Post-Bariatric Surgery Patient Management; Endocrinologist s Perspective Sangeeta R. Kashyap MD Associate Professor of Medicine Cleveland Clinic Lerner College of Medicine Department of Endocrinology, Diabetes and Metabolism Illinois AACE, Chicago 2016
Morbid Obesity in the 1700 s Hunterian Museum; Royal College of Surgeons. London UK
Etiology of Obesity-Complex and Multifactorial Genetic and epigenetic influences- 70% Acquired: 30% Increased caloric intake Biological influences of hormones (leptin, adiponectin etc.) Gut microbes Imbalance of signals related to energy regulation (gut/adipose vs. hypothalamic)
Characterization of -cell Failure in T2DM From UKPDS Factors associated with progression of pre-diabetes to diabetes Elevated FPG and increase in FPG High BMI Weight gain Younger age High plasma insulin Decreased insulin response to glucose Hypertension Poor -cell function Choice of treatment Illustration of coefficient of -cell failure over time in relation to A1C A1C (%) 14 12 10 8 6 4 2 Codeeicient of failure=0.47 A1C %/year R 2 =0.95 0 0 1 2 3 4 5 6 7 8 9 10 11 Time (years) Fonesca, Vivian A. Diabetes Care; Nov 2009;32, pg. S151
Overeating, inactivity (acquired/genetic) Insulin Resistance Muscle Liver Resistance arteries Large arteries Sympathetic nervous system Platelets Glucose Predisposition to atherothrombotic vascular disease Type 2 Diabetes Kashyap SR. et al. Diab Vasc Dis Res. 2007 Mar;4(1):13-9
Insulin Insulin Receptor Insulin Receptor Substrate X PI3 Kinase Nitric Oxide; GLUT transport SRC-related tyrosine kinase (MAP kinase) Extra-Cellular Matrix; Growth Factors
Lipotoxicity Adipocytes represent a storage depot for energy (i.e., fat). When the capacity of adipocytes to store fat is exceeded, there is an overflow of fat to: l Muscle insulin resistance l Adipocyte apoptosis, macrophage TNF l Liver HGP (GN); Steatosis l Pancreas insulin secretion l Arteries atherosclerosis
Look AHEAD RCT in Type 2 Diabetes;10 Years of Followup The Look AHEAD Research Group. N Engl J Med 2013;369:145-154.
Look AHEAD 2013 Greater, longer sustained wt. loss is necessary to produce clinical benefit
Lap Band Gastric Bypass Low Effectiveness Risk High
COMPARISON OF BARIATRIC OPERATIONS: The resolution of diabetes is dose related n = 22,094 patients; 2738 citations 1990-2002 Banding Gastric Bypass Duodenal Switch Excess weight loss Operative mortality Resolution of diabetes 47.5% 61.6% 70.1% 0.1% 0.5% 1.1% 47.8% 83.6% 97.9% Buchwald, Avidor, Braunwald, Jensen, Pories, Farbach, Schoelles JAMA 2004;292:1724-1737
Weight loss in the Swedish Obesity Surgery JAMA. 2012;307(1):56-65
Bariatric Surgery is Associated with a Reduced Mortality: the SOS Study 30% lower risk Of dying MI: 25 in control Group 13 in the Surgery group Cancer: 47 in The control group 29 in the surgery group Sjostrom L NEJM 2007: 357-741-752
Sjostrom L et al. N Engl J Med 2004;351:2683-93 SOS STUDY
Bariatric Surgery and Type 2 Diabetes Schauer et al., N. Eng. J. Med., 370:2002-13, 2014
Endpoints Primary Success rate of achieving HbA1c 6% Secondary Change in fasting plasma glucose (FPG) Change in BMI Change in lipids, blood pressure, hs-crp Change in medications Safety and adverse events
STAMPEDE Trial: Flow of Patients 218 patients screened HbA1c >7.0% BMI 27-43 kg/m 2 Age 20-60 years 150 randomized 50 Intensive medical therapy alone 50 Medical therapy plus gastric bypass 50 Medical therapy plus sleeve gastrectomy 8 withdrew consent 2 Lost to followup 2 Lost to follow-up Population for 3-Year Analysis 40 48 49 1 withdrew consent prior to surgery 91% retention Kashyap, Bhatt, Schauer et al. Diabetes, Obesity Metabolism 2009
Primary and Secondary Endpoints at 36 Months Parameter Medical Therapy (n=40) Bypass (n=48) Sleeve (n=49) P Value 1 P Value 2 HbA1c 6% 5% 37.5% 24.5% <0.001 0.012 HbA1c 6% (without DM meds) 0% 35.4% 20.4% <0.001 0.002 HbA1c 7% 40% 64.6% 65.3% 0.02 0.02 Change in FPG (mg/dl) -6-85.5-46 0.001 0.006 Relapse of glycemic control 80% 23.8% 50% 0.03 0.34 % change in HDL +4.6 +34.7 +35.0 <0.001 <0.001 % change in TG -21.5-45.9-31.5 0.01 0.01 % change in CIMT 0.048 0.013 0.017 0.36 0.49 1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy
Percentage of Patients on Insulin 60 50 40 % Patients 30 20 Medical Sleeve Gastric Bypass 10 0 Baseline Month3 Month6 Month12Month24Month36 Medical 52 54 44 40 47 55 Gastric Bypass 46 25 10 4 7 6 Sleeve 45 16 6 8 9 8 ACC 2014; Late Breaking Clinical Trials
Cardiovascular Medications at Baseline and Month 36 CV medications number (%) Medical Therapy (n=40) Bypass (n=48) Sleeve (n=49) Baseline None 0 (0) 3 (6.3) 2 (4.1) 1-2 19 (47.5) 17 (35.4) 28 (57.1) Month 36 > 3 21 (52.5) 28 (58.3) 19 (38.8) None 1 (2.5) 33 (68.8) * 21 (42.9) * 1-2 18 (45) 14 (29.2) 25 (51) > 3 21 (52.5) 1 (2.1) 3 (6.1) * P value <0.05 with Medical Therapy group as comparator
Quality of Life % Physical Health Components * ** ** Physical Functioning Role Limitations Mental Health Components ** * * <0.05 ** <0.001 (Compared to IMT) %
Adverse Events through 36 Months Parameter Medical Therapy (n=43) Bypass (n=50) Sleeve (n=49) GI complications 2 (5) 13 (26) 5 (4) Re-op 0 2(4) 2(4) Stroke 0 0 1 (2) Retinopathy 0 1 (2) 2 (4) Nephropathy 4 (9) 7 (14) 5 (10) Foot ulcers 0 2 (4) 1 (2) Excessive weight gain 7 (16) 0 0
Summary Bariatric surgery was more effective than intensive medical therapy in achieving glycemic control (hba1c < 6.0%) with weight loss as the primary determinant of this outcome. Many surgical patients achieved glycemic control without use of any diabetic medications (particularly insulin). Metabolic syndrome components (HDL, triglycerides, glucose, BMI) showed greater improvement after surgery.marked improvement in quality of life.
Diabetes Complications? Retinal data was negative at 2 years (Singh R et al. ADA scientific sessions, oral presentation 2014) Nephropathy/CKD; No worsening of GFR but?improvement--pilot study (N=15, Crt >1.3mg/dl) demonstrate no change in proteinuria, measured GFR (iothalamate testing), Cystatin C, or ß2 microglobulin 1 year following surgery (Navaneethan et. al. AJKD, in press) Fractures- Bone density drops by 10%; 31% in surgical and 25% in medical. (Magrabi A et al. ADA scientific sessions, 2013)
Limitations Single-center trial multicenter studies needed to determine if results can be generalized. Duration of Follow-up limited to 3 years so far Larger studies will need to determine potential benefit on cardiovascular events and diabetes related microvascular complications. Sample size insufficient to detect uncommon but significant complications of surgery or medical Rx
BMJ Oct 22, 2013 11 studies, 796 patients, BMI 27-53 Surgery superior to med Rx Wt. loss, HbA1c, T2DM remission, TG, HDL, remission of metabolic syndrome, QOL, medication reduction No difference in BP or LDL No CV events or death after surgery Anemia (15%), Reoperation (8%)
Based on the complete case analysis, the relative risk to achieve diabetes remission was 22 times higher (relative risk 22.1 (3.2 to 154.3, P=0.002) after bariatric surgery compared with non-surgical treatment.
Mortality Rates (%) of 8 Procedures in Diabetics, 2008-2012 3.5% 3.0% CABG Observed Mortality (%) 2.5% 2.0% 1.5% 1.0%.5%.0% Infrainguinal Bypass Lap Colectomy Lap Cholecystectomy Lap Appendectomy LRYGB Knee Arthroplasty 2008 2009 2010 2011 Lap Hysterectomy 2012 Mortality Rate of LRYGB = 3 in 1000 Aminian A, Brethauer SA, Kirwan JP, Kashyap SR, Burguera B, Schauer PR. How safe is metabolic/diabetes surgery? Diabetes Obes Metab. 2014 Oct 29.
Scientific Organizations with Guidelines/Position Statements that Support Metabolic Surgery for Treating T2DM Organization 2008 2014 National Institutes of Health NIH YES YES National Institute for Health and Care Excellence NICE YES YES The Obesity Society TOS YES YES American Diabetes Association ADA NO YES European Association for the Study of Diabetes EASD NO YES Diabetes UK NO YES International Diabetes Association IDF NO YES American Heart Association AHA NO YES American College of Cardiology ACC NO YES
Glucose Tolerance Following RYGB in Type 2 Diabetes 10 Before Surgery Plasma Glucose Conc. (mm) 9 8 7 6 5 12 Months 1 Month 6 Months 4 0 30 60 90 120 Time (min) Kashyap SR et al. IJO 2010
Proposed Mechanisms Negative caloric balance and weight loss Improvement in insulin sensitivity and lipotoxicity ; mobilization of ectopic lipids. Stimulation of the entero-insular axis and subsequent effects of B-cell function (early weight independent effects) Foregut hypothesis Hindgut hypothesis
Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes. Rubino and Marescaux. Ann Surg 2004. Can exclusion of duodenum and jejunum control diabetes independent from weight loss? GJB 8 rats compared to sham, pair fed, controls OGT and ITT performed one week post-op No significant difference in food intake are weight gain between groups
Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes. Rubino and Marescaux. Ann Surg 2004. >40% reduction AUC with glucose tolerance testing in GJB group Better insulin sensitivity with GJB Exclusion of duodenum and jejunum directly controls DM2 independent of wt loss or treatment of obesity
STAMPEDE Metabolic Substudy: Flow of Patients HbA1c >7.0% BMI 27-43 kg/m 2 Age 20-60 years 62 randomized 22 Intensive medical therapy alone 2 withdrew from substudy 2 withdrew consent 2 missed 12 month visit 20 Medical therapy + gastric bypass 1 missed 12 month visit 20 Medical therapy + sleeve gastrectomy 1 withdrew consent prior to surgery 1 missed 24 month visit Population for 1 Year Analysis 16 19 19 1 withdrew consent 1 missed 24 month visit Population for 2 Year Analysis 17 18 19 90 % retention
Clinical Outcomes at 2 years Kashyap SR. et al. Diabetes Care. 2013 Aug;36(8):2175-82 Parameter Medical Therapy Bypass Sleeve P Value 1 P Value 2 HbA1c 6% (12m) 6.25 44% 26.32% 0.02 0.19 HbA1c 6% (24m) 5.9% 33.3% 10.5% 0.09 1.00 Change in HbA1c (%) -1.1-3.1-2.5 0.001 0.06 Change in BMI (kg/m2) -0.2-8.7-8.2 <0.001 <0.001 Change in Total Body Fat (%) Change in Truncal Fat (%) +1.1-10.6-7.7 0.001 0.001 0.9-15.9-10.1 0.001 0.001 Change in Leptin +4864-11155 -16211 <0.001 <0.001 1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy
Gastric Bypass Normalizes Post Prandial Glucose Metabolism A. Glucose Measures During Mixed Meal Tolerance Test Baseline 300 B. Insulin Measures During Mixed Meal Tolerance Test Baseline 100 C. Glucose (mg/dl) 250 200 150 100 50 Medical RYGB Sleeve 0 Glucose Measures During Mixed Meal Tolerance Test Month 24 300 Insulin (uu/dml) D. 80 60 40 20 0 Insulin Measures During Mixed Meal Tolerance Test Month 24 100 Glucose (mg/dl) 250 200 150 100 Insulin (uu/dml) 80 60 40 20 50-10 0 30 60 90 120 Minutes 0-10 0 30 60 90 120 Minutes Kashyap SR et al. Diabetes Care. 2013 Aug;36(8):2175-82
Absolute Change in Insulin Sensitivity During the Mixed Meal Tolerance Test A. Increase in Pancreatic -cell Function B. Increase in Insulin Sensitivity 0.5 6.0 Increase in Oral Disposition Index 0.4 0.3 0.2 0.1 p=0.30 p=0.001 p=0.34 Increase in Matsuda Index 5.0 4.0 3.0 2.0 1.0 p=0.05 p=0.001 p=0.02 0.0 Medical Sleeve Gastric Bypass 0.0 Medical Sleeve Gastric Bypass *[(AUC ISR//AUC Glucose) x Matsuda Index]
Change in GLP-1 and GIP Response to Mixed Meal Tolerance Test A. Change in GIP Response to Mixed Meal Tolerance Test Baseline to Month 24 Change in GIP Response (pg/ml) 20 10 0-10 -20-30 p=0.59 p=0.001 p=0.05 Medical Sleeve Gastric Bypass B. Change in GLP Response (pmol/l) 15 10 5 0-5 Change in GLP-1 Response to Mixed Meal Tolerance Test Baseline to Month 24 p<0.001 p<0.001 p=0.07 Medical Sleeve Gastric Bypass
Results: Adiponectin Non remitters showed blunted response to bariatric surgery Malin, Kashyap et al. Diabetes, Obesity And Metabolism. 2014 Dec;16(12):1230-8
Malin et al. Diabetes, Obesity And Metabolism. 2014 Dec;16(12):1230-8
Summary Points Diabetes remission characteristic of bariatric surgery (RYGB>Sleeve Gastrectomy) and linked to improvements in post prandial glucose metabolism. Weight independent effects related to GLP-1 specific effects to increase insulin secretion For those who initially achieved remission but relapse subsequently, consider targeting additional weight/fat loss and adiponectin raising interventions. (diet/exercise/metformin/?sglt2) Continuous surveillance for micro- and macrovascular complications post-surgery is Key!!
Endocrine Complications of Surgery Hyperinsulinemic hypoglycemia Osteomalacia/osteoporosis and bone fractures Kidney stone (renal oxalate) Other vitamin and mineral deficiencies (iron, B12, vitamin d)
Hyperinsulinemic Hypoglycemia Differential Diagnosis: insulinoma, late dumping syndrome, and post-gastric bypass hypoglycemia (PGBH) Excessive GLP-1 may underlie PGBH Whipple s triad: 1) measured low blood glucose, 2) Symptoms of low blood glucose, 3) Correction of plasma glucose resolves symptoms PGBH treatment: dietary modification (low carb, high protein, fiber);medications (Acarbose, Diazoxide, Octreotide, and/or a calcium channel blocker) prior to pancreatic surgery. Neuroglycopenia may be present so ask elicit the history in patients!!
Bariatric Surgery Effects on Bone and Nephrolithiasis Bone, 2016-03-01, Volume 84, Pages 1-8
Metabolic Bone Disease Mechanical unloading, negative calcium, vitamin D balance leading to secondary hyperparathyroidism Increased bone turnover markers (ie. CTX, osteocalcin) 2.3 increase in RR osteoporotic fractures (Osteoporos Int. 2014 January ; 25(1): 151 158) Other risk factors: PPIs, menopausal status, steatorrhea, renal oxalate stones Consider oral/iv bisphosphonates after calcium citrate/vitamin D 3 repletion
Risk of Selected Nutritional Deficiencies Resulting from Bariatric Surgery Nutrient LAGB RYGB BPD/DS Macronutrients Thiamine a Iron b Vitamin B 12 Vitamin D Vitamin A LAGB = Laparoscopic adjustable gastric banding; RYGB = Roux-en-Y gastric bypass; BPD/DS = biliopancreatic bypass/duodenal switch a with persistent vomiting; b increased with menstruation
Nutritional Monitoring for the Bariatric Surgical Patient Routine CBC Chemistry profile Liver function tests Lipid panel HbA1c Micronutrients Iron, TIBC, Saturation Ferritin Folate Vitamin B12 25 (OH) vitamin D PTH
Routine Vitamin & Mineral Supplementation for RYGB Patients Supplement Dosage Multivitamin-mineral or prenatal 1-2 daily Calcium citrate a with vitamin D b 1,200-2,000 mg/day + 400-800 U/day Elemental iron c Vitamin B 12 40-65 mg/day 350 µg/day orally or 1,000 µg/mo intramuscularly Or 3,000 µg every 6 mo intramuscularly or 500 µg every week intranasally a Depending on dietary calcium intake b Daily dose determined by serum 25 (OH) vitamin D c For most menstruating women
Conclusions Bariatric surgery patients require close and frequent long-term follow up Each visit should address management and monitoring of the patients medical, nutritional and surgical condition Monitor absolute, percent and trajectory of weight loss and assess for weight regain
EVOLUTION IN MEDICINE 2015: DIABETES MEDICINE AND DIABETES/METABOLIC SURGERY
Acknowledgements STAMPEDE Team Sangeeta R. Kashyap, MD Philip R. Schauer, MD John P. Kirwan, PhD Stacy A. Brethauer, MD Julianne Filion, RN, BSN Beth Abood, RN Claire E. Pothier, MPH Deepak L. Bhatt, MD, MPH Steven Nissen, MD Statistics Kathy Wolski, MPH James Bena, M.S. Biochemical Analysis Sarah Neale, BSc Hazel Huang, MS Funding Ethicon endo-surgery (EESIIS 19900; PRS) RO1 DK089547 (PRS, SRK, JPK) ADA clinical translational award 1-11-26 CT (SRK) 1UL1RR024989 T32 DK007319 (SKM) CRU & Subjects