Overview 7/18/2017. Pat Rafferty PharmD, BCPS, CDE

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1 Pat Rafferty PharmD, BCPS, CDE Associate Professor St. Louis College of Pharmacy St. Louis, MO Veronica Brady PhD, FNP-BC, BD-ADM, CDE Nurse Practitioner Reno School of Medicine, Division of Endocrinology Reno, NV Metabolic surgery: Therapeutic outcomes and the role of continuous glucose monitoring in the management of hypoglycemia Disclosure to Participants Notice of Requirements For Successful Completion Please refer to learning goals and objectives Learners must attend the full activity and complete the evaluation in order to claim continuing education credit/hours Conflict of Interest (COI) and Financial Relationship Disclosures: Presenter: Pat Rafferty, PharmD, BCPS, CDE No COI/Financial Relationship to disclose Presenter: Veronica Brady, PhD, FNP-BC, BC-ADM, CDE No COI/Financial Relationship to disclose Non-Endorsement of Products: Accredited status does not imply endorsement by AADE, ANCC, ACPE or CDR of any commercial products displayed in conjunction with this educational activity Off-Label Use: Participants will be notified by speakers to any product used for a purpose other than for which it was approved by the Food and Drug Administration. Overview Mechanisms of DM improvement and remission after metabolic surgery Improvements in vascular outcomes Hypoglycemia following gastric bypass Role of CGM in hypoglycemia management 1

2 Scope of the Problem 2.1 billion obese people worldwide By 2030 estimated to be 50% of U.S. population 1 in 3 adults in U.S. Obesity 2 nd leading cause of preventable death in U.S. Economic impact = 2.8% of GDP 400 million worldwide with T2DM By 2025 will increase to 500 million Am J Prev Med 2012;42: Ther and Clin Risk Manage 2016;12: (accessed 6/4/17) Adult Obesity in U.S Asian Non-Hisp White Hispanic Non-Hisp Black cdc.gov/nchs/data/databriefs (accessed 4/2/17) Prevalence of T2 DM in U.S. adults Obesity 30 Type 2 DM Asian Non-Hisp White Hispanic Non-Hisp Black cdc.gov/nchs/data/databriefs (accessed 4/2/17) 2 nd Diabetes Surgery Summit Metabolic surgery should be recommended: Class III obesity (BMI 40 kg/m2) Class II obesity (BMI ) with poor glycemic control Surgery should be considered for patients with BMI with poor glycemic control Reduce BMI by 2.5 for Asian patients Obes Surg 2017;27:2-21 Diabetes Care 2016;39: Types of Bariatric Procedures Roux-en-Y bypass Biliopancreatic diversion (with or without duodenal switch) Vertical sleeve gastrectomy Adjustable gastric banding From , procedures in U.S. Surg Obes Relat Dis 2017; Khorgami Z Roux-en-Y Gastric Bypass (RYGB) 2

3 Biliopancreatic Diversion with Duodenal Switch (BPD-DS) Vertical Sleeve Gastrectomy (VSG) Adjustable Gastric Banding (AGB) Effects of metabolic surgery on intestinal hormones Procedure GLP-1 GIP PYY Ghrelin Roux-en-Y Gastric Bypass Biliopancreatic diversion/duodenal switch Laparoscopic adjustable gastric banding Sleeve gastrectomy Endocrinol Metab Clin N Am 2016;45: Roux-en-Y Restricted gastric pouch leads to reduced caloric intake 3

4 Roux-en-Y Decreased Ghrelin secretion from gastric fundus leads to suppressed appetite Roux-en-Y Increased GLP-1 secretion from small intestine in response to food increases insulin secretion, suppresses glucagon, delays gastric emptying and increases satiety Definitions of Glycemic Outcomes Outcome Complete Remission Partial Remission Improvement Recurrence Definition A1c < 6%, FBG < 100 for one year with no DM medications used A1c 6 6.4%, FBG for one year with no DM medications used Reduction in A1c (> 1%) or FBG (> 25) or reduction in A1c/FBG with decrease in DM medications for one year FBG 126 or A1c 6.5% OR need for DM medication after initial remission Annals of Surg 2013;258: Diabetes Care 2009;32: Mechanisms of DM Remission hepatic and peripheral insulin resistance Recovery of beta cell insulin secretion Early effects of bypass procedures: Resolution of DM parameters prior to wgt loss Foregut hypothesis Hindgut hypothesis Curr Opin Endocrinol Diabetes Obes 2015;22:21-28 Diabetes Remission Utah data 418 obese patients with RYGB Remission 62% at 6 years follow-up Review of SG studies 2713 patients Remission 78% at 5 years 191 obese patients with T2D receiving RYGB Remission 83% at 5 years JAMA 2012;308: Surg for Obesity and Rel Dis 2016; Juodeikis Z Ann Surg 2003;238: Diabetes Remission 108 T2D obese pts undergoing BPD At 5 years, 60% remission (A1c < 6.5, no meds) 466 T2D obese pts undergoing RYGB 69% remission at 3 years Review by Buchwald found remission: BPD-DS > RYGB > VSG > AGB Obesity Surg 2017, Scopinaro Am J Med 2009;122: Diabetes Care 2016; Purnell JQ 4

5 Medical Management vs Surgery STAMPEDE 150 pts with T2D - RYGB/VSG or medical management, BMI (mean BMI 37) 5-year data goal A1c < 6% Goal A1c: 5% med tx, 29% RYGB, 23% VSG Wgt loss: -5% med tx, -23% RYGB, -19% VSG NEJM 2017;376: Medical Management vs Surgery 706 T2D patients, BMI < 35 Remission Odds Ratio 14.1 for Surgery Improved glycemic control OR 8.0 for Surgery 410 T2D patients, BMI 30, RYGB vs med Remission Odds Ratio 76.4 for RYGB Annals of Surg 2015;261: Medicine 2016;95:1-11 Outcomes Mortality Micro- and Macro-vascular Potential for Legacy Effect Swedish Obese Subjects study 2010 obese patients who underwent surgery Reduced CV events in surgical group HR 0.47 for CV death, HR 0.67 for CV events Median follow-up 14.7 years Subset of T2D patients, median f/u 10 years DM remission OR 6.3 for surgical patients Microvascular HR 0.44, Macrovascular HR 0.68 JAMA 2012;307:56-65 JAMA 2014;311: Mortality VA data 2500 surgical patients 10-year mortality rate 13.8% vs 23.9% (controls) SOS data + Swedish national registry 6132 pts with T2D who received RYGB, f/u 3.5 yrs Overall mortality HR 0.42 for surgery group Fatal/non-fatal MI HR 0.51 CV death HR 0.41 JAMA 2015;313:62-70 Lancet Diabetes Endocrinol 2015;3: Microvascular Outcomes Meta-analysis of retinopathy 2966 patients, OR for new cases T2D obese patients post-surgery, 5-yr f/u Nephropathy 37% pre-op, Resolution in 58% Little data on neuropathy Obesity Reviews 2017;18: Surg Obes Rel Dis 2013;9:7-14 5

6 Effects of Surgery on Nephropathy Urinary albumin/creatinine ratio according to DM remission status Resolved Improved Unchanged/Worse Urinary alb/cr ratio Surg for Obes and Rel Dis 2013;9:7-14 Macrovascular Outcomes Review of patients for CV risk reduction Resolution of HTN 63%, Lipids 65%, DM 73% Males w/o CVD with T2D remission move from global CV risk of 18.4% to 4.7% Analysis of 2580 obese T2D surgical pts 5-year estimate for combined outcomes = HR 0.36 Composite of MI, CVA, All-cause death or microvasc event 5-year HR macrovascular events = 0.39 J Am Coll Surg 2013;216: Heart 2012;98: Legacy Effect 4683 T2D patients followed out to 10 years post-surgery Patients with remission had 29% lower risk of microvascular disease (HR 0.71) For patients who relapsed for every year spent in remission, risk of microvascular disease reduced by 19% Type 1 patients Adolescents Elderly Special Populations Diabetes Care 2016;39: Type 1 Diabetes Obesity in children with T1D 12.6% 50% of patients with T1D are obese or overweight Meta-analysis in T1D patients (n=142) Mean age at surgery 39, DM duration 20.8 years Mix of surgical procedures Baseline BMI 42.5, insulin requirement 0.86u/kg Obesity Surg 2016;26: Type 1 Diabetes - Outcomes A1c % Insulin requirements 0.39 units/kg BMI 12.9 kg/m2 Systolic BP 10 mm Hg 5-year study of 10 patients showed improvement in albuminuria and retinopathy Obesity Surgery 2016;26:

7 Type 1 Diabetes Small studies, poorly powered Lack of long-term followup DCCT/EDIC data: 1% A1c 30% Microvascular disease Presence of Legacy effect from surgery? NEJM 2005;22: Youth to Elder 41 adolescents with VSG (T2D 75%) 60% EWL at 24 months Resolution of T2D in 70% of patients 228 adolescents with VSG/RYGB Resolution of T2D in 95% of patients 103 patients 60 years old, VSG No differences weight loss, co-morbidities Eating and Weight Disorders 2017, Iossa A NEJM 2016;374: Surg Obes Relat Dis 2017;13: Disease Severity Nomogram Aminian et al reported May 2017 at meeting of American Surgical Association Assigns T2D patients stage of severity to help guide procedure selection Areas for future research Economic data Cost of Surgery vs. Lifetime cost of T2D Longer-term outcomes data Effect of weight re-gain When is the ideal time to perform surgery? In relation to T2D diagnosis, lower BMI? Clinical Endocrinology News 5/9/17 Areas for future research Predictors of remission Do BMI or Procedure choice matter? Influence of baseline BMI, insulin use on longterm outcomes Factors influencing recurrence of T2D Future Studies CARAT Canagliflozin for post-surgery patients with persistent T2DM Results expected Spring 2018 Microvascular Outcomes (MOMS Study) Core Outcome Set BARIACT Project UK Study to establish standardized outcomes for bariatric trials Diabetes Obes Metab 2017.doi: /dom PLoS Med 2016;13(11):1-17 BMJ Open 2017;7:e

8 Future Studies NIH/NIDDK study 6000 T2D patients undergoing RYGB Examining long-term outcomes Utah Population Database 9000 patients undergoing RYGB Subgroup analysis of T2D patients ARMMS-T2D 300 patients, 7-year follow up Case Study 55 year-old female, VSG in August 2015 BMI 12 points A1c 2.1% Systolic BP 18 points Remission of diabetes since October 2015 Diabetes Care 2016;39: References Adams TD. Diabetes Care 2016;39: Cohen RV. BMJ Open 2017;7:e Rubino F. Obesity Surg 2017;27:2-21 Merlotti C. Obes Reviews 2017;18: Vest AR. Heart 2012;98: Arterburn DE. JAMA 2015;313:62-70 Coleman KJ. Diabetes Care 2016;39: Kashyap SR. Diab Obes Metab 2017; CARAT trial Coulman KD. PLoS Med 2016;13(11):e Ashrafian H. Obesity Surg 2016;26: Faucher P. Obesity Surg 2016;26: Navarrete A. Surg Obes Relat Dis 2017;13: Iossa A. Eat Weight Disord 2017;s Eliasson B. Lancet Diabetes Endocrinol 2015;3: Sjostrom L. JAMA 2012;307:56-65 Buchwald H. Am J Med 2009;122: Svane MS. Curr Opin Endocrinol Diabetes Obes 2015;22:21-28 References Sjostrom L. JAMA 2014;311: Adams TD. JAMA 2012;308: Juodeikis Z. Surg for Obesity and Rel Dis 2016 Schauer PR. Annals of Surg 2003;238: Schauer PR. NEJM 2017;376: Finkelstein EA. Am J Prev Med 2012;42: Inge TH. NEJM 2016;374: Rubino F. Diabetes Care 2016;39: Müller-Stich BP. Annals of Surg 2015;261: Yan Y. Medicine 2016;95:1-11 Bužga M. Ther and Clin Risk Management 2016;12: Azim S. Endocrinol Metab Clin N Am 2016;45: Johnson BL. J Am Coll Surg 2013;216: Heneghan HM. Surg Obes Rel Dis 2013;9:7-14 Scopinaro N. Obesity Surg 2017 Buse JB. Diabetes Care 2009;32: Khorgami Z. Surg Obes Relat Dis 2017 Jan 25 Purnell JQ. Diabetes Care 2016;DOI /dc Pat Rafferty, PharmD, BCPS, CDE St. Louis College of Pharmacy patricia.rafferty@stlcop.edu ROLE OF CGM IN MANAGEMENT OF HYPOGLYCEMIA FOLLOWING GASTRIC BYPASS 8

9 Hypoglycemia vs Dumping Syndrome Dumping Syndrome Food reaches small intestine rapidly Flushing, tachycardia, hypotension Bloating, abdominal pain and diarrhea Hypoglycemia Occurs 1-3 hours after the meal Whipple s triad (symptoms, low BG, relief after treatment) Post Gastric-Bypass Hypoglycemia (PGBH) PGBH defined as BG < 60mg/dL First described by Service, et al in 2005 Presents months to years (usually > 1 year) following surgery Incidence of PGBH Adjustable Gastric Banding (AGB) Few cases (3-4% following OGTT) Patients without DM prior to surgery Occurs on avg 33 months after surgery Sleeve Gastrectomy (SG) 33-37% following OGTT Occurs 1 year after surgery Incidence of PGBH (cont) Roux-en-Y gastric bypass(rygb) Highest incidence of PGBH Most recent study by Lee, et al. (2016) showed incidence of 13.3% at 5 years Incidence of PGBH (cont) Keufurt et al. (2014) using CGM detected hypoglycemia in 75% of patients vs MMT 29% 88 months after surgery 3±1 events lasting 71±25 minutes per patient 38% of patients experienced nocturnal hypoglycemia Risk Factors for PGBH No history of diabetes prior to surgery (lower A1c) RYGB Female gender Number of years since surgery Lower BMI pre-surgery Greater weight loss at 6 months 9

10 Pathophysiology of PGBH? Increased β- cell mass? Increased GLP-1 production? Increased incretin levels? Decreased Ghrelin? Rapid weight loss improvement in insulin sensitivity Management of PGBH Dietary modification-small, low carb meals, soluble fiber, water intake with meal; pectin & guar gum Enteral feeding Acarbose mg TIDac Calcium channel blockers Somatostatin Diazoxide Management of PBGH (cont) Insulin aspart GLP-1 agonist Partial pancreatectomy Reversal of gastric bypass **Continuous Glucose Monitoring** USE OF CGM IN MANAGING PGBH What is CGM Sensor composed of microelectrode coated with glucose oxidase beneath biocompatible membrane, which converts glucose in the interstitial fluid into an electronic signal proportional to amount of glucose present. CGM at a Glance Provides BG readings every 5 minutes (288 readings/day) Lag time= 5 minutes Requires finger stick BG at least q12 hours for calibration Accurate for BG mg/dL 10

11 CGM Categories and Devices GlucoWatch 1999 Current devices DexCom G4 Platinum DexCom G5 Medtronic Guardian REAL-Time MiniMed Paradigm REAL-Time MiniMed 530G with Enlite FreeStyle Libre Pro Two categories: Professional- Medtronic ipro, FreeStyle Libre or DexComG4 Platinum Professional (blinded) Personal Medtronic ipro DexCom G4 Receiver-displays sensor BG readings (range up to 6 meters) Sensor-measures glucose levels q 5 minutes Transmitter- wirelessly sends BG readings to receiver Libre Pro Sensor Site Selection and Size of Transmitter 11

12 Detection of hyper/hypoglycemia Dexcom Download CGM provides a movie of BG readings as opposed to a snapshot. Grunberger, 2015 Medtronic download Libre Download CASE STUDIES LL 61 year old RN LL is a 61 year old female. Presents to clinic with complaints of hypoglycemia. She reports being 3 years post RYGB. She was found to have T1DM (GAD+) following surgery. Trialed on Victoza. She had 140# weight loss. She is a nurse and has had several episodes of severe hypoglycemia as well as 3 episodes of DKA resulting in loss of consciousness while working. 12

13 Initial Presentation BG readings testing 7-10x/d with BG ranging 65-HI. Amount of Insulin- Lantus 12 units in am and Novolog 0-11 units with meals/based on size of meal Hypoglycemic events L.L download September 2015 LL download March 2016 Management Based on CGM Current meds Tresiba 12 units in am, Novolog ½-5 units with meals. No further episodes of DKA and no episodes of hypoglycemia requiring assistance of another. Weight change? LL download April 2017 CGM Pitfall PD 58 year old trucker driver PD is a 58 year old female. She comes to clinic with complaints of hypoglycemia x 6 months. Home BG readings occasionally less than 40mg/dL. She is status post RYGB <2 years ago. No previous h/o diabetes, 80# weight loss. Tried and failed acarbose. 13

14 Blood Glucose Trends Take Home Message All patients being considered for bariatric surgery should have A1c testing done. CGM is a useful tool in assessing for and managing PGBH. Patients utilizing CGM for PGBH require close follow up to avoid the pit falls of prolonged hyperglycemia. 14

15 References Singh,E, & Vella, A. (2012). Hypoglycemia after gastric bypass surgery. Diabetes Spectrum, 25(4), Abrahamsson, N. et al. (2015).Hypoglycemia in everyday life after gastric bypass and duodenal switch. European Journal of Endocrinology, 173(1), doi: /E Lee, C.J. et al (2016). Risk of post-gastric bypass surgery hypoglycemia in nondiabetic individuals: A single center experience. Obesity, 24(6), doi: /oby Foster-Schubert, K.E. (2011). Hypoglycemia complicating bariatric surgery: Incidence and mechanisms. Current Opinion Endocrinology Diabetes Obesity, 18(2), doi: /MED Hanaire, H. et al. (2009). Usefulness of continuous glucose monitoring for the diagnosis of hypoglycemia after gastric bypass in a patient previously treatead for type 2 diabetes. Obesity Surgery, 20, doi: /s Contact Veronica Brady, PhD, FNP-BC, BC-ADM, CDE University of Nevada, Reno School of Medicine vbrady@med.unr.edu Bairain,S. (2013). Laparoscopic adjustable gastric banding and hypoglycemia. Case Reports in Endocrinology. doi.org/ /2013/ McLaughlin,T, Peck, M., Holst, J. & Deacon, C. (2010). Reversible hyperinsulinemic hypoglycemia after gastric bypass: A consequence of altered nutrient delivery. Journal of Clinical Endocrinology & Metabolism, 95(4), doi: /jc Lee, C.J., Clark, J.M., Schweitzer, M., Magnuson, T., Steele, K., Koerned, O., & Brown, T.T. (2015). Prevalence of and risk factors for hypoglycemic symptoms after gastric bypass and sleeve gastrectomy. Obesity,23(5), doi: /oby Shantavasinkul, P.C., Torquati, A., & Corsino, L. (2016). Post-gastric bypass hypoglycaemia: a review. Clinical Endocrinology,85, 3-9.doi: /cen