Surgery: Considerations and Research First Annual Minnesota Pediatric Obesity Conference Practical Approaches for Managing and Preventing Pediatric Obesity Surgery: Considerations and Research Sayeed Ikramuddin, MD

Aldolescent obesity

Disclosures Fellowship support: Ethicon, Covidien Research grant support: Covidien Proctorship: Ethicon I will discuss off label use of the gastric band system

Retrospective analysis 600 gastric bypass patients, of which approx 300 had T2DM Examined role of gastric bypass in treating T2DM and followed patients for as long as 14 years At that time, approx 80% were taking no medication and 99% of those with abnormal fasting glucose became euglycemic Pories, W.J., et al., Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg, 1995. 222(3): p. 339-50; discussion 350-2.

Bariatric surgery procedures Roux En Y Gastric Bypass (RNYGP) 50% of procedures in 2008 Laparoscopic Adjustable Gastric Banding (LAGB) 40% of procedures in 2008 Biliopancriatic Diversion w/ Duodenal Switch (Switch) 3-5% of procedures in 2008 Laparoscopic Sleeve Gastrectomy (LSG) 5-7% of procedures in 2008

Diabetes resolved = discontinued treatment, Diabetes improved = reduced treatment. Buchwald H. Estok R. Fahrbach K. Bantle D. Jensen MD. Pories WJ. Bantle JP. Sledge I. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. American Journal of Medicine. 122(3):248-256.e5, 2009 Mar.

Glycemia as an Endpoint Year Author N Level Therapy Control Outcome 2008 Dixon J 60 A LAGB (BMI 30-40 kg/m2) Medical management 72% Resolution of Type 2 DM 2007 Sjostrom L 4047 Surgery (GBP, GB, VBG) 24% reduction in mortality with surgery 2006 O’Brien PE 79 LAGB (BMI 30-34 kg/m2) Reduction in metabolic syndrome 93%- surgery vs. 46%- medical management 2004 Buchwald H 22,094 B Bariatric Surgery Meta Analysis 77% Resolution of Type 2 DM Adams TD 15,850 RYGBP Conventional treatment 92% reduction in diabetes related death le Roux CW 39 /LAGB Lean and obese patients improved insulin, GLP-1 response after RYGBP Lee WJ 158 C RYGBP < 35 kg/m2 RYGBP >35 kg/m2 76.5% success in BMI<35 kg/m2; 88.9% success in BMI 35–45 kg/m2, Cohen R 37   97% Resolution of Type 2 DM 2005 Torquati A 107 Wickremesekera K 31 Insulin resistance decrease at 6 days post surgery maintained after 12 months; This Slide shows a selected evidence list graded in line with ADA guidelines and shows that surgery is very effective at treating diabetes. All of these papers cited in this presentation, as well as those cited in our public comment from Dr. Denman, are included in the CD we have distributed This includes three randomized prospective trials and one meta-analysis. Dixon and Sjostrom were the subject of international media attention given there robust design and long term follow-up respectively. While scientific rigor declined as we move down the table, we see consistent findings from study to study and center to center that surgery is highly effective in achieving resolution of t2dm – resolution being normal a1c, normal fasting glucose and no requirement for medications; The studies have endpoints ranging from 1 to 14 years. Data is also included for patients with a BMI below 35kilogram per meter squared. While these studies lack sufficient power or follow-up, Cohen and Lee, both showed high success in the treatment of diabetic patients with gastric bypass. Two studies show a decrease in deaths in the surgery cohort compared a non-surgery cohort. Adams, published last year in the New England Journal of Medicine, showed an 92% reduction is diabetes associated deaths. 7 | 7 7

In which remission is defined as: No antihyperglycemic meds AND either A1c<6% or Glu<100, except in the case of both labs being available, in which case BOTH conditions must be met. When multiple lab values are available for one AV, the one closest to the midpoint (ie: 12, 24, 36 months, etc) is used. %Weight Loss (%WL) = [ (Weight Preop – Weight Postop) / Weight Preop ] *100

Gastric bypass Small divided gastric pouch (30 cc) Roux limb 75cm-150cm Biliopancreatic limb 20cm-100cm antecolic or retrocolic roux “Gold Standard”

Bypass considerations Longest followup moderate malabsorption (Iron, B12, Thiamine) hypoglycemia marginal ulcers excluded stomach internal hernia Higher perioperative complications

adjustable band Restrictive procecure Low volume high pressure band Pars Flaccida Approach adjust to produce wt loss of 0.5-1 kg/week

Band considerations Not FDA approved for < 18 very low short term morbidity and mortality poor results in the superobese explantation 10% long-term risk of slippage long-term risk of erosion need for adjustments

Procedures Band Sleeve Gastric bypass Duodenal switch

Sleeve considerations little long term data potential for leak insurance coverage an issue Increased incidence of GERD No nutritional complications ease of conversion to DS or to RNY

Duodenal switch Malabsorbtive and restrictive procedure most durable weight loss 4% incidence of revision for nutritional problems 42F sleeve (32-60) 100 cm common channel (50-125)

Effectiveness of Weight Management Programs in Children and Adolescents http://www.ahrq.gov/downloads/pub/evidence/pdf/childweight/chweight.pdf

Effectiveness of Weight Management Programs in Children and Adolescents http://www.ahrq.gov/downloads/pub/evidence/pdf/childweight/chweight.pdf

Introduction Weight Loss Surgery in Adolescents The treatment of the morbidly obese adolescent patient is controversial. No clear consensus on best treatment of the morbidly obese adolescent. Contention between bariatric surgeons and pediatricians.

Adolescent Obesity and Diabetes What is Known A steep rise in the prevalence of T2DM parallels the rise in obesity . Young patients with T2DM have rapidly progressive disease. 5 fold increase in the incidence of obesity since 1970’s Progressive retinopathy and ASHD noted within 5yrs of diagnosis of T2DM in young adults. Health-related QOL 5.5x more likely to be impaired compared to healthy kids. similar to those diagnosed as having cancer. # Kohn M and Booth M. Adol Med 2003 *Schwimmer JB, Burwinkle TM, Varni JW. JAMA 2003

Adolescent Obesity What is Unknown When is the best time in the course of development (physical and emotional) for surgical intervention? How is compliance in this patient population? What are the long-term nutritional sequelae? What are the multi-generational sequelae? What are the long-term outcomes and recidivism rates?

Bariatric surgery Outcomes Author (year) N Procedure (n) Age range Mean follow- up %EWL Compl. rate Deaths Lawson ML et al. (3 centers; 2006) 39 LRYGB (34) ORYGB (5) 13 to 21 1 year (n=30) 63% 39% (n=15) 1 (9 mos.) Sugerman, et al. (2003) 33 LRYGB (2) ORYGB (28) Open gastroplasty (3) 12 to 17 Up to 14 years 58% 40% (n=13) 2 (late) Stanford et al. (2003) 4 LRYGB (4) 17 to 19 17 mos. 87% 0% Strauss et al. (2001) 10 ORYGB (10) 15 to 17 > 1 year 55% 50% late (n=5) Rand et al. (1994) 34 ORYGB (30) Open gastroplasty (4) 11 to 19 6 years 66% NR Barnett et al. (2005) 15 Open gastroplasty (7) JIB (3) 13 to 17 (>9 mos.) (n=9) 64% 33%

Lap Band Outcomes Author (year) N Procedure (n) Age range Mean follow- up %EWL Compl. rate Deaths Silberhumer (2006) 50 LAGB (50) 9 to 19 35 mos. 61% 2% Dolan et al. (2003) 17 LAGB (17) 12 to 19 2 years 59% 12% (n=2) Agrisani (2005) 58 LAGB(58) 15-19 7 56% 10% band removal

Current Management of the Morbidly Obese Adolescent at the University of Minnesota Evaluation by multidisciplinary team(statewide). Pediatric gastroenterologist / weight loss specialist Pediatric psychologist Bariatric surgeon with > 50 cases adolescent Dietician: minimum of 6 months Intensive medical weight loss program Outpatient / inpatient treatment Bariatric surgery candidate Demonstrated compliance with medical weight loss Serious medical comorbidities

Demographics: LRYGB (n=30) Laparoscopic Weight Loss Surgery in Adolescents Mean age 17.0 (range 12-19) 8 patients ≤ 15 years Mean BMI 55 kg/m2 (range 35-100) Mean weight 156 kg (range 99-275 kg) All > 95th percentile for BMI Two patients with BMI > 90 kg/m2 were hospitalized ≥ 1 month preoperatively for intensive medical management.

Comorbid Diseases (Total 66) N Musculoskeletal Painful joints (10) Low back pain (6) Arthritis (2) 18 Pulmonary Obstructive sleep apnea (5) Asthma (4) Bronchitis (1) 10 Depression / Anxiety Cardiovascular Hypertension (4) Dyslipidemia (9) 13 GERD 5 Metabolic / Endocrine Type 2 diabetes mellitus (2) Polycystic ovary syndrome (3) Genitourinary Urinary stress incontinence (2) Renal stones (1) 3 Pseudotumor cerebri 2

Follow-Up Laparoscopic Weight Loss Surgery in Adolescents Range 0 to 45 months, mean 15.8 months. 14 patients had ≥ 12 month follow-up. Poor overall compliance with follow-up. 28.1% (n=9) lost to follow-up. Letters sent, phone calls made. Of those who didn't follow-up 55.6% (n=5) lost within first year 44.4% (n=4) lost after 18 months

Adolescent Outcomes

Results: LRYGB Weight Loss Weight Loss Surgery in Adolescents 12 y/o Pseudotumor cerebri BMI 47 33 months post op BMI 25.5 = 90% EWL Normal growth exceeding mid-parental height

Weight Loss Surgery in Adolescents Summary of Findings Weight Loss Surgery in Adolescents Adolescent bariatric surgery appears to be similar to adult bariatric surgery in terms of weight loss and complications. surgery safe in short term followup across the age spectrum followup can be more difficult than the adult population Absolute commitment to post-operative follow-up schedules need to be made pre-operatively with adolescent patients and their parents. evidence for choice of operation mixed

Band Lower BMI(30-40) it is the amount of weight loss not the method that determines the remission of type 2 diabetes Dixon et al JAMA January 23rd 2008

Glucagon-Like Peptide-1 or GLP-1 (“Enteroglucagon”) The Effects of Bariatric Surgery on Type 2 Diabetes The Entero-insular Axis Glucagon-Like Peptide-1 or GLP-1 (“Enteroglucagon”) Secreted by ileal “L-cells” in (rapid) response to a meal Actions Potent stimulator of insulin / supresses glucagon Slows gastric emptying Reduces appetite Increases beta cell mass Increased after gastric bypass (??) Peptide YY (PYY) Gastric Inhibitory Polypeptide (GIP) Wynne K. J Clin Endo Met, 2004

Select “known” peptides with various effects The Effects of Bariatric Surgery on Type 2 Diabetes The Entero-insular Axis Enteral glucose ingestion yields a greater insulin release than does parenteral glucose infusion * Secreted gut hormones effect insulin production, secretion and usage = “incretins” / “anti-incretins” Select “known” peptides with various effects * Elrick H. J Clin Endocrinol Metab. 1964

The Effects of Bariatric Surgery on Type 2 Diabetes The Entero-insular Axis 1967 – Gastric Bypass Rehfeld J, 2004

Peptides in T2DM GLP-1 response to mixed meal is blunted compared to non diabetics GIP response is blunted After weight loss GLP-1 response improves

Exaggerated GLP-1 and Blunted GIP Secretion are Associated with Gastric Bypass but not Gastric Banding Korner J, Bessler M, Inabnet WB et al. Surg Obes Relat Dis. 2007 Oct 10; [Epub ahead of print] .

Insulin response with OGTT RNY LaFerre et al JCEM 2008

Ghrelin Cummings et al NEJM

Bariatric Surgery: Effects on Weight Loss and Mortality 14 Control 29% 12 Control 10 -10 Band 8 Change in Weight (%) Cumulative Mortality (%) Surgery -20 VBG 6 4 p = 0.04 Gastric Bypass -30 2 Sjostrom, in the landmark Swedish Obesity Study, the SOS study, also published last year in the New England Journal of Medicine, showed a mortality reduction of 24% in the bariatric surgery arm at 15 years. They also showed a significant long term weight reduction in the surgical arm, with gastric bypass showing greater weight loss than gastric banding or vertical banded gastroplasty. Interestingly, this study included significant numbers of VBG patients which likely compromised the potential benefit when compared with a gastric bypass dominant population One of the largest differences in outcomes was the lower number of myocardial infarctions in the surgery group, 13 compared to 25, p = .0567 (chi- square dichotomous comparison 2 4 6 8 10 15 4 8 12 16 Years Years Sjostrom, L, et.al.; N Engl J Med. 2007;357:741-52 38 | 38 | | November 8, 2018 | Confidential 38 38

Case Matched Mortality (Mean Follow up of 7.1 years; out to 18 years All Subjects Matched Subjects Surgery Group (N = 9949) Control Group (N = 9628) (N = 7925) No ./10,000 person-yr /10,000 n/10,000 All causes of death 288 37.2 425 61.1 213 37.6 321 57.1 All deaths caused by disease 198 25.6 380 54.7 150 26.5 285 50.7 Cardiovascular disease 66 8.5 134 19.3 55 9.7 104 18.5 Coronary artery disease 17 2.2 46 6.6 15 2.6 33 5.9 Heart failure 2 0.3 7 1.0 0.4 6 1.1 Stroke 9 1.2 14 2.0 11 Other cardiovascular disease 38 4.9 67 9.6 31 5.5 54 Diabetes 24 3.5 19 3.4 Cancer 42 5.4 102 15.0 73 13.3 Other diseases 88 11.4 120 17.0 62 11.0 89 15.5 All nondisease causes 90 11.6 45 6.5 63 11.1 36 6.4 Accident unrelated to drugs 29 3.7 2.7 21 3.0 Poisoning of undetermined intent 1.9 4 0.6 1.6 0.7 Suicide 8 5 0.9 Other nondisease cause 25 3.2 18 10 1.8

Conclusion Type 2 DM is a complex disease It is most strongly associated with obesity Patient and physicians struggle to meet therapeutic goals Bariatric surgery is established as a treatment of obesity The effect on diabetes is profound Clinical trials will allow for treatment of lower BMI individuals Adolescents want to look like their peers but they also want to eat like their peers