Effectiveness of intermittent fasting for weight loss in individuals with obesity: A meta-analysis of randomized controlled trials.

AIM: To assess whether intermittent fasting (IF) diets are associated with improvement in weight loss, metabolic parameters, and subjective well-being, in people with obesity. DATA SYNTHESIS: We performed a Meta-analysis of Randomized Controlled Trials longer than 2 months, retrieved through an extensive search on MedLine, Cochrane CENTRAL Library, and Embase online databases, comparing weight loss with IF diets and control diets in people with Body Mass index (BMI) > 30 kg/m2. We retrieved 9 trials, enrolling 540 patients. IF was not associated with a significantly greater reduction of body weight or BMI at any time point with respect to controls or in respect to continuous restricted diets, with low-to moderate quality of evidence; no significant difference in efficacy between alternate day fasting and time restricted eating was found. Differences in fasting plasma glucose, total or high-density lipoprotein cholesterol or blood pressure at any time point were not statistically significant, whereas a reduction of low-density lipoprotein cholesterol (MD -8.39 [-15.96, -0.81] mg/dl, P = 0.03; I2 = 0%) was observed at 2-4 months, but not in the longer term. Data on psychological parameters and overall well-being were insufficient to perform a formal meta-analysis, whereas a qualitative synthesis did not show any difference between IF and controls. CONCLUSIONS: IF is not associated with greater or lesser weight loss than non-intermittent fasting diets. Further data on psychological parameters and overall well-being are needed to properly assess the role of IF diets in the management of obesity.

Factor analysis as a tool to explore the heterogeneity of type 2 diabetes: A feasibility study.

AIM: Diabetes is currently classified based on pathogenetic mechanisms and Type 2 diabetes (T2DM) can be considered a residual heterogeneous category. Factor analysis (FA) identifies a limited number of calculated variables related to a larger number of measured parameters, capable of explaining most of their variance. Aim of the present study was to verify the feasibility of the application of FA for the development of pathogenetic models of individual cases of T2DM, using three available databases. METHODS: Firstly, a model of FA was applied to an existing dataset of non-diabetic patients, identifying three factors associated with fasting or post-prandial hyperglycemia. These factors were then calculated in: - patients enrolled in a retrospective observational study, assessing time to failure to diabetes treatment in three cohorts of patients (metformin or sulfonylurea monotherapy, or no pharmacological therapy); - in a retrospective cohort of patients failing to dual oral therapy and initiating treatment with DPP4 inhibitors; - in patients enrolled in a case-control study onincident cancer in T2DM subjects initiating insulin treatment. RESULTS AND CONCLUSIONS: Despite limitations, our results confirm the feasibility of approaching the characterization of T2DM through the identification of dimensional factors, providing additional and complementary information to that obtained with cluster analysis.

Effectiveness of low-carbohydrate diets for long-term weight loss in obese individuals: A meta-analysis of randomized controlled trials.

AIM: To assess whether low-carbohydrate (LC) diets are associated with differences in weight loss and well-being in people with obesity, and their cardiovascular and renal safety. MATERIALS AND METHODS: A meta-analysis of randomized controlled trials longer than 3 months, retrieved through an extensive search on MedLine and Embase databases, comparing weight loss with LC and control diets in people with body mass index (BMI) greater than 30 kg/m2 , was conducted. RESULTS: We retrieved 25 trials. Compared with controls, LC diets were associated with significant reduction of body weight at 3-4 (MD -2.59 [-3.93, -1.25] kg) and 6-8 months (MD -2.64 [-4.32, -0.95]), but no difference at 10-14 and 18-30 months, and significantly greater BMI reduction at 3-4 months (-1.66 [-2.70, -0.61] kg/m2 ), but not at other time points. Because only four trials reported data on renal function and psychological variables, renal safety and impact on well-being could not be assessed. Differences in fasting plasma glucose at any time point were not statistically significant. No significant differences in total or LDL cholesterol or blood pressure were found in the long term, whereas a long-term reduction of triglycerides (23.26 [-45.53, -0.98] mg/dl at 18-30 months), and increase of HDL cholesterol (MD 4.94 [0.30, 9.57] mg/dl at 18-30 months), were observed. CONCLUSION: LC diets are associated with greater short-term weight loss than non-carbohydrate-restricted diets and a longer term favourable effect on cardiovascular risk factors. Further evidence on long-term efficacy and renal safety is needed before LC diets can be recommended as the preferred diets in obese people.

Efficacy and effects of bariatric surgery in the treatment of obesity: Network meta-analysis of randomized controlled trials.

AIMS: Bariatric surgery (BS) is recommended for subjects with a Body Mass Index (BMI) over of 40 kg/m2 or with a BMI between 35 and 40 kg/m2 with obesity-related comorbidities. Aim of the study was to compare different types of BS with medical therapy (MT) for the treatment of obesity. DATA SYNTHESIS: We conducted a network-meta-analysis (NMA) including randomized clinical trials comparing different BS techniques versus MT in people with obesity, with a duration ≥24 weeks (PROSPERO, #CRD42020160359). Primary endpoint was BMI. Indirect comparisons of different types of surgery were performed by NMA. Types of BS included: laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass, sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD); greater curvature plication (GCP); one-anastomosis gastric bypass (OAGB); Laparoscopic Vertical Banded Gastroplasty (LVBG) and duodenal switch (DS). 43 trials were retrieved in this metanalysis. BS was associated with a significant reduction in BMI, systolic blood pressure, triglyceride and fasting glucose, and with a significant increase of HDL cholesterol when compared to MT. In direct comparisons, RYGB was more effective than LAGB, LVBG, and GCP, but less effective than DS, whereas LAGB was less effective than LVBG and SG. In the NMA, DS and BPD appeared to be more effective than other procedures. CONCLUSIONS: BS produces a greater weight loss than MT in morbidly obese patients, inducing a greater improvement of obesity-associated metabolic parameters. Available data are insufficient to assess the effect of BS on mortality. Different surgical procedures are heterogeneous for efficacy and safety.

Obesity as a risk factor for hospitalization in COronaVirus Disease-19 (COVID-19) patients: Analysis of the Tuscany regional database.

BACKGROUND AND AIMS: Aim of the present study is to determine the role of obesity as a risk factor for COronaVirus Disease-19 (COVID-19) hospitalization. METHODS AND RESULTS: This observational study was performed using Istituto Superiore di Sanità (ISS) Tuscany COVID-19 database by the Agenzia Regionale Sanità (ARS), including all COVID-19 cases registered until April 30th, 2020, with reported information on chronic diseases. The principal outcome was hospitalization. An age and gender-adjusted logistic regression model was used to assess the association of clinical and demographic characteristics with hospitalization. Further multivariate models were applied. Of 4481 included subjects (36.9% aged over 70 years), 1907 (42.6%) were admitted to hospital. Obesity was associated with hospitalization after adjusting for age and gender. The association of obesity with hospitalization retained statistical significance in a fully adjusted model, including possible confounders (OR: 2.99 [IC 95% 2.04-4.37]). The effect of obesity was more evident in younger (<70 years) than in older (≥70 years) subjects. CONCLUSIONS: The present data confirm that obesity is associated with an increased risk of hospitalization in patients with COVID-19. Interestingly, the association of obesity with hospitalization was greater in younger (<70 years) patients.

Insulin resistance and obesity affect monocyte-derived dendritic cell phenotype and function.

AIM: Cardiovascular disease (CVD) is prevalent in women after menopause, which may be associated with obesity, insulin resistance and metaflammation. Despite the recognized role of immunological mechanisms in vascular remodeling, the role of dendritic cells (DCs) is still unclear. The aim was to characterize monocyte-derived DCs (Mo-DC) in post-menopausal patients with type 2 diabetes (T2DM) and obese woman, without clinical manifestations of atherosclerosis. METHODS: Obese post-menopausal women with or without T2DM were enrolled and were compared to age-matched healthy women. DCs obtained from patients were phenotypically and functionally characterized by flow cytometry and mixed lymphocyte reaction. MRNA integrins expression was assessed by real time RT-PCR; circulating fetuin-A and adiponectin levels were measured by ELISA. RESULTS: Phenotypic dysregulation of Mo-DC reported was related to a defective allogenic lymphocyte stimulation and to an increased mRNA of CD11c, CD18 and DC-SIGN/CD209 which regulate their adhesion to vascular wall cells. Fetuin-A and adiponectin levels were significantly altered and negatively correlated. Hyperglycaemia significantly impaired CD14+ transdifferentiation into Mo-DC. CONCLUSIONS: These data show a dysfunction of Mo-DCs obtained from precursors isolated from T2DM obese post-menopausal woman without any documented clinical CV event. Association of obesity to diabetes seems to worsen DC's phenotype and function and increase vascular inflammation.

Metabolic surgery for the treatment of type 2 diabetes: A network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery (MS) with medical therapy (MT) for the treatment of type 2 diabetes (T2D). MATERIALS AND METHODS: We conducted a network-meta-analysis (NMA) including randomized clinical trials comparing different MS techniques versus MT in people with T2D, with a duration of ≥24 weeks. Primary endpoints were glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and diabetes remission. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and Mantel-Haenzel odds ratios for categorial variables, were calculated using random effect models. Types of MS included: laparoscopic adjustable gastric banding (LAGB), Roux-en-Y gastric bypass, sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD); greater curvature plication (GCP); one-anastomosis gastric bypass (OAGB); and duodenojejunal bypass. RESULTS: The 24 retrieved trials included 1351 patients (1014 with MS and 337 with MT). The mean baseline BMI was 36.8 kg/m2 . MS was associated with significantly greater reductions in HbA1c and FPG and greater diabetes remission when compared to MT. In the NMA, a significant reduction in HbA1c was observed with OAGB and SG. All surgical procedures were associated with a significant increase in diabetes remission, except GCP and LAGB. All procedures were associated with a reduction of body mass index (BMI). CONCLUSIONS: Metabolic surgery is an interesting option for the treatment of T2D, although further data are needed to demonstrate its long-term efficacy and safety. Present data are not sufficient to modify current recommendations, which consider MS a possible treatment for T2D in those with a BMI >35 kg/m2 .

Obesity Therapy: How and Why?

BACKGROUND: Obesity represents the second preventable mortality cause worldwide, and is very often associated with type 2 Diabetes Mellitus (T2DM). The first line treatment is lifestyle modification to weight-loss, but for those who fail to achieve the goal or have difficulty in maintaining achieved results, pharmacological treatment is needed. Few drugs are available today, because of their side effects. OBJECTIVE: We aim to review actual pharmacological management of obese patients, highlighting differences between Food and Drug Administration - and European Medicine Agency-approved molecules, and pointing out self-medications readily obtainable and widely distributed. METHODS: Papers on obesity, weight loss, pharmacotherapy, self- medication and diet-aid products were selected using Medline. Research articles, systematic reviews, clinical trials and meta-analyses were screened. RESULTS: Anti-obesity drugs with central mechanisms, such as phentermine and lorcaserin, are available in USA, but not in Europe. Phentermine/topiramate and naltrexone/bupropion combinations are now available, even though the former is still under investigation from EMA. Orlistat, with peripheral mechanisms, represents the only drug approved for weight reduction in adolescents. Liraglutide has been approved at higher dose for obesity. Anti-obesity drugs, readily obtainable from the internet, include crude-drug products and supplements for which there is often a lack of compliance to national regulatory standards. CONCLUSIONS: Mechanisms of weight loss drugs include the reduction of energy intake or the increase in energy expenditure and sense of satiety as well as the decrease of hunger or the reduction in calories absorption. Few drugs are approved, and differences exist between USA and Europe. Moreover, herbal medicines and supplements often sold on the internet and widely used by obese patients, present a risk of adverse effects.

Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): Data from randomized controlled trials.

AIM: Glucagon-like peptide 1 receptor agonists (GLP1-RA) have been associated with an increased risk of pancreatitis and pancreatic cancer. Prior meta-analyses of randomized controlled trials failed to show any significant increase of risk; however, those meta-analyses did not include the recently published cardiovascular outcome trials (CVOT) with GLP1-RA, which provide a substantial additional body of data. The aim of the present meta-analysis is to assess the effect of GLP1-RA on pancreatitis, pancreatic cancers and cholelithiasis. MATERIALS AND METHODS: A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. RESULTS: Of the 113 trials fulfilling inclusion criteria, 13 did not report information on pancreatitis, whereas 72 reported no events in all treatment groups. The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms (MH-OR [95% CI] 0.93 [0.65-1.34], P = .71, and 0.94 [0.52-1.70], P = .84, respectively), whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected. CONCLUSIONS: Presently available data confirm the safety of GLP-1 receptor agonists for pancreatitis. Conversely, therapy with those drugs is associated with an increased risk of cholelithiasis, which deserves further investigation.

Lower and higher-potency statins on glycemic control in type 2 diabetes: A retrospective cohort study.

AIMS: Evidences showed a link between statins and new-onset diabetes and large clinical trials in type 2 diabetes (T2DM) suggested a mild glycemic progression in statin treated. Since this effect has not yet elucidated in real world, we investigated the effects of different statins on glycemia in T2DM clinic outpatients. METHODS: In a retrospective cohort study, we recorded at 6 and 12months modifications of fasting glucose (FPG), HbA1c, diabetes intensification therapy and target rate for HbA1c in 421 T2DM non-users and new statin users. Statins were categorized with low or high potency. RESULTS: Compared to statin users, no statin group showed a significant HbA1c reduction from 52.8±14.0mmol/mol to 48.2±8.5 (p=0.003) at 6months and 48.6±8.8 (p=0.007) at 12months. This trend without statins was also observed in FPG starting from 7.1±2.0mmol/l to 6.7±1.6 (p=0.12) at 6months and 6.6±1.5 (p=0.032) at 12months. Statins determined a significant diabetes treatment intensification: 48.7% vs 27.4% (p=0.002) with hazard ratio 2.4 [95% CI 1.14-5.2], p=0.022. HbA1c target was significantly lower in statin users 62.0% vs 75.4%, p=0.042. Only lower-potency statins showed a significant reduction of HbA1c from 52.0±11.1mmol/mol to 50.7±9.0 (p=0.017) and 50.7±9.5 (p=0.038) at 6 and 12months, respectively. The same effect for these statins was registered in FPG from 7.5±2.2mmol/l to 7.0±1.6 (p=0.021) at 6months and 7.2±1.5 (p=0.026) at 12months. CONCLUSIONS: In patients receiving statin therapy a greater intensification diabetes therapy is need. This impact seems to be less pronounced by statins with lower potency.

Motivational enhancement therapy in obese patients: A promising application.

A pilot uncontrolled study aimed at investigating the efficacy of a motivational enhancement therapy adapted for obesity was conducted on 71 obese patients (59 females). Treatment consisted of 5 weekly group sessions and 3 weekly individual sessions. Outcome measures included Treatment, Motivation and Readiness test (TREMORE) and anthropometric measures. Patients showed a significant reduction of all anthropometric parameters (with exception of waist circumference), and a significant improvement of TREMORE scores at the end of the treatment. The motivational interviewing program applied in the current study appears to be effective and consistent with both patient recommendations and health care clinic demands.

All roads bring to Rome: a different way for predicting success in the therapy of obesity through psychological features.

PURPOSE: Obesity treatment based on lifestyle modifications is characterized by a high proportion of treatment failures. The study of predictors of success could be useful for a better definition of therapeutic needs in individual patients. Few studies have attempted a comprehensive assessment of psychological factors related with treatment response. Aim of the study is the identification of psychological and psychopathological features associated with a good treatment response in patients referring for obesity. METHODS: This prospective observational study was conducted on a consecutive series of 270 obese patients and a six-month follow-up was performed. At enrollment, a complete medical history was collected and, psychopathology and psychological features were assessed with: General psychopathology: Symptom Checklist 90-revised, Eating Disorder Examination-Questionnaire, Obesity Related well-being and Treatment, Motivation and Readiness test. RESULTS: Among the 231 patients evaluated at follow-up, the mean weight loss was 3.2% of initial body weight and 68 patients (29.4%) reached the pre-defined therapeutic target of 5% weight loss. Higher psychopathology was associated with a worse outcome in women only; whereas motivation was higher in patients achieving therapeutic targets among men, but not in women. CONCLUSIONS: Mean weight loss obtained with lifestyle interventions is confirmed to be rather small and a more accurate selection of patients to be enrolled in lifestyle intervention programs is needed. The present study provides some intriguing information on predictors of weight loss, which could be useful for the identification of patients with a higher chance of succeeding with lifestyle programs for the treatment of obesity.

False and true pre-treatment predictors of weight loss in obese patients starting a program for lifestyle change.

PURPOSE: Weight loss treatment effectiveness and cost-effectiveness may be improved by the identification of patients who are more prone to participate and gain benefit from specific interventions. Aim of the present study is to identify easily available additional predictors of weight loss among data usually present in the medical records of obese/overweight patients attending an outpatient clinic for a non-pharmacological lifestyle change program. RESULTS: 268 patients, 74 men and 195 women (age 43.2 ± 11.9 years, BMI 38.9 ± 6.8 kg/m(2)) were enrolled. Among these patients, only 35.6 % men and 22.7 % women completed the 6-month protocol. Among participants, 50.7 % lost at least 5 % initial body weight after 6 months (SUCCESSES), while 49.3 % failed (FAILURES). Baseline nutritional parameters (total Kcal, lipid, carbohydrate, protein and alcohol intake) were not significantly different in successes when compared to failures, while a significant difference between groups was observed for baseline diastolic blood pressure (DBP); free fat mass (FFM); muscle mass (MM); total body water (TBW); HDL cholesterol; ALT; AST; γGT. After dividing into quartiles the not-normally distributed variables, successes had AST values above median (3rd and 4th quartiles; χ (2) = 0.003). At multivariate analysis (linear regression), the OR was 3.34 (1.42-7.85; p = 0.006). CONCLUSIONS: In our patients, baseline liver enzyme levels (AST in particular), but not baseline quantitative and qualitative dietary intake, were significantly different in successes versus failures and could therefore represent a predictor of success. In conclusion, AST could represent a usually available biomarker that could be used as a predictor of outcome (weight loss) in obese patients starting a lifestyle change program.

Fit and motivated: outcome predictors in patients starting a program for lifestyle change.

BACKGROUND: In previous pilot studies we have demonstrated that the Treatment Motivation and Readiness Test (TRE-MORE) is capable of predicting the outcome of obesity therapy and that a higher muscle mass (MM) is associated with a greater weight loss. Purposes of the present study were: to confirm the predictive value of TRE-MORE scores and MM, using a standardized non-pharmacologic intervention for weight loss; to explore the relationship between TRE-MORE and MM; to discriminate predictors of attendance from predictors of final therapeutic success. METHODS: A consecutive series of 331 patients was enrolled and addressed to a standardized treatment protocol. RESULTS: Mean weight loss at 6 months was -5.03%. Among participants, 48.7% lost at least 5% initial body weight after 6 months and had significantly higher TRE-MORE total scores and MM. Weight loss was significantly associated with baseline MM, TRE-MORE-3, and a lower number of previous diets. Significantly lower TRE-MORE-3 scores were associated with drop-out. CONCLUSION: The present study confirms that therapeutic success is predicted by TRE-MORE scores and, independently from these, by estimated MM (after adjustment for BMI). TRE-MORE total score is a predictor of failure, but not of attendance, whereas drop-out patients showed a lower score only in TREMORE-3 subscale which investigates lifestyle habits.

Are psychopathological features relevant predictors of glucose control in patients with type 2 diabetes? A prospective study.

Type 2 diabetes has been associated with an increased prevalence of psychopathology, in comparison with matched non-diabetic controls. However, the cross-sectional design of most studies does not allow causal inferences. The aim of the present study is the exploration of this possible association in patients with type 2 diabetes, in a longitudinal fashion. This prospective observational study was conducted on a consecutive series of 250 type 2 diabetic outpatients and a 1-year follow-up period was performed. At enrollment, a complete medical history was collected and hemoglobin A1c was measured. General psychopathology was assessed using the Symptom Checklist 90-revised and the Eating Disorder Examination Questionnaire. Among the 187 patients available at follow-up, factors associated with unsatisfactory glycemic control at follow-up were baseline hemoglobin A1c, insulin therapy, a longer duration of diabetes, higher scores on the Eating behavior, and Somatization scales. At multivariate analysis, the attainment of hemoglobin A1c ≤ 7 % was associated with baseline hemoglobin A1c (p = 0.01), insulin therapy (p = 0.016), and Eating behavior (p = 0.02), whereas duration of diabetes and Somatization were no longer significant after adjusting for confounders. The results of the present study suggest that clinical features have a much greater impact on attainment of therapeutic goals than psychopathology. However, there are several aspects, such as temperament, motivation, self-efficacy, and well-being, not assessed in the present study, which could be crucial. These areas should be adequately explored for obtaining an overall picture of the psychological determinants of appropriate metabolic control in diabetes.

Different modulation of dipeptidyl peptidase-4 activity between microvascular and macrovascular human endothelial cells.

Dipeptidyl peptidase 4 (DPP-4) is an enzyme that is produced by endothelial cells in different districts and circulates in plasma. Patients with type 2 diabetes show a reduction in active Glucagon-Like Peptide-1 (GLP-1) that could be due to impairment of secretion or its degradation or both. GLP-1 is rapidly inactivated in vivo, mainly by the DPP-4. Some authors suggest that Metformin has no direct inhibitory effect on DPP-4 activity and that Metformin and the other biguanides enhance GLP-1 secretion; others suggest a possible role of Metformin in the inhibition of the DPP-4 activity. In order to better elucidate the role of insulin sensitizers on the modulation of GLP-1 circulating levels, DPP-4 activity and mRNA expression were measured in cultured human aortic endothelial cells (HAEC) and human microvascular dermal endothelial cells (HMVEC) exposed to high glucose, Metformin and Rosiglitazone. Present data show that hyperglycemia is capable of increasing in a significant manner the DPP-4 activity only in microvascular endothelial cells. Rosiglitazone is able to modulate in a negative manner the expression of DPP-4 but not its activity in macrovascular endothelial cells, while at 24 h of exposure it is able to increase significantly DPP-4 activity but not its expression in microvascular endothelial cells. Metformin at 48 h only in microvascular endothelial cells is able to reduce in a significant manner (p = 0.01) the activity of DPP-4 but not its expression. The modulation of DPP-4 is site specific.

Adipokines as possible new predictors of cardiovascular diseases: a case control study.

Background and Aims. The secretion of several adipocytokines, such as adiponectin, retinol-binding protein 4 (RBP4), adipocyte fatty acid binding protein (aFABP), and visfatin, is altered in subjects with abdominal adiposity; these endocrine alterations could contribute to increased cardiovascular risk. The aim of the study was to assess the relationship among adiponectin, RBP4, aFABP, and visfatin, and incident cardiovascular disease. Methods and Results. A case-control study, nested within a prospective cohort, on 2945 subjects enrolled for a diabetes screening program was performed. We studied 18 patients with incident fatal or nonfatal IHD (Ischemic Heart Disease) or CVD (Cerebrovascular Disease), compared with 18 matched control subjects. Circulating adiponectin levels were significantly lower in cases of IHD with respect to controls. Circulating RBP4 levels were significantly increased in CVD and decreased in IHD with respect to controls. Circulating aFABP4 levels were significantly increased in CVD, while no difference was associated with IHD. Circulating visfatin levels were significantly lower in cases of both CVD and IHD with respect to controls, while no difference was associated with CVD. Conclusions. The present study confirms that low adiponectin is associated with increased incidents of IHD, but not CVD, and suggests, for the first time, a major effect of visfatin, aFABP, and RBP4 in the development of cardiovascular disease.