Adipose tissue pollutants and obesity Monteiro, R.; Teixeira, D.; Pestana, D.; Calhau, C.
Departamento de Biomedicina, Unidade de Bioquímica, Faculdade de Medicina, Universidade do Porto, 4200-319 Porto, Portugal; Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal; Unidade de Saúde Familiar Pedras Rubras, Agrupamento de Centros de Saúde Maia-Valongo, 4470-105 Maia, Portugal; Nutrição e Metabolismo, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal; ProNutri – Clinical Nutrition & Disease Programming, CINTESIS – Center for Health; Technology and Services Research, Porto, Portugal The social and economical burden of obesity, due to its increasing preva- lence and associated comorbidities has led to its consideration as a prior- ity in health management. Apart from being of utmost importance in the genesis of obesity, the imbalance between calories ingested and energy expenditure explains only part of obesity etiology. Alongside with this, the mere increase in adipose tissue accumulation is not responsible for obesity-associated pathologies, which seem more dependent on location of adipose tissue accumulation, adipose tissue cellularity, and adipocyte dysfunction. Recently, the accumulation of lipophilic environmental pol- lutants on virtually all living organisms has been highlighted. With the ac- knowledgement that adipose tissue serves as the main reservoir for these compounds, came the recognition that their presence in that tissue goes beyond serving as main accumulation. In fact, adipose tissue constitutes one of the main targets of environmental toxicant actions. Evidence is be- ing gathered, from different research groups, including our own, on the
effects of adipose tissue pollutants and obesity and its comorbidities. In this regard, the growing production and release into the environment of chemical compounds from different chemical classes, along with human exposure from environmental and food sources bring an additional player in to the discussion of obesity origins. Furthermore, either acting locally or being released from their adipose tissue reservoir, these chemicals com- pounds, some of which have been demonstrated to possess endocrine-dis- rupting ability, impose pressure onto energy homeostasis regulation, pre- disposing to obesity and adipocyte dysfunction.
Conflict of Interest: None disclosed.
Funding: Research relating to this abstract was funded by FCT (Fundo Social
Europeu, Programa Operacional Potencial Humano da EU (POPH); PEst-OE/ SAU/UI0038/2011, SFRH/BPD/40110/2007, SFRH/BD/46640/2008, SFRH/ BD/64691/2009).
RS14 – Pharmacotherapy
RS14:1Current drugs for obesity: From actual availability to future perspectives
Van Gaal, L.F.
Department of Endocrinology, Diabetology and Metabolism, Faculty of Medicine, Antwerp University / Belgium
Obesity is becoming increasingly common and is recognized as a major public health problem worldwide. Overweight (BMI > 25) prevalence ranges from 30-50 % and clear obesity (BMI > 30) is also becoming in- creasingly prevalent.
It has been shown that an intentional weight reduction of 5-10 % may lead to a marked improvement in cardiovascular risk factors and a substantial reduction up to 20-25 % in co-morbidity. The 10% weight loss option has been reported to be associated with a reduction of 25-30 % of visceral fat, associated with an improvement of glucose tolerance (30%), triglyceride levels (30%), blood pressure (10 %) and factors of hemostasis and fibrino- lysis (10-30 %). Although dietary approach and lifestyle adaptation re- mains the cornerstones of obesity therapy, long-term success is extremely disappointing – even after intensified therapeutic approaches, such as VLCD, dietary therapy, physical exercise and behavioral treatment. Over the last years, obesity research has been focused on the exploration of new biochemical pathways and on new pharmacological intervention potentials. Large-scale, long term studies have demonstrated that the use of pharmacological agents are able to induce significant weight loss (5- 10%) in addition to dietary/physical activity approaches and important reduction of co-morbidities as well, fulfilling the targets of 20-30 % risk reduction. Characteristics of an ideal anti-obesity agent include safe mol- ecules without major side effects, promoting a weight reduction in a dose dependent manner, having long lasting effects not leading to addictive properties and/or toxicity.
Among anti-obesity agents in Europe, we have orlistat, the naltrexone/ bupropion combination and high dose liraglutide.
In the US we have additionally lorcaserin as a 5-HT2c serotonin agonist and the low dose phentermine/topiramate as approved drugs.
Orlistat as a lipase inhibitor has been used for many years in the 120 mg formulation, as well as the 60 mg OTC format. Orlistat shows modest weight reduction, has a beyond weight loss effect on LDL cholesterol and delays the onset of type 2 diabetes in obese individuals with prediabetes (37 % risk reduction beyond lifestyle).
The tolerability is very good, except for the expected gastro intestinal side effects of steatorrhea in case of too high fat intake.
Bupropion is an anti-depressant, also used for smoking cessation; when used in combination with naltrexone, a β-opioid receptor antagonist, weight loss effects reach an absolute weight loss of 7-8 kg, depending on the patients studied, roughly 5.5 % placebo substracted. It has an accept- able safety profile (a cardiovascular outcome trial is ongoing) but is un-
fortunately, although approved, not yet available in the majority of the EU countries. In the injectable drug categories, liraglitude 3 mg as a GLP-1 receptor agonist, recently became available: liraglutide offers an absolute weight loss, close to 10 kg (6-7 kg difference approx. when compared to placebo). From the extensive Scale trial program, it was shown liraglu- tide has a very good efficacy and safety; besides the well-known gastro intestinal adverse events (nausea, vomiting) it shows additional benefit on glucose tolerance (reduction of pre diabetes), on blood pressure and car- dio vascular biomarkers. In a maintenance study after a LCD significant weight maintenance could be obtained.
Recently, the consistent findings of 3 years’ observation have been pub- lished, focusing on both efficacy, tolerability and safety.
Future development perspectives of anti-obesity drug will very likely fo- cus on combination therapy, mainly in the peptide field.
RS14:3
Triple hyoglycaemic therapy as a novel therapeutic strategy in medical management of obesity
Lipworth, S.1; Iftikhar, M.2; Amir, Z.3; Balaratnam, J.3; Boparai, A.3;
Coppack, S.3; Emmanuel, J.3
1University of Oxford, 2Barts And The London School Of Medicine, 3Barts Health
Nhs Trust
Intruduction: Obesity affects just over a quarter of adults in England
(Public Health England, 2016). There is an urgent need for novel evidence based therapeutic regimes to underpin the emerging field of medical man- agement of obesity. Recent randomised placebo controlled trials (RCTs) have shown the glucagon-like peptide-1 agonist (GLP1) liraglutide to be efficacious in a dose dependent manner for weight loss in both diabetics and non-diabetics. In diabetic patients Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with weight loss which is significantly increased when they are used in conjunction with a GLP1 agonist. Use of hypoglycaemic agents in combination with the primary aim of weight loss is currently not widespread practice.
Methods: 504 patient records were examined between January 2014 and
September 2016. Of these 202 met the inclusion criteria of being in one of the treatment groups and having at least two BMI readings available. Data was treated non-parametrically and corrections for multiple compari- sons performed using the Bonferonni method. Mean and median time adjusted ratio of BMI change was calculated for each group. Groups were as follows: Metformin alone, metformin + GLP, metformin + SGLT2i, or metformin + GLP + SGLT2i (triple).
Results: There was no statistically significant difference between baseline
characteristics of the cohort between the treatment groups as determined by one-way ANNOVA. Our cohort contains a disproportionately large number of females (66.3%) and all groups had a mean and median first BMI recording > 40 Kg/m2 (Class III obesity). There was a significant dif- ference between distributions of % change in BMI per year between the treatment groups (p = 0.030). An inspection of pairwise tests revealed a significant comparison between triple therapy and metformin (median % BMI change per year 1.74 vs –0.495, p = 0.004 (0.04 after adjustment for multiple comparisons)). None of the other pairwise comparisons were significant (median % BMI change 1.91, 1.37 for Metformin + GLP/Met- formin + SGLT respectively). Patients on metformin as single therapy gained weight (median increase 0.5% in BMI per year).
Conclusion:Our results are important as they highlight the potential use
of SGLT2i/GLP combinations in obese patients for whom surgery is not viable and other interventions such as lifestyle changes alone or medica- tion such as Orlistat are inadequate. They are also notable because our cohort suffers from more severe obesity than those from recent RCTs. Further expansion and analysis of this dataset is likely to strengthen the case for an RCT looking at combination hypoglycaemic therapy in obese patients.
RS14:4
Naltrexone/bupropion is well tolerated and had no effect on serious adverse events in participants receiving antidepressant medication, including SSRIs, in a large randomized double-blind study
Halseth, A.1, Gilder K.1, Shan K.1, Acevedo L.1, Smith S.2
1Orexigen Therapeutics, Inc., La Jolla, CA, USA, 2Florida Hospital Translational
Research Institute For Metabolism And Diabetes, Orlando, Fl, Usa
Introduction: Extended-release naltrexone 32 mg/bupropion 360 mg
(NB) is approved for chronic weight management as an adjunct to diet and physical activity. This study assessed the effect of NB on cardiovascu- lar (CV) events in overweight/obese participants at elevated CV risk. Ran- domized participants (NB or placebo [PBO]) received an internet-based weight management program. Participants were required to lose ≥2% body weight at 16 weeks, without a sustained increase in blood pressure, to continue study drug.
Methods: This study was terminated early after the second interim anal-
ysis, which corresponded to 50% of the primary endpoint data being collected. Data on CV endpoints were previously published. The current analyses focused on adverse events in participants on antidepressants at baseline, as they were excluded from Phase 3 trials.
Results: The intent-to-treat (ITT) population (PBO N = 4450, NB
N = 4455) was 54.5% female, 83.5% white, mean age of 61 yrs, mean BMI 37.3 kg/m2, 22.8% with a history of depression, 23.1% on antidepres- sant medication, including 15.4% on SSRI. The incidence SAEs in par- ticipants receiving antidepressants was similar between NB (10.7%) and PBO (9.9%) and was also similar to that observed in the overall popula- tion (9.5% NB, 8.1% PBO). SAEs in those on SSRIs were similar between NB (10.1%) and PBO (9.4%). For those on antidepressants or just SSRIs, AELDSDs were similar to those observed in the overall population and were primarily GI disorders.
Conclusion: Obesity increases the risk of developing depression. Data
from these analyses demonstrate that for participants taking NB and anti- depressants, including SSRIs, there is a similar adverse event profile as the overall population and revealed no evidence of an additional health risk with combined use.
Conflict of Interest: Some authors are employees of Orexigen Therapeutics, Inc. Funding: Research relating to this abstract was funded by Orexigen Therapeutics,
Inc. RS14:5
Effect on body weight of naltrexone/bupropion in overweight and obese participants with cardiovascular risk factors in a large randomized double-blind study
Halseth, A.1, Gilder K.1, Shan K.1, Acevedo L.1, Buse J.2
1Orexigen Therapeutics, Inc., La Jolla, CA, USA, 2University Of North Carolina
School Of Medicine; Chapel Hill, Nc, Usa
Introduction: Extended-release naltrexone 32 mg/bupropion 360 mg
(NB) is approved for chronic weight management as an adjunct to diet and physical activity. This study assessed the effect of NB on cardiovascu- lar (CV) events in overweight/obese participants at elevated CV risk. Ran- domized participants (NB or placebo [PBO]) received an internet-based weight management program. Participants were required to lose ≥2% body weight at 16 wks, without a sustained increase in blood pressure, to continue study drug.
Methods: This study was terminated early after the second interim anal-
ysis, which corresponded to 50% of the primary endpoint data being collected. Data on CV endpoints were previously published. The current analyses focus on change in body weight.
Results: The intent-to-treat (ITT) population (PBO N = 4450, NB
N = 4455) was 54.5% female, 83.5% white, mean age 61 yrs, mean BMI 37.3 kg/m2; 85.2% had T2DM, 32.1% had CV disease. At 52 wks, the ITT-LOCF analysis showed greater least squares mean percent change in
body weight (LSM%ΔBW) with NB (-3.1%; 95% CI -4.8, -1.4) vs PBO (–0.3%; 95% CI -1.9, 1.4). Both groups lost more weight in an ontreatment analysis (NB [-7.3%] and PBO [-3.9%]). The odds ratios of 5% and 10% weight loss were 3.3 and 4.1, respectively, in NB over PBO. At 104 wks, the on-treatment LSM%ΔBW was -6.3% with NB (n = 1137) vs -3.5% with PBO (n = 741). Major reasons for NB withdrawal were adverse events (AE, 29%) and patient decision (21%), with GI disorders being the most common AEs leading to NB withdrawal.
Conclusion: Weight loss with NB in this study, in an older population
predominantly with diabetes and elevated CV risk, was somewhat lower than that observed in overweight/obese participants without T2DM and similar to participants with T2DM in Phase 3 studies.
Conflict of Interest: Some authors are employees of Orexigen Therapeutics, Inc. Funding: Research relating to this abstract was funded by Orexigen Therapeutics,
Inc.