Treating Obesity in Patients with Down Syndrome and other Developmental Delay Syndromes Angela Fitch, MD, FACP, FOMA Associate Director MGH Weight Center Massachusetts General Hospital/Harvard Medical School 1 obesitymedicine.org Disclosures • Bariatrix/Set Point Health: Advisory Board • Phenomix Advisory Board • Gelesis Advisory Board • MsMedicine Advisory Board • FoundHealth Advisory Board 2 Objectives • Recognize the special issues with obesity facing patients with Down Syndrome and other developmental delays • Review the outcomes of patients with Down Syndrome and other genetic disorders in our comprehensive center. • Understand that anti-obesity medications and surgery are options for patients with the developmental challenges and how to tailor them to their needs 3 Syndromes and Obesity Without Developmental Delay With Developmental Delay • POMC deficiency • Prader Willi • Leptin deficiency • Bardet-Biedl Syndrome • Alstrom Syndrome • MC4R deficiency • Cohen Syndrome • Carpenter Syndrome • Albright’s Hereditary Osteodystrophy • Rubinstein-Taybi Syndrome 4 Syndromes and Obesity Genetic Syndromes Complicated by Obesity • Turner Syndrome • Down Syndrome • Autism Spectrum Disorders 50% more likely to have obesity by age 5 5 Obesity and Developmental Delay • Children of mothers with obesity 70% more likely to fail fine motor test by age 3 • Children of fathers with obesity 75% more likely to fail the test’s personal-social domain — an indicator of how well they were able to relate to and interact with others by age 3 • Children with 2 parents with obesity 3 times more likely to fail problem solving test by age 3 6 Genetic Obesity Syndromes • Typically associated with hyperphagia • Early onset obesity prior to age 6 • Many have a host of other identifiable characteristics • Most have fairly significant developmental delays 7 What works for obesity treatment? • Structure • Accountability • Metabolic advantage • Environmental/stimulus control https://www.the-scientist.com/feature/the-enormity-of-obesity-50015 8 Obesity Treatment Pyramid Shared Decision Making BMI > 40 Surgery 30-40% wt loss BMI > 35 w/comorbidity (60-80% EWL) Endoscopic therapy 10-20% wt loss BMI > 30 10% wt loss BMI > 27 with Pharmacotherapy Some get 20% comorbidity Treatment Treatment Intensity Prescriptive Nutritional Interventions 5-10% wt loss Lifestyle Modification 2-5% wt loss Health Risks BMI 9 10 https://www.mc4r.org.uk/ POMC Deficiency – Early onset obesity without developmental delay • Normal development • Early onset obesity and hyperphagia • Red hair and pale skin • Adrenal insufficiency • Prevalence: < 50 cases reported • Targeted treatment with setmelanotide 11 MC4R Deficiency • Heterozygote MC4R mutations most common form of monogenetic obesity (5-6% of people with obesity) • No specific targeted treatment • Increased lean mass, increased linear growth • Hyperphagia, early onset obesity • ? Benefit of setmelanotide (MC4R agonist) 12 Prader Willi • Loss of function on chromosome 15 (paternal) • 1 in 10,000-30,000 worldwide • Hyperphagia, behavior issues, developmental delay, poor feeding and hypotonia early in life, delayed linear growth • Studies looking at specific medication options • Treat with intensive behavior and medications/surgery if able. 13 Syndromes and Obesity Genetic Syndromes Complicated by Obesity • Turner Syndrome • Down Syndrome • Autism Spectrum Disorders 50% more likely to have obesity by age 5 14 Turner Syndrome and Obesity • 1 in 2,500 live born females • 10% of all first trimester miscarriage • One functioning X Chromosome (XO) • Females only • Associated with short stature, delayed puberty, learning disabilities (ADHD) • Impaired glucose metabolism noted 15 Autism and Obesity • 10-17 yo with autism and intellectual disability 20% have obesity while 15% have obesity in general population. (CDC) • Overlap with ADHD • Treatment can be difficult due to medication side effects • Medications can lead to weight gain • Metformin, GLP-1 can be useful, surgery when indicated • Motivational behavioral interventions 16 Down Syndrome Overview • Most common chromosomal disorder – 1:700 live births in US • Trisomy 21 • Life expectancy – 60 years today – 25 yo in 1983 17 Brian Skotko, M.D. 18 19 Conditions associated with Down Syndrome • Hearing loss (up to 75% may be affected) • Obstructive sleep apnea (between 50 -75%) • Eye diseases, like cataracts (up to 60%) • Heart defects present at birth (50%) • Intestinal blockage at birth requiring surgery (12%) • Hip dislocation (when the thigh bone slips out of the hip socket) (6%) • Thyroid disease (4-18%) • Iron deficiency anemia (10%) • Leukemia (1%) in infancy or early childhood • Hirschsprung disease (<1%) • Alzheimer’s Disease with age • Obsessive Compulsive disorder/anxiety • Cervical spine instability 20 • Gait disorders Down Syndrome and Obesity • 25-75% of people with Down Syndrome in various publications with overweight or obesity • OR 2.17 for women and 0.85 for men for obesity 21 Factors predisposing to obesity • Short stature • Low resting metabolic rate • Sleep apnea • Gait/orthopedic abnormalities • Metabolic syndrome • Eating behaviors/OCD • Low testosterone levels 22 Considerations in treatment • Living situation (home vs group home) • Working situation • Cardiac history • Osteoporosis • Behavior and mood disorders • Other medications • Increase celiac disease 23 Anti-obesity Medications Adjunct to nutritional, physical activity, and behavioral therapies for patients with BMI ≥ 30 or BMI ≥ 27 with co-morbidities Objectives: • Treat disease ‒ Adiposopathy or sick fat disease (SFD) ‒ Fat mass disease (FMD) • Facilitate management of eating behavior • Slow progression of weight gain/regain • Improve the health, quality of life, and body weight of the patient with overweight or obesity 5-10 percent weight loss may improve both metabolic and fat mass disease 24 Obesity Algorithm®. ©2017-2018 Obesity Medicine Association. Reference/s: [239] Central Mechanisms of Action of Anti-obesity Meds GLP-1 Food Intake 5HT Lorcaserin* Dexfenfluramine* GLP-1 NPY Topiramate POMC NE CART Phentermine Dopamine Bupropion/ Naltrexone POMC = ProOpioMelanoCortin neuron lisdexamphetamine NPY = NeuroPeptide Y AgRP = Agouti-Related Peptide 25 * Off market Current Anti-Obesity Medications FDA Approved Off label Use FDA approved for BED Phentermine Metformin lisdexamphetamine Schedule IV Diethylpropion Semaglutide/Exenatide Phendimetrazine Canagliflozin for diabetes Schedule III Benzphetamine (Dapa-,Empa-) Orlistat Pramlintide Phentermine/Topiramate Schedule IV Topiramate for seizures, Zonisamide migraines Naltrexone/Bupropion Bupropion for depression Liraglutide Naltrexone for addiction 26 Case 1 - AT • 34yo female lives with a caregiver/roommate • Champion Special Olympic weight lifter 27 https://www.guelphmercury.com/community-story/8296492-hefty-competition-in-guelph-for-special-olympics-athletes/ Case 1-AT • Phentermine 18.75mg • Topiramate 100mg BID • 203lbs to 167lbs • 20% weight loss • BMI 40 to 33 28 Case 2- MG • 35yo living with parents • Phentermine, semaglutide, topiramate 29 • Initial weight 341lbs to 308lbs, up to 318lbs with COVID • BMI 64 to 56 • > 10% weight loss 30 Case 3-TW • 19yo lives with parents • Fasting insulin 61 • A1c normal 31 • Metformin 2000mg – (wt 250lbs to 231lb 10% weight loss) • Phentermine 18.75mg – (wt 231lb to 221lb 5% wt loss) • Dance video 60 min daily 32 Case 3 - CO • 40 yo male • Fasting insulin 31 • Lived in a group home • Nephrectomy for until COVID hydronephrosis • BMI 39 • Dementia 33 Case 3 - CO 34 • Therapeutic carbohydrate reduction • Initial wt 208lbs to 201lbs came to live with mom 35 Case 4 - NB • 26yo male • Lives with mom and dad who are divorced • Loves to work out • Father with obesity, mom very lean • Father enables • BMI 34, wt 206 lbs 36 169lbs 20% weight loss Metformin alone 37 Case 5 - AW • 27yo female • Lives with mom and dad • Goes to gym every day • Dad tends to enable • On sertraline, Vyvanse at baseline 38 • Liraglutide 3mg • 147lbs to 135lbs almost 10% • Trial of Gelesis 100 next 39 Gelesis100 for obesity treatment 40 Gelesis100 Use 41 Gelesis100 outcomes 42 In Summary • Medications likely work for obesity in patients with developmental delay and other syndromes associated with obesity! Treat obesity in this population! • Use medications that fit the patient best in their treatment goals and side effect profile • Consider medication cost and coverage • Discuss long term use • Work on behavior charts, motivation and physical activity • Identify secondary issues and treat (hypothyroid, insulin resistance, sleep apnea) • Environmental issues can be challenging 43 Questions? [email protected] 44.