Post-Bariatric Hypoglycemia (PBH): Diagnostic and Therapeutic Strategies

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1 Post-Bariatric Hypoglycemia (PBH): Diagnostic and Therapeutic Strategies Mary-Elizabeth Patti MD Investigator and Adult Endocrinologist Research Division Director, Hypoglycemia Clinic Joslin Diabetes Center Associate Professor of Medicine Harvard Medical School

2 DISCLOSURES Collaborative R44 NIH grant: Xeris Pharmaceuticals, Harvard Engineering Supply support: Dexcom, Insulet Investigator-initiated research grant: Medimmune, Janssen Previous site investigator: Xoma Multicenter ARMMS clinical trial: Funding support: NIH U01 Consultant: Eiger Pharmaceuticals

3 Joslin Christopher Mulla Allison Goldfine CRC Nurses & Staff Kathy Foster Lauren Richardson Pam Walcott Patients! Emmy Suhl RD Nicole Patience RD Joanne Rizzotto RD Jonathan Dreyfuss Hui Pan Ping Li Ali Bajwa Ipsa Arora Rohit Kulkarni Susan Bonner-Weir Gordon Weir Franco Folli Stefano La Rosa Thank you to Harvard School of Engineering Eyal Dassau Alejandro Laguna Stamatina Zavitsanou Sunil Deshpande Frank Doyle BIDMC Radiology Elisa Franquet Gerald Kolodny George Watts Surgery David Lautz Jim Moser Other Colleagues Marzieh Salehi UT San Antonio Adrian Vella Mayo Clinic Tracey McLaughlin Stanford University Jens Holst University of Copenhagen Funding NIDDK-SBIR (with Xeris) Dexcom Insulet NIH U01 ARMMS

4 Hypoglycemia is Increasingly Recognized After Bariatric Surgery Normal Anatomy Roux-en-Y Gastric Bypass (RYGB) Vertical Sleeve Gastrectomy (VSG) Fundoplication and Other Upper Gastrointestinal Surgery

5 Post-Bariatric Hypoglycemia (PBH) Hypoglycemia is increasingly recognized in patients following bariatric surgery gastric bypass > sleeve gastrectomy Mild postprandial hypoglycemia can be considered a component of the postprandial dumping syndrome Mild cases responsive to dietary management to limit simple CHO

6 Severe Post-Bariatric Hypoglycemia (PBH) A subset of patients have severe hypoglycemia: Requiring assistance of others Neuroglycopenia: seizures, falls, loss of consciousness, motor vehicle accidents Often hypoglycemia unawareness Job/income loss, cognitive dysfunction, loss of driving, disability Characterized by rapid spike in glucose after meals, excessive GLP1 and insulin secretion, later postprandial hypoglycemia Often require both medical nutrition therapy & multiple medications to achieve safety Therapy focused to reduce glycemic excursions

7 OVERVIEW Clinical presentation of post-bypass hypoglycemia syndrome Diagnostic strategies How can we differentiate whether symptoms are due to hypoglycemia or other conditions in post-bariatric patients? How can we define the underlying cause of hypoglycemia? Current concepts of pathophysiology Practical management strategies

8 Representative Patient History 66 year old female with obesity since adolescence (BMI 48 kg/m2) No personal or family history of DM or hypoglycemia Laparascopic Roux-en-Y gastric bypass without complications Symptoms of dumping syndrome immediately postoperatively, resolved with dietary modification Presented at 24 months postop (BMI 35 kg/m 2, stable) with palpitations, sweating, and confusion Could this be hypoglycemia?

9 Hypoglycemia Symptoms Adrenergic Tremor Palpitations Anxiety Cholinergic Sweating Hunger Paresthesias Neuroglycopenia Impaired cognition Seizures Consciousness These symptoms are often nonspecific! Overlap with dumping syndrome occurring after meals in bariatric patients Consider also: anxiety, cardiovascular disease, orthostatic hypotension

10 Hypoglycemia Symptoms Adrenergic Tremor Palpitations Anxiety Cholinergic Sweating Hunger Paresthesias Neuroglycopenia Impaired cognition Seizures Consciousness Hypoglycemia Unawareness: A Threat to Safety loss of adrenergic or cholinergic warning symptoms abrupt onset of neuroglycopenia can result in serious falls, motor vehicle accidents, seizures, loss of consciousness

11 What is Required to Define Hypoglycemia? A. Low capillary glucose at time of symptoms B. Low plasma glucose at time of symptoms C. Relief of symptoms by raising glucose D. A and C E. B and C Answer: E Defines Whipple s triad Why is plasma glucose required? cold exposure, vasospasm, meter error Allen O. Whipple surgeon

12 Patient History (continued) Presented to clinic for initial appointment Complained about feeling fatigued, slightly confused Venous glucose 34 mg/dl (1.9 mm) Responded within 15 minutes to 15 g CHO Fulfilled Whipple s triad We were lucky! Hypoglycemia confirmed

13 Diagnostic Strategies

14 Clinical Evaluation of Possible PBH History of Episodes Symptoms? Onset? Type of surgery? Weight trajectory? Severity? Neuroglycopenia? Assistance required? Relation to fasting, meals Provocative foods? Nocturnal symptoms? Coexisting medical issues? Meds? Record-keeping can be helpful Food & symptom log Blinded CGM to identify patterns CGM not for diagnosis as less accurate in hypoglycemia range Typical Patterns in PBH More than 1 year after GI surgery 1-3 hours after eating More common after simple CHO Worse with liquids>solids Not when fasting Occasionally: during/after exercise during overnight hours (2-4 AM)

15 The Roller Coaster of Post-Bypass Glycemia Postprandial spikes 70 Some nocturnal lows Postprandial lows Range: ; 15% of readings under 70 (0-25%)

16 Glycemic Patterns in Post-Bariatric Hypoglycemia

17 Glycemic Patterns in Post-Bariatric Hypoglycemia: Response to Mixed Meal during Research Studies Rapid spike after eating Normal fasting glucose Glucose (mg/dl) * * Time (min) Rapid drop after peak Goldfine & Patti, JCEM 2007

18 Which of the following are not typical patterns in PBH? A. Hypoglycemia before breakfast B. Hypoglycemia beginning 6 months after gastric bypass C. Hypoglycemia 2 hours after last meal D. A, B E. All of the above Answer: D If fasting hypoglycemia or shortly after surgery, not typical of PBH consider alterative diagnoses!

19 What other diagnoses shoud we be considering? Insulinoma 22% present with postprandial hypo Inadequate nutrition/weight loss Adrenal insufficiency Autoimmune hypoglycemia Other systemic disease (liver, kidney) Medication effects Alcohol use Comprehensive history, exam, & targeted labs needed!

20 Patient History (continued) Symptoms occur 5 times per week Symptoms typically occur within 1-2 hours after eating More likely to occur after eating simple CHO No symptoms upon awakening in AM Has been using husband s glucometer Most of readings at time of symptoms are mg/dl Occasionally has autonomic symptoms when glucose >200

21 No prior hypoglycemia Weight stable No relevant medications Patient History (continued) No family history of MEN1 components or hypo No alcohol Exam: BMI 34, otherwise normal Fasting labs: glucose 82 mg/dl, cortisol 12 ug/dl, hemoglobin A1c 5.3%

22 What are the Next Best Step(s) in her Evaluation? A. Oral glucose tolerance test B. 72 hour inpatient fasting test C. Mixed meal tolerance test D. Food, symptom, and glucose log E. Venous sample at time of hypoglycemia, if not already obtained Answers: C, D, E

23 Can We Provoke Hypoglycemia? How? Oral glucose tolerance test? Not well-tolerated in post-gi surgery patients Can provoke severe dumping 10% of healthy have glucose <50 mg/dl during GTT, without neuroglycopenia or EEG changes Hypoglycemia during OGTT physiological hypoglycemia! Hogan et al Mayo Clin Proc 1983

24 Can We Provoke Hypoglycemia? How? What about mixed meal tolerance test? Protein, carbohydrate, and fat No standard at present Liquid vs. solid Varying CHO content: g Be prepared! possible severe hypoglycemia requiring assistance Ensure safe testing environment, ability to rescue

25 What is appropriate glucose threshold to define hypoglycemia? NOT symptoms alone nonspecific, can reflect dumping in this population Strict definition best: Plasma glucose <54 mg/dl* (3 mm) at time of neuroglycopenic symptoms Symptoms promptly relieved with oral CHO *Diabetes Care 2017 ADA/EASD recommendations for hypoglycemia definition

26 What about measuring insulin levels? Insulin responses quantified in clinical studies of PBH during prolonged fast: insulin suppressed (<3 uu/ml) Challenges with post-meal hypoglycemia: Rapid increases in insulin levels after meals At time of subsequent hypoglycemia, insulin not suppressed (e.g. >3 uu/ml, or the lower limit of assay) Secretion Clearance time Plasma Insulin

27 When should we do prolonged inpatient fast? A. All patients with PBH with typical symptoms B. Patients who have fasting hypoglycemia C. Patients who have hypoglycemia early after surgery (<6-12 months) D. Never! E. B and C E. We reserve inpatient fasting to rule out insulinoma for those with atypical symptom patterns fasting, early postop, or unresponsive to therapy.

28 Should we do imaging to exclude insulinoma? Rarely Fasting hypoglycemia & nonsuppressed insulin Other atypical clinical features Lack of response to therapy Imaging for insulinoma notoriously challenging Consider CT, MRI, endoscopic ultrasound Very rare need for arteriogram or selective arterial calcium stimulation testing

29 Symptoms Adrenergic, Cholinergic, or Neuroglycopenic Possible Hypoglycemia Glucose Level During Symptoms? <70 mg/dl >70 mg/dl Can hypoglycemia be confirmed at the time of symptoms? Hypoglycemic Sx + neuroglycopenia Documented glc <50 (venous glucose preferred, spontaneous or provoked*) Relief with CHO YES Hypoglycemic Disorder Assess Patterns & Severity,?Neuroglycopenia R/O Other Causes of Hypoglycemia** NO Unlikely Hypoglycemia Consider Dumping Syndrome, CV Disorders Postprandial pattern? >6 mo after surgery? Likely Post-Bariatric Hypoglycemia Syndrome Initial Treatment Nutrition, Acarbose Salehi Patti JCEM 2018 Fasting or nocturnal hypoglycemia? Started < 6 mo after bariatric surgery? Incomplete Response Frequent Neuroglycopenia Atypical symptoms for post-bariatric hypoglycemia! Consider other hypoglycemic disorders Reassess Patterns With Diary/Masked CGM, Consider Further Hormonal Testing***, Additional Meds****

30 OVERVIEW Clinical presentation of post-bypass hypoglycemia syndrome Diagnostic strategies How can we differentiate whether symptoms are due to hypoglycemia or other conditions in post-bariatric patients? How can we define the underlying cause of hypoglycemia? Current concepts of pathophysiology Practical management strategies

31 Altered Glucose Patterns after Mixed Meal in PBH Spike after eating Nonsurgical Normal fasting glucose Nadir Salehi 2014

32 Altered Postprandial Metabolism after Mixed Meal in PBH Spike after eating Insulin Levels Glc Absorption Insulin Secretion GLP-1 Levels Nadir Salehi 2014

33 Roux-en-Y Gastric Bypass (RYGB) Rapid delivery of nutrients to foregut Early & high peak of glucose Postprandial secretion of GLP1 (10x) GLP1R inh Insulin secretion in postprandial state suppression of insulin secretion with hypoglycemia clearance of insulin Other hormones Insulin-independent glucose uptake Neural effects Postprandial Hypoglycemia

34 Role of Altered Counterregulation?

35 Reduced Counterregulatory Responses during Hypoglycemic Clamp after RYGB Glucagon pre post- RYGB Cortisol post- RYGB Epinephrine Norepinephrine post- RYGB post- RYGB Abrahamsson et al Diabetes 2016

36 What About the Pancreas in Severe PBH? Anti-Glucagon Stain CONTROL Patient 1 Patient 2 Patient 3 Partial pancreatectomy for refractory hypoglycemia Not performed any longer as not curative No insulinoma Diffuse increase in islet number Islets of varying size & shape Patti et al Diabetologia, 2005; Service NEJM 2005

37 RYGB: Patients requiring pancreatectomy for severe hypoglycemia (n=6) Controls: Organ donors or benign tumors (n=10) Reubi & Patti, Diabetologia 2010; increased size/number not consistently observed (Butler et al) Islet Size in Some Series of Patients with Severe PBH Anti- Insulin Staining Control Post-RYGB Insulinoma Islet Size (mm2) PBH CON * Islet number per mm2 PBH CON

38 β-cell Mass is Not a Dominant Contributor! PBH is a Functional Disorder, not Anatomic! Acute feeding via G tube into bypassed stomach largely resolves excessive GLP1 and insulin secretion and hypoglycemia Acute inhibition of GLP1 signaling improves hypoglycemia Partial pancreatectomy does not cure hypoglycemia!

39 Both Insulin-Dependent and Independent Mechanisms Contribute to Hypoglycemia Intestinal hormones Bile acids Altered intestinal mucosa Intestinal glucose uptake Altered gut-liver-brain axis Altered counterregulation

40 OVERVIEW Clinical presentation of post-bypass hypoglycemia syndrome Diagnostic strategies How can we differentiate whether symptoms are due to hypoglycemia or other conditions in post-bariatric patients? How can we define the underlying cause of hypoglycemia? Current concepts of pathophysiology Practical management strategies

41 Goals of Therapy Reduce frequency and severity Improve safety Unlikely complete elimination of hypoglycemia

42 Safety: Test glucose before driving, before bed, and in situations where hypoglycemia likely: After meals, after exercise Nocturnal, especially if AM headaches, vivid dreams, sweating Consider diagnostic or personal CGMS to detect trends early and treat before becomes severe, especially in those with unawareness. Family instruction in glucagon use It is effective as therapy! Medical ID Clinical Management Strategies Correct nutrient deficiencies: B12, D, B-complex, Fe, Ca, minerals Cornstarch (grocery, Extend, UCAN) Glucagon Kit

43 All of the following are important options for initial treatment of PBH except A. Eliminate all carbohydrates B. Controlled consumption of low glycemic index carbohydrates C. Acarbose D. Instruction in use of glucagon for family E. Instruction in treating acute hypoglycemia with simple carbohydrates Answer: A. Complete elimination of all carbs may contribute to reduced nutritional status, risk of hypoglycemia during sleep/activity, reduced responsiveness to glucagon.

44 Medical Nutrition Therapy is the Cornerstone of Treatment of PBH Prevention: reduce stimulus for insulin secretion Avoid intake of simple carbohydrates (high GI) Controlled portions of complex carbs (low GI)» Starting point: 30 g/meal, vary by response Not total CHO elimination reduce glycogen stores, reduce responsiveness to glucagon Standard Diet Controlled CHO Diet Reduced glycemic excursions Nielsen 2016

45 10-Point Nutrition Plan for PBH Dietary measures alone are often not sufficient in severely affected patients but remain the cornerstone of therapy! Suhl et al. SOARD 2017

46 Choose Low Glycemic Index CHO (GOOD!) Avoid High Glycemic Index CHO Suhl et al. SOARD 2017

47 Stepped Pharmacology for PBH Acarbose: Disaccharidase inhibitor Aim: slow CHO absorption postprandial glucose spike stimulus for insulin secretion Often limited by abdominal gas Start gradually, increase to maximum 300 mg/day Can be administered only or in higher doses before meal usually producing hypoglycemia May have improved efficacy if taken 15 minutes before eating

48 Effects of Acarbose : Peak Glucose, Nadir Glucose, Insulin Peak, GLP1 Glucose Insulin GLP1 Valderas Obesity Surgery 2012

49 Stepped Pharmacology for PBH Acarbose Octreotide or pasireotide to incretin & insulin secretion options: preprandial SQ and monthly IM 50 μg pre-meal to start Often limited by diarrhea Occasional worsening of hypoglycemia immediately after injection, possibly due to inhibition of glucagon secretion

50 Somatostatin Analogues? Octreotide or pasireotide? Myint 2012 Eur J Endo SSTR1, 2, 3, 5 with pasireotide LJM de Heide SOARD 2017

51 Stepped Pharmacology for PBH Acarbose Octreotide or pasireotide to incretin & insulin secretion options: preprandial SQ and monthly IM 50 μg pre-meal to start Often limited by diarrhea; gallstones Occasional worsening of hypoglycemia immediately after injection, possibly due to inhibition of glucagon secretion Diazoxide to reduce insulin secretion, limited by edema Other - small response to calcium channel blockade, anticholinergics, metformin, GLP1 agonists, glucocorticoids in my experience Consider if severe: G tube feeds into remnant stomach. Reversal of bypass when feasible. NOT pancreatectomy - not curative, not a mass problem

52 G-Tube Delivery of Nutrients into the Bypassed Stomach in PBH Patient Yields Normal Insulin Secretion Oral G-tube Oral G G tube data O G GLP1 Plasma Glucose O GIP O Insulin G O G G Glucagon McLaughlin T JCEM 2010

53 G-Tube Delivery of Nutrients into the Bypassed Stomach in Severe PBH Patients Can Be Therapeutic Oral G-tube Options for chronic Rx: Bolus Overnight Continuous Different formulas & rates Avoid CHO by mouth CHO via G-tube tolerated Limited by quality of life issues McLaughlin T JCEM 2010

54 Not Pancreatectomy! - Symptom Recurrence is Nearly Universal after Partial Pancreatectomy Symptom- Free Survival Median time to recurrence of hypoglycemia 16 mo 64% were post-bariatric No difference in subsets of bariatric, +SACST, pathology Vanderveen et al. Surgery 2010

55 Consider Reversal of Bariatric Surgery for Severe PBH Davis et al, 2018; Arora et al, 2018

56 SUMMARY OF THERAPEUTIC APPROACHES Monitoring Hypo Safety/Education Medical Therapy Dietary Modification Surgical Therapy JCEM review 2018 Salehi Patti 2018

57 Thank You!