Disclosures. Obesity and the Continuum of Dysglycemia, Prediabetes and Diabetes OUTLINE

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1 Obesity and the Continuum of Dysglycemia, Prediabetes and Diabetes Sam Dagogo-Jack, MD, DM, FRCP A. C. Mullins Endowed Chair in Translational Research Professor of Medicine & Director Division of Endocrinology, Diabetes, and Metabolism Director, General Clinical Research Center University of Tennessee Health Science Center Memphis, Tennessee Disclosures Sam Dagogo-Jack, MD Research Grants: NIH/NIDDK Clinical Trial Contracts (UTHSC): AstraZeneca Novo Nordisk Boehringer Ingelheim Consultant/Advisory Board: Merck, Novo Nordisk, Boehringer Ingelheim, Janssen, Sanofi, Amgen OUTLINE Discuss the integrated pathophysiology of obesity and dysglycemia Review lifestyle and multimodality interventions for reversal of dysglycemia Understand the principles of obesity pharmacotherapy and future directions in early intervention 1

2 Interplay of Genes and the Environment OBESITY Energy Intake Energy Expenditure Genes Environment Insulin Resistance + beta-cell Dysfunction Type 2 Diabetes Adapted from Dagogo-Jack S. Diabetes Care, 211 Obesity: Chronic Disequilibrium Between Intake and Output Genetic Predisposition Twin studies show ~5% concordance of obesity Energy Expenditure Energy Intake REE EEE TEF NEAT Appetite, Satiety, Food Choices The Human Gastrointestinal Microbiome The human microbial gene load (microbiome) contains approximately 1 times as many genes as does the human genome. Metagenomics focuses on the role of human and commensal microbial genes in health and disease. a- Prokaryotic phyla were identified by using an alignment of an 18,38-sequence dataset b- Not related to any known genera. DiBaise JK et al. Mayo Clin Proc 83:6-69, 28 2

3 Fecal Transplantation Experiments Energy Weight Change Increase in body fat (%) a, Gas-chromatography mass-spectrometry quantification of short-chain fatty acids in the caeca of lean and obese C57BL/6J mice b, Bomb calorimetry of faecal gross energy content (kcal/ g) of lean (+/+, ob/+; n=9) and obese (ob/ob; n=13) C57BL/6J mice c, Colonization of germ-free wild-type C57BL/6J mice with a caecal microbiota from obese donors results in increased wt. Total body fat content was measured before and after a 2-week colonization, using DEXA. *P<.5, **P=.1, ***P=.1) Turnbaugh PJ, et al. Nature 26;, Intestinal Flora Associated with Weight Loss in Humans Percentage of total sequences Relative abundance of Bacteroidetes and Firmicutes Lean controls include stool samples taken 1 yr apart (Mean + SE) Change in bacteroidetes abundance (%) Abundance of Bacteroidetes following weight loss > 2% weight loss for the CARB-R diet and > 6% for the FAT-R diet. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Nature 26;: Obesity and Diabetes Diabetes Mortality 6 5 Nurses Health Study Relative Risk < Body Mass Index (kg/m 2 ) Colditz et al. Am J Epidemiol. 199;132:5. (Nurses HS) Waaler HT. Acta Med Scand. 198;679 3

4 Pathophysiological Defects in T2DM Insulin resistance Increased glucose reabsorption Hyperglycemia Increase d lipolysis Increased hepatic glucose production Insulin Action and Secretion in Normal vs. Prediabetic Subjects ISI-clamp( mol/kg.min -1 /pm) HOMA-IR Insulin Sensitivity * ** ** *** FPG < H PG <1 <1 <1 >1 IFG IFG-IGT * Insulin Resistance Disposition Index Insulin Secretion (pm) Cavaghan et al. J Clin Invest 1997;1:53-37 Disposition Index # # FPG < H PG <1 <1 >1 <1 IFG IFG-IGT *P=.. **.2, ***P<.1, #P=.2 Dagogo-Jack S, Askari H, Tykodi G. JCEM 9: , 29.

5 Pathophysiological Defects in T2DM and Prediabetes Insulin resistance Increased glucose reabsorption Hyperglycemia Increased lipolysis Present in prediabetes Increased hepatic glucose production The Continuum of Dysglycemia The Continuum of Dysglycemia DPP Research Group. Diabet Med 2:137-1, 27; Haffner SM, et al. Diabetologia 36:12-16, 1993; Papanas N, et al.nat Rev Endocrinol 7:682-69, 211 5

6 Population Prevalence (%) of CKD Stages 1 by Diabetes and Prediabetes Status, NHANES CKD diagnosed with egfr by MDRD equation Plantinga L, et al. Clin J Am Soc Nephrol 5: , 21 Pathobiology of Prediabetes in A Bi-racial Cohort (POP-ABC)? Question Dagogo-Jack S, et al. J Clin Endocrinol Metab 99:178-87, 21 Pathobiology of Prediabetes in A Bi-racial Cohort (POP-ABC) Baseline OGTT in African- Americans Caucasians with parental T2DM Age: yr IGT IFG NFG NGT IFG/ IGT T2DM Baseline assessment Baseline assessment Baseline/ repeated assessments every 3 months x 5 years Baseline assessment NFG NGT IFG IGT IFG/ IGT T2DM Progressors Dagogo-Jack S, et al. J Clin Endocrinol Metab 98:12-128,

7 Progression from Normoglycemia to Prediabetes All subjects (P=.7855) White Black Developed Prediabetes: 11 (29.5%) Developed T2DM: 1 (2.9%) Maintained NGR: 232 (67.6%) Dagogo-Jack S, et al. J Clin Endocrinol Metab 99(6):E178-87, 21 Glycemic Excursions Among Black and White Offspring of T2DM Parents 6 5 White Offspring Black Offspring Percent of Subjects Percent of Subjects Change in FPG from Enrollment (mg/dl) 6 5 White Offspring Change in FPG from Enrollment (mg/dl) Predictors of Incident Prediabetes Age Male gender Behavioral Adiposity 2hrPG Adiponectin C-reactive protein Insulin sensitivity Insulin secretion Lipid profile Dagogo-Jack S, et al. J Clin Endocrinol Metab 99:178-87, 21; Boucher A, et al. Metabolism 6:16-167, 215 7

8 A. FHQ Score MAQ/FHQ Body Mass Index (kg/m 2 ) Behavioral Predictors (r =.1, P=.1) C 1 2 >3 Metabolic Syndrome Components * ** B 1 Progression (%) MAQ (MET-hrs/week) (r = -.12, P=.3) Body Mass Index (kg/m 2 ) D 38.6% 38.1% 31.% 28.% MAQ/FHQ Quartiles OUTLINE Discuss the integrated pathophysiology of obesity and dysglycemia Review lifestyle and multimodality interventions for reversal of dysglycemia Understand the principles of obesity pharmacotherapy and future directions in early intervention Diabetes Prevention Program (DPP) DPP Study Design Screen Randomize (IGT) Lifestyle (n = 179) Metformin (n = 173) Placebo (n = 182) Diabetes Incidence Rates (per 1 pers-yr) Lifestyle Metformin Placebo 12 8 Caucasian African American Hispanic American Indian Asian % Risk Reduction DPP Research Group. NEJM 36:393-3, 22; Diabetes Care 28:888-89,25 8

9 Primary T2DM Prevention Trials Year Study Follow-up Intervention Outcome 1982 Bedford 1 yr Diet + SU Decrease 1991 Malmo 1 yr Diet + exercise Decrease 1997 Da Quing 6 yr Diet + exercise Decrease, 51% 21 DPS, Finland 3 yr Diet + exercise Decrease, 58% 22 DPP 2.8 yr Diet+Ex vs. Met Decrease, 58% 22 TRIPOD 2.6 yr Troglitazone Decrease, 59% 22 STOP-NIDDM 3.3 yr Acarbose + Diet Decrease, 25% 2 XENdos yr Orlistat + Diet Decrease, 37% 26 DREAM 3 yr Rosiglitazone Decrease, 6% 28 ACT NOW 2- yr Pioglitazone Decrease, 72% 26 IDPP-1 3 yr L/S + Met Decrease, 26-28% 29 IDPP-2 3 yr L/S + Pio Pio not additive to L/S 21 Navigator 5 yr Nateglinide No effect Valsartan Decrease, 1% 21 CANOE yr Rosi+Met Decrease 69% Echouffo-Tcheugui JB, Dagogo-Jack S. Nat Rev Endocrinol 8: , 212 Frequency (%) Normal Diabetes DPP: Regression from Prediabetes to Normal Glucose Regulation NEJM 36:393-3, 22 Lifestyle Metformin Placebo Look AHEAD: Effects of ILI on Metabolic Endpoints 5-1 % Weight change p< Year 3 Year DSE ILI HDL (mg/dl) 3 p< Year 3 Year DSE ILI A1c (%) p< Year 3 Year DSE ILI Triglycerides (mg/dl) -1-2 P= Year DSE ILI 9

10 Prevalence of remission 16 Intensive lifestyle intervention Diabetes support and education Duration of remission Intensive lifestyle intervention Diabetes support and education Prevalence, % 8 Estimate, % Year >1 >2 >3 Continuous Remission (Partial/Complete) Number of Years Transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (FPG <126 mg/dl and HbA1c <6.5%) on no DM meds Gregg EW, et al; Look AHEAD Research Group. JAMA. 38: , 212 OUTLINE Discuss the integrated pathophysiology of obesity and dysglycemia Review lifestyle and multimodality interventions for reversal of dysglycemia Understand the principles of obesity pharmacotherapy and future directions in early intervention Antidiabetes Medications, Degludec Dulaglutide Choices: 1

11 Weight Gain & Hypoglycemia: Common Features Weight gain Majority of type 2 diabetes patients overweight/obese Exacerbated by insulin, TZDs and sulfonylureas Preventive Approach Lifestyle counseling DPP- inhibitors Metformin GLP-1 receptor agonists SGLT-2 inhibitors Hypoglycemia Many diabetes patients have had hypoglycemia Exacerbated by insulin and sulfonylureas Preventive Approach Diabetes education DPP- inhibitors Metformin GLP-1 receptor agonists SGLT-2 inhibitors Principles of Obesity Pharmacotherapy R76. Pharmacotherapy for overweight and obesity should be used only as an adjunct to lifestyle therapy and not alone. R77. The addition of pharmacotherapy produces greater weight loss and weight loss maintenance compared with lifestyle therapy alone. R78. The concurrent initiation of lifestyle therapy and pharmacotherapy should be considered in patients with weight-related complications that can be ameliorated by weight loss. R79. Pharmacotherapy should be offered to patients with obesity, when potential benefits outweigh the risks, for the chronic treatment of their disease. Short-term treatment (3-6 months) using weight-loss medications has not been demonstrated to produce longer-term health benefits and cannot be generally recommended based on scientific evidence. Garvey WT, et al. AACE/ACE CPG Care of Patients with Obesity. Endocr Pract. 216 Jul;22 Suppl 3:1-23. Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline Caroline M. Apovian, Louis J. Aronne, Daniel H. Bessesen, Marie E. McDonnell, M. Hassan Murad, Uberto Pagotto, Donna H. Ryan, and Christopher D. Still Who should be considered for drug treatment of obesity? BMI 27 kg/m 2 with 1 comorbidities BMI 3 kg/m 2 with no comorbidities Apovian CM, et al. JCEM1:32-362,

12 CCK1R, CCK1 receptor; GLP1R, GLP-1 receptor; CTR, calcitonin receptor; DAT, dopamine active transporter; DVC, dorsal vagal complex; GHSR, GH secretagogue receptor; MCH1R, melanin-concentrating hormone 1 receptor; Y1/Y5R, Y1/Y5 receptor; Y2R, Y2 receptor; YR, Y receptor; OR, -opioid receptor. [Adapted from G. W. Kim et al: Clin Pharmacol Ther. 21;95:53 66], Apovian C, et al. JCEM 1: , 215 Weight loss with Orlistat at year 3. kg 5.8 kg 12mg 3 time/day with each main meal containing fat Torgerson JS, et al. Diabetes Care 2, 27: Effects of Lorcaserin on Body Weight Adverse Events Headache: 18% vs. 11%, Yr 1 Smith, S. R., New England Journal of Medicine (3):

13 Effects of Phentermine/Topiramate on Body Weight Adverse Events (7-15% v 2-9%) Change from baseline (%) Dry mouth Paresthesia Constipation Insomnia Dizziness Dysgeusia Gadde et.al The Lancet 211, 377(977): Effect of Naltrexone/Buproprion on Body Weight Adverse Events (6-27% v 3-9%) Nausea Headache Constipation Insomnia Dizziness Vomiting Change from baseline (%) Greenway, F. L., The Lancet 21, 376(971): Pi-Sunyer X, et al. NEJM 215;373:

14 Network Metaanalysis: SUCRAs for Weight Loss and Adverse Event Outcomes SUCRA Probability of Having Fewest Adverse Events SUCRA Probability of Being Highest Ranked in Achieving >5% Weight Loss SUCRA- surface under the cumulative ranking probabilities Khera R, et a. JAMA. 216;315:22-23 Practice of Obesity Pharmacotherapy Women of reproductive potential R112. Weight-loss medications must not be use in pregnancy (Grade A; BEL 2,upgraded due to high relevance). R113. All weight-loss medications should be used in conjunction with appropriate forms of contraception in women of reproductive potential (Grade A; BEL 1). R11. Weight-loss medications should not be used in women who are lactating and breast-feeding (Grade D). Addiction/alcoholism R118. In patients with obesity and alcohol or other addictions, consider using orlistat or liraglutide 3 mg (Grade A; BEL 1). Lorcaserin (abuse potential due to euphoria at supra-pharmacological doses) and naltrexone ER/bupropion ER (lowers seizure threshold) should be avoided in patients with alcohol abuse, and naltrexone ER/bupropion ER is contraindicated during alcohol withdrawal (Grade A; BEL 1). Garvey WT, et al. AACE/ACE CPG Care of Patients with Obesity. Endocr Pract. 216 Jul;22 Suppl 3:

15 Practice of Obesity Pharmacotherapy Cardiovascular disease and cardiac arrhythmia R9. In patients with established atherosclerotic CVD, orlistat and lorcaserin are preferred weight-loss medications (Grade A). Liraglutide 3 mg, phentermine/topiramate ER, and naltrexone ER/bupropion ER are reasonable to use with caution, and to continue if weight-loss goals are met, with careful monitoring of heart rate and blood pressure (Grade A; BEL 1). R95. Orlistat and lorcaserin are preferred weight-loss medications in patients with a history or risk of cardiac arrhythmia (Grade B). Naltrexone ER/bupropion ER, liraglutide 3 mg, and phentermine/topiramate ER are not contraindicated but should be used cautiously with careful monitoring of heart rate and rhythm (Grade A). CVOTs are planned or ongoing for all weight-loss medications except orlistat. Garvey WT, et al. AACE/ACE CPG Care of Patients with Obesity. Endocr Pract. 216 Jul;22 Suppl 3:1-23. Future Directions Central Pathways Energy Expenditure Energy Intake REE EEE TEF NEAT Appetite, Satiety, Food Choices C Substances That Promote Negative Energy Balance (Weight Loss) b BDNF 15

16 Leptin Therapy In Humans Farooqi et al. J Clin Invest 11: , 22 MCR -MSH POMC CART Leptin Model of Homeostatic Circuit Regulating Energy Balance through the Melanocortin Receptor (MCR). Increased adiposity leads to increased leptin production in fat tissue. Leptin stimulates neurons in the arcuate that coexpress the anorexigenic hormones a-msh and CART. Leptin also inhibits neurons in the arcuate that coexpress the orexigenic hormones AGRP and NPY. The neurons in the arcuate project to other regions of the hypothalamus where a-msh binds to its receptor, MCR, resulting in an up-regulation of anorexigenic effectors such as CRH and TRH and a down-regulation oforexigenic effectors such as melanin concentrating hormone (MCH) and orexin. AGRP acts as an antagonist of MCR. Adapted from List JF, Habener JF. NEJM 38: , 23. Weight Loss Surgery Gastric Banding Gastroplasty Roux-en-Y Gastric Bypass Sleeve Gastrectomy Biliopancreatic Diversion 16

17 SOS Study: Weight Changes over a 1-Yr Period Weight Change (%) N= 7 for 2 yr cohort N= 173 for 1 yr cohort Years of Follow-up Sjöström L, Lindroos A-K, Peltonen M, et al. N Engl J Med 351: , 2 Sjöström L, Peltonen M, Jacobson P, et al. JAMA 311: , 21. Current Recommendations American Diabetes Association 216 Bariatric surgery: Adults with BMI >35 kg/m 2 and T2DM, esp. if associated comorbidities and failing lifestyle and drugs Patients with T2DM who have undergone bariatric surgery need lifelong lifestyle support and medical monitoring. Insufficient evidence to recommend surgery for BMI < 35kg/m 2 AACE/ACE 216: R12. Patients with BMI of kg/m 2 without coexisting medical problems if procedure would not be associated with excessive risk (A) R121. BMI 35 kg/m 2 and 1 or more comorbidities (Grade A) BMI 3 kg/m 2 (Grade B-C evidence for weight and CVD risk) ADA. Diabetes Care 216;39:S9-S51; Garvey WT, et al. AACE/ACE CPG. Endocr Pract. 216 Jul;22 Suppl 3:1-23; Keating CL, et al. Diabetes Care 29;32:58-58; Courcoulas AP, et al. JAMA Surg 21;19: target of weight control 17

18 Thank You 18