects on carbohydrate metabolism and it was prospectively shown in XENDOS study that orlistat promoted long-term weight loss and prevented T2DM onset in obese individuals with normal and impaired glucose tolerance at baseline over four years. This benefit could be associated to the weight loss itself, to the limited absorption of lipids and reduction of plasma free fatty acids, to increased production of incretins or to modulation of secretion of cytokines by adipocytes, all effects secondary to orlistat treatment. A proposed strategy is to identify subjects at highest risk to receive a drug intervention, using lifestyle interventions alone at the community level.
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Pharmacological treatment of obesity.
Mancini, MC, Halpern, A
Arquivos brasileiros de endocrinologia e metabologia. 2006;(2):377-89
Abstract
This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.