For Asian individuals the BMI numbers are 27.5 and 25 respectively These values are from the NICE guidelines of 2014

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1 Ken Cathcart DO FACE We need to define several things to start the talk Obesity is defined medically as a BMI of greater than 30 or a BMI >27 with co-morbidities such as hypertension, type 2 DM, dyslipidemia, and sleep apnea For Asian individuals the BMI numbers are 27.5 and 25 respectively These values are from the NICE guidelines of 2014 Success of a treatment is not returning someone to a normal BMI, but weight loss that has been show to improve a patients health status in controlled medical studies Multiple studies have shown that losses of 5 to 10% from baseline weight improve health status These improvement are shown in lipids, A1C/FBS, systolic/diastolic BP Malnutrition Immunosuppression (susceptibility to infection) Optimal nutrition Normal immune function Overnutrition Immunoactivation (susceptibility to inflammatory disease) Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:

2 Overnutrition and genetics Adipocyte Macrophages Endocrine inflammatory signals Fat insulin resistance Paracrine and autocrine inflammatory signals Preadipocyte Weight gain MCP-1 TNF-α Leptin VEGF Weight gain Endothelial cell Angiogenesis Physical stress/oxidative damage to endothelium? Insulin resistance JNK NF-κB IL-6 IL-1β TNF-α Liver insulin resistance Systemic insulin resistance Muscle insulin resistance Macrophage recruitment FFA MCP-1 Hypertension, dyslipidemia, hyperglycemia, hyperinsulinemia ATHEROSCLEROSIS Adapted from de Luca C, Olefsky JM. Nat Med. 2006;12:41-2. Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H Macrophage Macrophage recruitment Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112: Triglyceride VLDL C-II C-III B-100 and FFA VLDL = very low density lipoproteins HDL-C Small dense LDL Hypertension Glucose FFA Insulin FFA Insulin Sympathetic nervous system Glycogen CO 2 Triglyceride (intramuscular droplet) Eckel RH et al. Lancet. 2005;365: Atherogenic CRP IL-6 PAI-1 Angiotensinogen Leptin Resistin MCP-1 TNF-α Adipocytokines (adipokines) Antiatherogenic Adiponectin Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115: We know that the first sign of the metabolic changes is progressive insulin resistance The insulin resistance worsens with puberty, age and weight gain The defect progresses with free fatty acids being uncontrolled leading to insulin deficiency Normal glycemia Insulin resistance rises, leading to beta cells working overtime to secrete more insulin Insulin resistance Beta cells are unable to produce the insulin needed to compensate for the increased level of insulin resistance, causing glucose levels to rise, leading to type 2 diabetes* *Type 2 diabetes is diagnosed when FPG is 126 mg/dl. 3 Adapted from International Diabetes Center, Minneapolis, MN. 1 FPG = fasting plasma glucose. 1. Bergenstal RM et al. Endocrinology. 4th ed. Philadelphia, PA: WB Saunders Company;2001: Ramlo-Halsted BA, Edelman SV. Clin Diab. 2000;18: American Diabetes Association. Diabetes Care. 2008;31(Suppl1):S12 S54.

3 Fasting plasma insulin ( U/mL) Loss of b-cell function th percentile 50th percentile 5th percentile 7 DM Insulin sensitivity index (S I ) ( 10-5 min -1 / U/mL) The therapies will be divided into diet/exercise, medications, and surgery I cannot talk about combination therapies as there is just enough time Increased insulin resistance Adapted from Kahn SE et al. Diabetes 1993;42: Hippocrates 2500 years ago treated obesity with diet and exercise The Arab world wrote the basic treatise that was used for the next 400 years it was based on using vegetables and fruits modern diet therapy is traced to 1863 when William Banting an undertaker lost 50 pounds in 1 year using a a low carbohydrate diet prescribed by Dr. Wiliam Harvey the patient published the account himself using his own money A calorie deficit of 500 kcal/day produces a weekly deficit of 3500 calories in 1 week This would produce a weight loss of 1 pound per week, but this is not true

4 In general weight loss is not linear but is rapid at first in the first 3-6 months then decreases in a logarithmic fashion to a plateau. The plateau correlates with serum decreases of Leptin and T3 treatment with T3 does not re-start the weight loss but Leptin does DIRECT was a study done in 49 primary care practices in Scotland and England ( Lancet: 391: Feb 2018 pg ) The control group was usual care plan while the treatment group was a calorie diet/day with no strict exercise prescription in either treatment arm 306 adults with type 2 with a mean BMI of 35 were randomly assigned to either group at 12 months the treatment group was 10 kg lighter the control group was 1 kg less. 24% of the treatment group lost greater than or equal to15kg at one year Diabetes remission was defined by an A1C value of less than 6.5% after 2 months off all antidiabetic medications At 12 months 74% of the intervention group and 18% of the control group were off diabetes medication A1C was 6.4% in the treatment group and 7.2 % in the control group By the end of the study 46% of the intervention group and 4% of the control group met the criteria of remission with 31/36 patients with greater than 15 kg/weight loss having remission (86%) VLCD less than 1000 cal/day faster weight loss 16.1% to 9.7% for conventional diets at 8 months but at 1 year the same Low carb diets give faster weight loss for 6 months, but at one year the weight loss is the same

5 Medications: there are currently 6 medications that are FDA approved medications for weight loss Phentermine, orlistat, phentermine/toprimate ER, Locaserin, liraglutide 3.0 mg, naltrexone sustained release/bupropion SR Orlistat =Xencal lipase inhibitor Phentermine/toprimate ER=Qysmia an adrenergic agonist/neurostabilizer Locaserin = Belviq 5-HT2c receptor agonist Naltrexone SR/buproprion SR=Contrave opioid receptor antagonist/ dopamine/ne receptor reuptake inhibitor All of the medications work compared to placebo Phentermine 5.1% at 28 weeks Orlistat 3.1% at 1 year Qysmia 6.6% at 1 year Belvig 4.6 % at 1 year Contrave 4.8% at 56 weeks Liraglutide 5.4% at 56 weeks (Saxenda is the 3.0 mg dose)

6 If you carefully look at each of the studies of any of these medications one quickly recognizes the so called 4 week rule The 4 week rule is simple If one starts the medication and sees a patient back at 4 weeks for a repeat weigh in If one loses more than 3 pounds at 4 weeks you will get greater than 5% weight loss

7 Thereaux et al (JAMA Surgery online Feb 2018) studied a population based cohort trial of all patients that underwent GI weight loss surgery in France over a 6 year period of time. (n=15,650 diabetics on medication =1633) 49.9% of the patients that underwent the GI surgery were no longer on any diabetes medicines versus 9% in the non-surgically treated patients In the groups of patients that were not diabetic when having GI surgery only 1.2% of the surgery treated group initiated medication versus 12% of the control group at 6 years (p<0.001) However that means 50.1% of all the patients treated still needed diabetes medications proving that type 2 is a genetic disease not a obesity disease Contraindications for surgery Untreated depression or psychosis Severe cardiac disease that precludes anesthesia Coagulopathy Drug or alcohol abuse New data shows that the best outcomes for weight decrease to a BMI of 30 occurs if surgery is done on patient s with a BMI of less than 40 (a 13.3 fold more likely occurrence) Bray et al. Endo Metab Clin N Am : Saunders, et al. Endo Metab Clin N Am 45: Estruch, et al. NEJM 2013: 368: Sjostrom, etal. NEJM : Wing, et al. NEJM 2013:369: Schwartz, et al. Endo Reviews 38: , 2017

8 Lancet Diabetes Endocrinol series 6: