Gastroparesis BBDC Clinical Diabetes Symposium 9/8/2018 Joseph Auer, MD Assistant professor, gastroenterology, University of Kentucky

Resources and reviews Am J Gastroenterol 2013; 108:18–37; doi: 10.1038/ajg.2012.373; published online 13 November 2012 Diabetes Ther (2018) 9 (Suppl 1):S1–S42 https://doi.org/10.1007/s13300-018-0454-9

Disclosures I have no financial disclosures I will be mentioning some off-label use of medications during this activity.

Objectives Upon completion of this activity, participants will be able to: Select appropriate diagnostic testing for the evaluation of gastrointestinal comorbidities in patients with diabetes.

Diabetic autonomic Neuropathies Early glycemic control slows progression Gi associated neuropathies Esophageal dysmotility Gastroparesis enteropathies

Diabetic gastroparesis 20-50% of diabetics Type 1 dm (27-65%) … more common occurrence than in type 2 >10 years of type 2 dm …30% 34 years Mean age of onset More frequent in women Unclear why – perhaps hormonal

Diagnosis (syndrome) Symptoms Clinical symptoms in the absence of mechanical obstruction (peptic ulcer disease, gastric outlet obstruction, etc…) Documentation of delayed gastric emptying Degree of delay correlates poorly with severity of symptoms. Diagnosis (syndrome) Nausea, vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain. Functional dyspepsia , accelerated gastric emptying, PUD, H. Pylori, may present with the same symptoms. (ability to distinguish functional dyspepsia from idiopathic gastroparesis currently has limited value as treatments overlap but an important distinction for diabetic gastroparesis) Symptoms

Clinical Characteristics and distribution 36% idiopathic Significant proportion may be post- viral. 29% diabetic 13% postgastric surgery 7.5% Parkinson's disease 4.8% collagen vascular disorders 4.1% intestinal pseudoobstruction 6% miscellaneous causes Majority of cases occur in women for idiopathic as well as diabetic cases (unclear why). Soykan I, Sivri B, Saroseik I, et al.: Demography, clinical Characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 43:2398-2404 1998 PMID: 9824125

Differential Remember there are Other reasons to consider for gastroparesis even in the setting of diabetes Parkman, American Gastroenterological Association Technical Review on the Diagnosis and Treatment of Gastroparesis. GASTROENTEROLOGY 2004;127:1598

Gastric function / motility Turns out to be a very complicated process enteric neural plexus sympathetic and parasympathetic hormonal pacemaker cells – interstitial cells of cajal Damage to enteric nerves may disrupt normal mechanisms of motility / emptying. *Reservoir *Mixer *Empties

Gastric function / motility “The emptying of liquids is exponential. In contrast, the emptying of large solid particles only begins after sufficient grinding, resulting in a lag phase followed by the emptying of the viscous chyme mainly in a linear fashion” i.e. liquids empty much more easily Krishnasamy, S. & Abell, T.L. Diabetes Ther (2018) 9(Suppl 1): S9

Mechanisms of Diabetic gastroparesis Hormonal issues: * GLP-1(glucagon like peptide) secreted by the small intestine in response to nutrients slows gastric emptying * Amylin co-secreted with insulin (in response to glp-1) also slows gastric emptying

Krishnasamy, S. & Abell, T.L. Diabetes Ther (2018) 9(Suppl 1): S16

Diabetes and Gastroparesis Glycemic control is fundamental to treating gastroparesis. Hyperglycemia (at levels as low as 144 - 8 mmol / L) Delayed gastric emptying of both liquid and solids Variable dysrhythmias (gastric and intestinal) Tachygastrias , antral hypomotility Decreased effect of erythromycin and likely other motility drugs. Apoptosis of enteric neurons Loss of interstitial cells of Cajal (gastric pacing) Chaikomin, World J Gastroenterol 2006 September 21; 12(35): 611-5621

Medications and delayed gastric emptying Opioid analgesics Anticholinergic agents Tricyclic antidepressants Calcium channel blockers Progesterone Octreotide Proton pump inhibitors H2-receptor antagonists Interferon alfa L-dopa Fiber Exenatide Sucralfate Aluminum hydroxide antacids adrenergic receptor agonists Glucagon Calcitonin Dexfenfluramine Diphenhydramine Alcohol Tobacco/nicotine Tetrahydrocannabinol Camilleri, Clinical Guideline: Management of Gastroparesis, Am J Gastroenterol 2013; 108:18–37 Parkman, American Gastroenterological Association Technical Review on the Diagnosis and Treatment of Gastroparesis. GASTROENTEROLOGY 2004;127:1592–1622

Gastroparesis Evaluation Scintigraphic gastric emptying of solids is the standard for the evaluation of gastric emptying and the diagnosis of gastroparesis. The most reliable method and parameter for diagnosis of gastroparesis is gastric retention of solids at 4 h measured by scintigraphy. Studies of shorter duration or based on a liquid challenge result in decreased sensitivity in the diagnosis of gastroparesis. Patients with diabetes should have blood glucose measured before starting the gastric emptying test, and hyperglycemia treated with test started aft er blood glucose is < 275 mg / dl. EGD evaluation to exclude other processes. UGI series or other small bowel imaging to exclude mechanical obstruction.

Gastric scintigraphy Patient consumes standard radiolabeled meal within 10 min 99-m technetium sulfur colloid- labeled low-fat, egg-white meal (120 g) Optimize glycemic control (<275) and medications that slow emptying 2-3 days before procedure Imaging standing at 1, 2, 4 hours Delayed emptying > 60% at 2 hours or 10% retention at 4 hours

Other testing modalities (not standard practice) MRI with gadolinium Single photon emission CT Stable-isotope gastric emptying breath testing Wireless motility capsule electrogastrography

Diagnosis and Management Current evidence does not show benefit. Camilleri, Am J Gastroenterol. 2013 Jan;108(1):18-37

Treatment / Diet If possible, improve the underlying issue Glycemic control: difficult in the face of rapid and slowed emptying Medications Avoid narcotics for pain symptom Diet and education is the primary intervention Gastroparesis diet – multiple publications available. Small frequent meals (~6 meals per day) with liquids Low residue avoid fibrous food requiring gastric trituration Fibrous food promotes bezoar formation Avoid fatty foods – slows gastric emptying. < 40 gms per day Remember liquids require little gastric motility. May transition to blenderized diet when symptoms are more severe.

Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM Conclusion: CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis. April 2018

Prokinetic Medications Metoclopramide (FDA approved for gastroparesis) Erythromycin Domperidone not available in US without investigational new drug clearance from FDA Like Reglan without central effects

Metoclopramide Maybe it was the metoclopramide Mechanism: Dopamine receptor antagonist central/peripheral, 5-HT3 antagonist, 5-HT4 agonist. Prokinetic and antiemetic properties. Side effects CNS side effects in 20–30% Tardive dyskinesia is real and potentially irreversible. FDA box warning Parkinson type syndrome Dystonic reaction Risk of tardive dyskinesia Hyperprolactinemia May prolong qt Dosing: 5- 20 mg qid (use lowest dose possible) Maybe it was the metoclopramide

Erythromycin Mechanism: Motilin receptor agonist. No antiemetic effect. Side effects Nausea, vomiting, abdominal pain Qtc may be prolonged and Ekg should be obtained at baseline and during tx Tachyphylaxis limits long term use Dosing: 125mg to 250 mg bid to tid. (use in lowest effective dose)

Domepridone Mechanism: Peripheral D2 antagonist – increases antral contractions, decreased fundal relaxation, improves antroduodenal coordination. Side effects Prolonged QT – need ekg and follow periodically Do not use with qtc > 470 ms in men and > 450 ms in women Dosing: 10- 30 mg po QID. Not available in US without IND. Sounds similar but totally different

Nausea Antiemetics Phenothiazines Serotonin 5-ht3 antagonists promethazine Serotonin 5-ht3 antagonists Ondansetron Antihistamines Diphenhydramine TCA Nortriptyline, mirtazapine Avoid amitriptyline due to more prominent anticholinergic effects

Medication Algorithim Camilleri, Clinical Guideline: Management of Gastroparesis, Am J Gastroenterol 2013; 32

Gastric Electrical Stimulation GES may be considered for compassionate treatment in patients with refractory symptoms, particularly nausea and vomiting. Symptom severity and gastric emptying have been shown to improve in patients with diabetic gastroparesis, but not in patients with idiopathic or postsurgical gastroparesis. Camilleri, Clinical Guideline: Management of Gastroparesis, Am J Gastroenterol 2013; 108:18–37

Other options Gastrectomy Surgical pyloroplasty gastrojejunostomy Cam Acupuncture Ginger

Camilleri, Clinical Guideline: Management of Gastroparesis, Am J Gastroenterol 2013; 108:24

Krishnasamy, S. & Abell, T. L. Diabetes Ther (2018) 9(Suppl 1): 1