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

2. Resources and reviews
Am J Gastroenterol 2013; 108:18–37; doi: /ajg ; published online 13 November 2012
Diabetes Ther (2018) 9 (Suppl 1):S1–S42

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

4. 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.

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

6. 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

7. 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

8. 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: PMID:

9. 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

10. 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

11. 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

12. 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

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

14. Diabetes and Gastroparesis
Glycemic control is fundamental to treating gastroparesis.
Hyperglycemia (at levels as low as 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):

15. 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

16. 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.

17. 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

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

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

20. 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.

21. 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

22. 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

23. 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: mg qid (use lowest dose possible)
Maybe it was the metoclopramide

24. 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)

25. 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: mg po QID.
Not available in US without IND.
Sounds similar but totally different

26. 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

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

28. 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

29. Other options Gastrectomy Surgical pyloroplasty gastrojejunostomy Cam
Acupuncture
Ginger

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

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