Gastric dumping syndrome medical therapy

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Medical Therapy

Medical therapy for dumping syndrome includes diet and drug therapy.

Level of evidence	Type of evidence
I	Evidence from meta-analysis of multiple, well-designed, controlled studies (randomized trials with low false-positive and low false-negative errors)
II	Evidence from at least 1 well-designed, quasi-experimental study (randomized trials with high false-positive and high false-negative errors)
III	Evidence from well-designed, quasi-experimental studies (nonrandomized, controlled, single-group, pre–post, cohort and time or matched case–control series)
IV	Evidence from well-designed, non-experimental studies (comparative and correlational descriptive and case studies)
V	Evidence from case reports
Grade of recommendation	Level of evidence
A	Level I evidence or consistent findings from multiple studies (level II, III or IV)
B	Level II, III or IV evidence with generally consistent findings
C	Level II, III or IV evidence with inconsistent findings
D	Little or no systematic empirical evidence

Diet

Dietary Modifications (Level III; Grade B)

• Decrease carbohydrate intake
  • Avoid simple sugars like soda, candy sweets, and cookies
• Increase protein intake
• Increase fat intake
• Increase fiber intake
• Fluid restriction
• Dairy and dairy product restriction
• Shorter meals
• Lying supine for 30 minutes after a meal

Dietary Foods

The following is a table that illustrates the types of food to take and avoid in the case of dumping syndrome.

Breads, Cereals, Rice and Pasta	Foods To Choose	Foods to Avoid
6-11 servings each day One serving equals: 1 slice bread, 1 cup ready-to-eat cereal 1/2 cup cooked cereal, rice, or pasta	Breads, bagels, rolls, unsweetened cereals, pasta, potatoes, rice, crackers, and soup (only if taken one hour after solid foods at medium temperature).	Sweet rolls and doughnuts Sweetened cereals Pancakes and waffles with syrup Soup (taken with solid foods)
Fruits	Foods to Choose	Foods To Avoid
2-4 servings each day One serving equals: 1 medium size fresh, 1/2 cup canned, 3/4 cup juice	All fresh fruit Drained, unsweetened canned fruit Unsweetened frozen fruit 100 percent pure juice (taken one hour after meals)	Canned fruits in heavy syrup Sweetened frozen fruit Sweetened juice (that is, punch or sports drinks) Candied fruit
Milk and Dairy Products	Foods To Choose	Foods to Avoid
Limit to 2 servings each day One serving equals: 1 cup milk or yogurt	Plain or unsweetened yogurt Skim, 2 percent, or whole milk (taken one hour after meals)	Milkshakes and chocolate milk Sweetened yogurt
Meats, Poultry, Fish, Dry Beans, Peas, Eggs and Cheese	Foods to Choose	Foods to Avoid
2-3 servings or a total of six ounces daily One serving equals: 2-3 ounces cooked meat, chicken, or fish (about the size of a deck of cards) or 1/2 to 3/4 cup cottage cheese or tuna fish or one egg, 1/2 cup cooked beans, two tablespoons peanut butter, or one ounce of cheese. Choose leaner cuts of beef and meat and limit the amount of high-fat items like eggs and cheese.	All meat, fish, poultry, peanut butter, cheese, eggs, and dried beans or legumes	Any not tolerated
Vegetables	Foods to Choose	Foods to Avoid
3-5 servings each day One serving equals: 1 cup raw, 1/2 cup cooked or chopped.	All vegetables	Any not tolerated
Fats, Condiments and Beverages	Foods to Choose	Foods to Avoid
	All butter, margarine, cream, oil, and salad dressings Salt, herbs, spices, and condiments Any sugar-free beverage (coffee, tea, diet soda, etc., taken one hour after solids)	Sweet pickles or relish Sweetened drinks (regular lemonade, soda) Any others not tolerated
Snacks, Sweets, and Desserts	Foods to Choose	Foods to Avoid
	Sugar-free gelatin Sugar-free pudding Sugar-free candy Sugar substitutes	Sugar Candy and chocolate Cakes and cookies Ice cream and sherbet Honey, syrup, and jelly Sugar alcohols such as sorbitol, xylitol, and mannitol

 

Dietary Supplements (Level III; Grade C)

• Delay glucose absorption:
  • Pectin
  • Guar gum
  • Glucomannan

Drug Therapy

The two main stays for pharmacological intervention are Acarbose (Glucobay, Precose, Prandase) and Somatostatin analogues such as Octreotide (Sandostatin).

	Acarbose (Level III; Grade B)	Octreotide (Level II; Grade A)
Use	Late dumping syndrome	Early and Late dumping syndrome
Mechanism of Action	Inhibits carbohydrate absorption	Strong inhibitor of the gut hormones (especially insulin)
Dose	Initiate effect: 50mg daily (QD) For complete resolution of symptoms: 50/100mg three times daily (TID). Especially beneficial in diabetics with dumping syndrome	Initiate effect: 25-50μg S.C two-three times daily (BID or TID) Maximum effect: 100-200μg S.C two-three times daily (BID or TID) Long-acting (New) I.M once monthly
Effect	Decreases postprandial hyperglycemia	Decreases symptoms Improves Sigstad's score Inhibits vasodilation Decrease Insulin levels Decrease gastric emptying Inhibits splanchnic vasoconstriction
Additional information	Limited to diarrhea severity Therapy role not yet clarified	Good for long-term refractory dumping syndrome Side effects are the reason for stopping long-term therapy. Treat this by giving an extra dose before sleeping or a pancreatic enzyme replacement. Short-acting improves symptoms New long-acting release is effective, increases weight and improves the quality of life Safe Last resort drug

Somatostatin analogues

• Pasireotide has a higher affinity than Octreotide and is more effective but it does not reduce dumping syndrome symptoms as well as Octreotide.
• Even though it has been safe and effective no results of its clinical trials have been published to date.
• People with severe cases take medicine such as cholestyramine or proton pump inhibitors (such as pantoprazole) to slow their digestion.
• Treatment – Most patients with dumping can be treated conservatively with dietary changes (frequent small meals that are high in fiber and protein and low in carbohydrates, separation of liquid from solid during meals) [9,10]. Symptoms tend to resolve in most patients as they learn to avoid foods that aggravate the problem (eg, simple sugar).
• Octreotide may also help in severe cases of dumping but is rarely required [8]. A study of 30 patients with dumping treated with either subcutaneous octreotide, administered three times a day, or its long-acting formulation (Octreotide LAR), which is given monthly, reported that both significantly reduced dumping symptoms and improved quality of life [12].
• Patients preferred monthly treatment.
• The rare patient with intractable dumping symptoms who fails dietary and medical therapy may require reoperation [9,10]. In patients who had a distal gastrectomy, conversion from a loop gastrojejunostomy to a Roux-en-Y reconstruction is the procedure of choice. This operation slows gastric emptying by impairing motility of the Roux loop. Thus, gastric remnant of no more than 25 percent should be left to avoid postoperative Roux stasis syndrome (see 'Roux stasis syndrome' below).
• In patients who had a prior loop gastrojejunostomy without gastrectomy, simple takedown of the gastrojejunostomy usually resolves dumping syndrome, provided that normal antropyloric and duodenal functions are maintained.

Clinicians treat dumping syndrome through dietary alterations by encouraging patients to reduce simple carbohydrate intake. Patients must avoid forbidden foods and change their eating behaviors (patients should cut food into small pieces, chew thoroughly, eat slowly, and wait 1 hour after a meal before drinking beverages).7,8

Patients whose symptoms persist often respond to octreotide 25 to 100 mcg subcutaneously 30 minutes before meals or long-acting depot injections of octreotide 10 to 20 mg/month. This somatostatin analogue slows gastric emptying, delays small bowel transit, and inhibits vasoactive peptide release.13,14

For late dumping syndrome, administering acarbose 25 mg before breakfast, lunch, and dinner often alleviates rebound hypoglycemia. Acarbose inhibits carbohydrate absorption in the small intestine, prevents postprandial hyperinsulinemia, and reduces insulin concentrations. Acarbose alleviates postprandial hypotension and tachycardia by slowing the gastric empting rate and subsequently delivering high-osmolality nutrients to the duodenum in a more measured way.14,15

Considerations for Oral Dosing after Bariatric Surgery · Procedures that truncate the stomach reduce gastric mixing, which is important in the disintegration process of oral forms of medication. · RYGB increases the stomach’s pH and may decrease solubility of weakly acidic drugs. · RYGB surgery reduces drug (and food)/biliopancreatic secretion mixing; therefore, drugs that depend on bile salts to enhance their solubility (eg, cyclosporine, phenytoin, levothyroxine, tacrolimus) may be compromised after RYGB. · RYGB bypasses the duodenum and the proximal jejunum and may shorten passage time through the intestine. Drugs with poor water solubility and extended-release formulations may have inadequate transit time for dissolution and absorption. · Studies have documented decreased bioavailability for several drugs after RYGB surgery (eg, amoxicillin, azithromycin, cyclosporine A, levothyroxine, nitrofurantoin, mycophenolic acid, phenytoin, phenobarbital sirolimus, tacrolimus, tamoxifen). · Procedures that reduce the stomach size may increase mucosal toxicity of nonsteroidal anti-inflammatory drugs, salicylates, oral bisphosphonates, and oral iron tablet formulations. · Any procedure that causes dumping increases gut transit time and may decease drug absorption.

RYGB = Roux-en-Y gastric bypass. Adapted from references 17- 21.

Treatment approaches for dumping syndrome include dietary modifications, pharmacologic interventions and, possibly, surgical re-intervention or continuous tube feeding. Some treatments are indicated solely for late dumping (e.g. acarbose), whereas others are potentially beneficial for both early and late dumping (e.g. somatostatin analogues). The effectiveness of some of these approaches has not been clearly established as most studies included relatively few patients and were not adequately controlled. The level of evidence and grade of recommendation, as described in Table 1, supporting the use of each of these approaches in dumping syndrome is provided.

Table 1. Levels of evidence and grades of recommendation Level of evidence Type of evidence I Evidence from meta-analysis of multiple, well-designed, controlled studies (randomized trials with low false-positive and low false-negative errors) II Evidence from at least 1 well-designed, quasi-experimental study (randomized trials with high false-positive and high false-negative errors) III Evidence from well-designed, quasi-experimental studies (nonrandomized, controlled, single-group, pre–post, cohort and time or matched case–control series) IV Evidence from well-designed, non-experimental studies (comparative and correlational descriptive and case studies) V Evidence from case reports Grade of recommendation Level of evidence A Level I evidence or consistent findings from multiple studies (level II, III or IV) B Level II, III or IV evidence with generally consistent findings C Level II, III or IV evidence with inconsistent findings D Little or no systematic empirical evidence Dietary modification (level of evidence: III; grade of recommendation: B)

Dietary modification is the initial approach used to manage dumping syndrome and is usually beneficial for a majority of patients [3, 10, 16, 43-47]. Therefore, proper patient education about dietary modification is very important and should be repeated before all subsequent treatment approaches. In addition, clinicians caring for patients after bariatric surgery should be aware of dietary approaches for the management of dumping syndrome. Clinicians should advise patients with dumping syndrome to reduce the amount of food consumed at each meal. Patients should also delay fluid intake until at least 30 min after meals. Rapidly absorbable carbohydrates should be eliminated from the diet to prevent late dumping symptoms such as hypoglycemia. Instead, patients should be advised to eat a diet consisting of high-fibre and protein-rich foods; consumption of fruit and vegetables should be encouraged whereas alcoholic beverages are better avoided. Patients should also eat slowly and chew well. Education about the glycemic index of different foods may also be helpful for patients with dumping syndrome. If these recommendations are not effective or are not followed properly, patients should be advised to lie down for 30 min after meals to delay gastric emptying and reduce the symptoms of hypovolemia [1, 16]. Dietary supplements (level of evidence: III; grade of recommendation: C)

Dietary supplements that increase the viscosity of food (e.g. guar gum, pectin and glucomannan) slow the rate of gastric emptying and delay glucose absorption. A number of short-term studies involving the ingestion of up to 15 g of guar gum or pectin with each meal have demonstrated the efficacy of these dietary supplements in slowing gastric emptying, reducing GI hormone release, improving hyperglycemia and controlling dumping symptoms (Table 2) [48-57]. A single study reported that glucomannan significantly improved glucose tolerance but had no effect on glucose absorption in children with dumping syndrome who underwent various types of gastric surgery [57]. However, the palatability and tolerability of many dietary supplements are poor. Because dietary supplements are high in fibre, some patients may experience gas and bloating. Furthermore, dietary recommendations to delay fluid intake until at least 30 min after meals means that consumption of viscous, gel-forming dietary supplements with dry food may pose a choking hazard and cause bowel obstruction as a result of a delay in the transit of food through the GI tract.

Table 2. Summary of pectin, guar Gum and glucomannan studies in dumping syndrome Study Design Treatment Results 1Efficacy was determined by comparing assessments performed before and after treatment. Abbreviations: GIP, glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide; OGTT, oral glucose tolerance test. Jenkins et al. [48] Case series N = 9 Pectin 14.5 g, single administration before OGTT1 • Normalized glycemia

• Prevented hypoglycemic symptoms

Jenkins et al. [49] Case series N = 11 Pectin 14.5 g, single administration before OGTT1 • Significantly reduced high postprandial levels of glucose, insulin and enteroglucagon

• Reduced hypoglycemia

Leeds et al. [50] Case series N = 12 Pectin 15 g, single administration before OGTT1 • Improved glycemia and vasomotor symptoms

• Reduced insulin levels

• Prolonged gastric emptying

Lawaetz et al. [51] Case series N = 4 Pectin 15 g, single administration before OGTT1 • Reduced vasomotor symptoms

• Decreased levels of insulin, glucagon, neurotensin and GIP

• Slowed initial gastric emptying

Andersen et al. [52] Case series N = 5 Pectin 5 g, single administration before meal1 • No effect on symptoms or gastric emptying rate Speth et al. [53] Double-blind, randomized, controlled study N = 9 Acarbose 50–100 mg, pectin 4.2 g, acarbose 50 mg plus pectin 4.2 g, placebo, after standard breakfast • Acarbose and acarbose plus pectin inhibited postprandial hyperglycemia and hypoglycemia

• Acarbose plus pectin inhibited hyperinsulinemia

• Acarbose, pectin and combination reduced hypoglycemic symptoms

Harju et al. [54] Double-blind, controlled study N = 11 Guar gum 5 g or placebo with meals for 1 week • Improved dumping symptoms Harju et al. [55] Double-blind, controlled study N = 11 Guar gum 5 g or placebo after a meal • Slowed gastric emptying Harju et al. [56] Case series N = 16 Guar gum 5 g with a glucose challenge meal1 • Improved symptoms Kneepkens et al. [57] Case series N = 8 Glucomannan 1.3 g before OGTT1 • Significantly improved glucose tolerance

• No effect on glucose absorption

Pharmacologic intervention

Pharmacologic intervention plays an important role in the management of dumping syndrome in patients who fail to respond to dietary modification. Several studies have evaluated acarbose or somatostatin analogues in patients with dumping syndrome (described in detail below). The efficacy and tolerability of other pharmacologic agents have mainly been presented as case reports, and clinical evidence supporting their use in dumping syndrome is more limited.

Acarbose (level of evidence: III; grade of recommendation: B)

Acarbose is an α-glycosidase hydrolase inhibitor that slows carbohydrate digestion in the small intestine, thus blunting postprandial hyperglycemia and subsequent hypoglycemia. Several small studies demonstrated that acarbose improved glucose tolerance, reduced GI hormone release, reduced the incidence of hypoglycemia and improved symptoms in patients with dumping syndrome (Table 3) [8, 34, 53, 58-66]. However, the use of acarbose as a treatment approach for dumping syndrome is limited by the fact that it affects only late dumping symptoms and may result in side effects related to carbohydrate maldigestion, such as bloating, flatulence and diarrhoea.

Table 3. Summary of acarbose studies in dumping syndrome Study Design Treatment Results 1Efficacy was determined by comparing assessments performed before and after treatment. 2Alpha-glucosidase inhibitor not specified. 3Fifty percent reduction in the number and severity of hypoglycemic events. Abbreviations: CGM, continuous glucose monitoring; GIP, glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1; OGTT, oral glucose tolerance test; TID, three times per day; VIP, vasoactive intestinal peptide. McLoughlin et al. (58) Case series N = 10 Acarbose 100 mg or placebo single administration before OGTT • Improved glycemia and symptoms

• Reduced increase in plasma levels of GIP and insulin

• No change in gastric emptying rate

Gerard et al. (59) Double-blind, randomized, controlled study N = 24 Acarbose 100 mg or placebo single administration before OGTT • Improved reactive hypoglycemia

• Reduced increase in plasma levels of insulin

• Inhibited glucose-induced glucagon suppression

Lyons et al. (60) Double-blind, randomized, controlled study N = 13

Acarbose 50 mg or placebo single administration before standard breakfast

• Significantly attenuated hyperglycemia

• Reduced increase in plasma levels of GIP, enteroglucagon and insulin

• No effect on plasma levels of neurotensin, VIP and somatostatin

• No significant effect on symptoms

	n = 9	Acarbose 50 mg TID or placebo for 1 month	

• No significant reduction in the number or severity of dumping attacks

• Most patients preferred acarbose

Hasegawa et al. (61) Case series N = 6 Acarbose 50–100 mg TID before meals for 1 month1 • Attenuated glucose and insulin fluctuations

• Improved dumping symptoms

Ozgen et al. (62) Case series N = 21 Acarbose 150 mg/day before meals for 2 weeks and 300 mg/day for the remainder of the 3-month treatment period1 • Reduced early hyperglycemic and hyperinsulinemic response

• Reduced reactive hypoglycemia

Ng et al. (8) Case series N = 6 Acarbose 12.5 mg before a meal1 • Improved postprandial hypoglycemia De Cunto et al. (63) Case series N = 4 Acarbose 25–100 mg before meals1 • Stabilized postprandial glucose Valderas et al. (64) Case series N = 8 Acarbose 100 mg before a meal1 • Avoided postprandial hypoglycemia

• Reduced hyperinsulinemic response

• Reduced GLP-1 secretion

Ritz et al. (34) Case series N = 8 Acarbose 50–100 mg, TID for 6 weeks1 • Eliminated dumping symptoms

• Improved CGM profile

Speth et al. (53) Double-blind, randomized, controlled study N = 9 Acarbose 50–100 mg, pectin 4.2 g, acarbose 50 mg plus pectin 4.2 g, placebo, after standard breakfast • Acarbose and acarbose plus pectin inhibited postprandial hyperglycemia and hypoglycemia

• Acarbose plus pectin inhibited hyperinsulinemia

• Acarbose, pectin and combination reduced hypoglycemic symptoms

Vilarrasa et al. (66) Multicenter, retrospective, systematic case series N = 22 Alpha-glucosidase inhibitors2 50 mg/8 h orally • 4 patients (18%) had a partial response3 Somatostatin analogues (level of evidence: II; grade of recommendation: A)

Somatostatin analogues are an effective treatment option for patients with well-established dumping syndrome who fail to respond to and/or do not tolerate initial dietary modification and acarbose treatment. Somatostatin analogues target various steps in the pathophysiology of dumping syndrome, including delaying gastric emptying, delaying transit through the small intestine, inhibiting the release of GI hormones, inhibiting insulin secretion and inhibiting postprandial vasodilation [15, 67-78]. Somatostatin inhibition of GLP-1 secretion is mediated via activation of the somatostatin receptor subtype (sst) 5, with a lesser effect through sst2 [79]. Both short-acting and long-acting formulations of somatostatin analogues have demonstrated efficacy by slowing gastric emptying, improving hypoglycemia and reducing early and late dumping symptoms (Table 4) [15, 66, 80-95].

Table 4. Summary of somatostatin analogue studies in dumping syndrome Study Design Treatment Results 1Efficacy was determined by comparing assessments performed before and after treatment. 2Complete resolution of hypoglycemic events. 3Fifty percent reduction in the number and severity of hypoglycemic events. Abbreviations: GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide; LAR, long-acting release; OGTT, oral glucose tolerance test; VIP, vasoactive intestinal peptide. Subcutaneous octreotide Hopman et al. (80) Double-blind, randomized, controlled study N = 12 Octreotide 50 µg vs placebo before OGTT • Improved symptoms and suppressed postprandial rise in pulse rate

	 	 	• Reduced peak insulin and increased nadir glycemia
	 	 	• Slowed GI transit

Primrose and Johnston (81) Double-blind, randomized, cross-over, controlled study N = 10 Octreotide 50 µg or 100 µg vs placebo before OGTT • Reduced early dumping and abolished late dumping symptoms

• Suppressed early dumping-associated changes in haematocrit and pulse rate

	 	 	• Inhibited hypoglycemia

Tulassay et al. (82) Double-blind, randomized, controlled study N = 8 Octreotide 50 µg vs placebo before OGTT • Suppressed rise in pulse rate, haematocrit and plasma levels of VIP

	 	 	• Prevented postprandial hypoglycemia
	 	 	• Inhibited rise in plasma insulin and GIP

Geer et al. (83) Double-blind, randomized, controlled study N = 10 Octreotide 100 µg vs placebo before OGTT • Prevented symptom development including late hypoglycemia before OGTT

	 	 	• Inhibited rise in plasma levels of glucose, glucagon, pancreatic polypeptide, neurotensin and insulin
	 	 	• Slowed gastric emptying and GI transit

Richards et al. (84) Double-blind, randomized, controlled study N = 6 Octreotide 100 µg vs placebo before OGTT • Prevented symptom development

• Induced phase III migrating motor complex in the small intestine

	 	 	• Decreased postprandial intestinal motor activity

Gray et al. (85) Double-blind, randomized, cross-over, controlled study, N = 9 Octreotide 100 µg vs placebo before OGTT • Suppressed symptoms and rise in pulse rate

• Inhibited insulin release

• Prevented hypoglycemia

Hasler et al. (86) Double-blind, randomized, cross-over, controlled study, N = 8 Octreotide 50 µg vs placebo before OGTT • Suppressed symptoms and rise in pulse rate

• No effect on change in haematocrit, inhibition of insulin release, prevention of hypoglycemia or gastric emptying rate

Arts et al. (15) Single-arm, open-label study, N = 30 Octreotide 50 µg for 3 days1 • Suppressed rise in pulse rate and haematocrit

• Inhibited postprandial hypoglycemia and rise in insulin plasma levels

• Improved early and late dumping symptoms

Vilarrasa et al. (66) Multicenter, retrospective, systematic, case series, N = 13 Octreotide 50/100 μg/12 h • 3 patients (23%) had a complete response2

• 5 patients (38.4%) had a partial response3

Long-term Treatment With Subcutaneous Octreotide Geer et al. (83) Double-blind, randomized, controlled study, N = 10 Octreotide 100 µg vs placebo; mean treatment period, 15 months. • Provided sustained symptom control

• Resulted in minimal side effects

• Provided stable fasting plasma glucose levels, normal liver function tests and an average weight gain of 11% during a 12-month period

• Most patients able to resume employment

Vecht et al. (87) Single-arm, open-label study N = 20 Octreotide 25–200 µg; mean treatment period, 37 months1 • Provided early relief of early and late symptoms in all patients

• Long-term effects less beneficial

	 	 	• Symptom relief persisted in 80% of patients at 3 months

Didden et al. (88) Single-arm, open-label study, N = 34 Octreotide 25–50 µg; mean treatment period 93 months • Provided early relief of early and late symptoms in all patients

• Long-term effects less beneficial

	 	 	• 47% of patients discontinued therapy because of side effects or lack of efficacy

Long-Acting Octreotide Penning et al. (89) Single-arm, open-label study N = 12 Octreotide LAR 10 mg every 4 weeks for 6 months vs subcutaneous octreotide • Both formulations improved symptoms

• Octreotide LAR was superior at increasing body weight and improving quality of life

Arts et al. (15) Single-arm, open-label study N = 30 Octreotide LAR 20 mg for 3 months vs subcutaneous octreotide 50 µg for 3 days • Both formulations had a beneficial effect on dumping symptoms, hypoglycemia and pulse rate

• Subcutaneous octreotide was more effective than octreotide LAR in improving hypoglycemia

• Octreotide LAR was associated with significantly greater improvements in quality of life and was preferred relative to subcutaneous octreotide

Pasireotide Deloose et al. (90) Double-blind, randomized, cross-over, controlled study, N = 9 Pasireotide 300 µg vs placebo for 2 weeks • Suppressed increase in pulse rate and late hypoglycemia

• Increased peak glycemia

• Delayed gastric emptying

Somatostatin analogues may be administered subcutaneously three times daily as a short-acting formulation or intramuscularly once every 2 to 4 weeks as a long-acting formulation. Short-acting formulations may be more effective at improving some dumping symptoms such as hypoglycemia [15, 81-83, 85]; however, the need for repeated injections throughout the day is often a major limitation to the long-term administration of short-acting formulations. Long-acting formulations are preferred by patients because of less frequent administration and the associated improvements in quality of life [15, 89]. The most common adverse events associated with somatostatin analogues are diarrhoea, nausea, steatorrhea, gallstone formation and pain at the injection site. Despite the occurrence of steatorrhea, which is generally mild, patients with dumping syndrome who receive long-term somatostatin analogue therapy experience a weight gain of approximately 1% [1]. Gallstone formation may influence treatment selection for dumping syndrome [96, 97]. Furthermore, during both short-term treatment and long-term treatment, a proportion of patients with dumping syndrome do not respond to currently available somatostatin analogues [1, 15, 87-89]. Somatostatin analogues have not received regulatory approval for the treatment of dumping syndrome.

Pasireotide is a multireceptor-targeted somatostatin analogue with high affinity for 4 of the 5 somatostatin receptor subtypes, including sst2 and sst5. The affinity of pasireotide for sst5 is higher than that of octreotide [98, 99]. A recent case report demonstrated that pasireotide inhibited GLP-1 and insulin release more effectively than octreotide, resulting in improved control of postprandial hyperinsulinemic hypoglycemia after a gastric bypass [100]. A pilot study also demonstrated that pasireotide suppressed the increase in pulse rate and late hypoglycemia, and delayed gastric emptying [90]. However, pasireotide did not demonstrate a significant improvement in dumping symptoms, and approximately 20% of patients in the pilot study discontinued treatment because of GI events [90]. A recent phase 2, dose-escalation study evaluated the pharmacokinetics, efficacy and safety of subcutaneous pasireotide followed by long-acting release (LAR) pasireotide in dumping syndrome (NCT01637272: N = 43) [17, 101]. Pasireotide effectively controlled postprandial hypoglycemia and improved changes in pulse rate and haematocrit in patients with dumping syndrome. Both subcutaneous and LAR pasireotide were well tolerated, and no new safety signals were identified [101]. Another phase 2 study, which compared the efficacy, safety and quality of life of LAR lanreotide versus placebo in dumping syndrome, was recently completed, but no results have been published to date (NCT01923649) [102]. Other Pharmacologic Interventions (level of evidence: V; grade of recommendation: D)

Other pharmacologic interventions, such as diazoxide, nifedipine and exendin 9-39 have also been evaluated for the management of dumping syndrome. Diazoxide is a potassium channel activator that inhibits calcium-induced insulin release. Anecdotal evidence suggests that off-label diazoxide administered at doses ranging from 100 mg to 150 mg three times daily may be effective in the treatment of late dumping symptoms, but no effect on early symptoms is expected because of its mode of action [103]. A recent multicenter, retrospective, systematic case series reported that treatment of six patients who developed hyperinsulinemic hypoglycemia after bariatric surgery with diazoxide (168.7 ± 94 mg/day orally) resulted in a partial response (defined as a 50% reduction in the number and severity of hypoglycemic events) in three patients (50%) [66]. Nifedipine, a calcium channel blocking agent, successfully controlled persistent hyperinsulinemic hypoglycemia in a case report of an adult patient with dumping syndrome that occurred after gastric bypass surgery [104]. Administration of nifedipine in combination with verapamil to 10 patients who developed hyperinsulinemic hypoglycemia after bariatric surgery resulted in a partial response in five patients (50%) [66]. Continuous infusion of the GLP-1 receptor antagonist exendin 9-39 has recently been shown to correct hypoglycemia after gastric bypass, which may result in a new therapeutic approach for the management of dumping syndrome. The benefit observed with exendin 9-39 therapy is consistent with the role of GLP-1 in the development of postprandial hypoglycemia after gastric bypass [18]. Because these pharmacologic interventions have only been evaluated in small studies, current evidence supporting their efficacy in dumping syndrome is generally quite limited. Surgical re-intervention or continuous enteral feeding

Despite the availability of several effective therapeutic options, some patients will continue to experience treatment-refractory dumping syndrome. Surgical re-intervention or continuous enteral feeding is additional therapeutic approaches that can be considered in this situation.

Surgical re-intervention (level of evidence: IV; grade of recommendation: C)

Most patients with postprandial hypoglycemia after Roux-en-Y gastric bypass respond to dietary modification and pharmacologic intervention. However, a subset of patients with severe post-Roux-en-Y gastric bypass hypoglycemia may respond inadequately, and surgical re-intervention may be considered. In general, surgical re-intervention procedures are largely ineffective, and some procedures (e.g. pancreatectomy) are rarely performed because of lack of effectiveness and high morbidity. A study of patients who underwent partial pancreatectomy because of noninsulinoma pancreatogenous hypoglycemia demonstrated that nearly 90% experienced recurrent symptoms suggestive of hypoglycemia [105]. Fewer than half of patients (48%) were deemed to have achieved a highly or moderately successful surgical outcome, and 25% experienced no apparent benefit [105].

Various surgical re-interventions have been used, including gastric tube placement, gastric bypass reversal with or without concomitant sleeve resection and gastric pouch restriction (Table 5) [66, 103, 105-123]. A special consideration is the association between hypoglycemia after Roux-en-Y gastric bypass and nesidioblastosis that may result in serious and refractory neuroglycopenic symptoms, which respond to pancreatic resection and re-resection [124]. Because the development of hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover, nesidioblastosis has not been established as the cause of late dumping syndrome [125].

Table 5. Summary of surgical re-intervention studies for post-Roux-en-Y gastric bypass in dumping syndrome Study Patients Procedure Results 1Two additional patients (N = 12) with concomitant pancreatic resection excluded from the gastric pouch restriction subgroup but are included in the pancreatic resection subgroup. 2Resection of 80% of the total pancreatic volume starting from the pancreatic tail. 3Roux-en-Y gastric bypass or other malabsorptive procedure. Abbreviation: GLP, glucagon-like peptide. Gastric bypass reversal Patti et al. [103] Case report N = 1 Gastric bypass reversal • Ineffective in reversing hypoglycemia

• Partial pancreatectomy required

Campos et al. [106] Prospective study N = 5 Gastric bypass reversal, N = 2; modified sleeve gastrectomy, N = 3 • No postoperative episodes of neuroglycopenia

• No or minimal hypoglycemic episodes

• Hypocalcemia became responsive to oral replacement therapy

Lee et al. [107] Case report N = 2 Gastric bypass reversal • Ineffective in reversing hypoglycemia Vilallonga et al. [108] Retrospective database analysis N = 9 Gastric bypass reversal; patients with marked normalization of the gastrostomy tube glucose tolerance test • No new episodes of severe hypoglycemia

• 3 patients received a concomitant sleeve gastrectomy

• Severe gastroesophageal reflux disease and/or chronic diarrhoea reported by some patients

Vilarrasa et al. [66] Multicenter, retrospective, systematic case series N = 3 Gastric bypass reversal • Hypoglycemia resolved in 2 patients (67%)

• Hypoglycemia persisted in 1 patient (33%) but was controlled by alpha-glucosidase inhibitors

Rao et al. [109] Case report N = 1 Laparoscopic gastric bypass reversal • Marked reduction in hypoglycemia burden 9 months after reversal Carter et al. [110] Retrospective analysis N = 3 Sleeve gastrectomy • Dumping symptoms and hypoglycemia resolved

• 1 patient developed portal vein thrombus and seroma

• 2 patients were readmitted to hospital and required supplemental nutrition

Lakdawala et al. [111] Case series N = 5 Laparoscopic conversion to sleeve gastrectomy • Dumping syndrome resolved

• No complications were reported

Huang et al. [112] Case report N = 2 Laparoscopic conversion to loop duodenojejunal bypass with sleeve gastrectomy • Dumping symptoms resolved

• After 6 months, the Sigstad's score decreased to 2 points

• No complications were reported

Huang et al. [113] Case report N = 1 Laparoscopic conversion to modified duodenal switch • Dumping symptoms resolved

• No complications were reported

Gastric pouch restriction Z'graggen et al. [114] Case series N = 101 Gastric pouch downsized; silastic (Fobi) ring around pouch, n = 6; adjustable band, n = 4 • No new hypoglycemic episodes

• All had symptomatic improvement (assessed via the Sigstad score)

de Heide et al. [115] Case report N = 1 Laparoscopic adjustable banding for pouch dilatation • Subjective improvement in symptoms Vilarrasa et al. [66] Multicenter, retrospective, systematic case series N = 1 Resection of the ‘candy cane’ roux limb • Patient was symptom-free 1 year after procedure Pancreatic resection Patti et al. [103] Case series N = 3 Distal pancreatectomy (80%), n = 2; subtotal pancreatectomy (85%), n = 1 • 1 patient who previously had an unsuccessful gastric bypass reversal and distal pancreatic resection required a total pancreatectomy for recurrent symptoms

• 1 patient had improvements but still experienced episodes of hypoglycemia

• 1 patient had no hypoglycemic episodes

Clancy et al. [116] Case report N = 2 Distal pancreatectomy (80%), n = 1; subtotal pancreatectomy (95%), n = 1 • 80% pancreatectomy2 unsuccessful; pancreaticoduodenectomy required

• Subtotal pancreatectomy successful

Alvarez et al. [117] Case report N = 1 Distal pancreatectomy • Symptom-free for >10 months Barbour et al. [118] Retrospective analysis N = 2 Distal pancreatectomy, n = 1; duodenum-preserving pancreatic head resection, n = 1 • Symptoms resolved after distal pancreatectomy

• Patient with pancreatic head resection had persistent symptoms and underwent distal pancreatectomy

Z'graggen et al. [114] Case series N = 31 Distal pancreatectomy and Fobi ring around gastric pouch, n = 2; distal pancreatectomy (50%–60%) and removal of pouch band, n = 1 • No new hypoglycemic episodes Rumilla et al. [119] Case series N = 27 Partial pancreatectomy • 8 patients had recurrent or ongoing mild symptoms

Mathavan et al. [120] Retrospective study N = 9 Distal pancreatectomy (80%) • 2 patients had complete symptom resolution

• 3 had occasional symptoms

• 2 had frequent symptoms

• 2 patients had severe symptoms refractory to medical therapy (calcium channel blockers, diazoxide and octreotide)

• Both patients had extended (95%) pancreatic resection; 1 had resolution of symptoms and symptoms persisted in the second patient

Vanderveen et al. [105] Retrospective chart review N = 33 Pancreatic resection • Approximately 40% of patients had moderate or highly successful surgical outcomes, with an improvement in hypoglycemic symptoms Rabiee et al. [121] Case report N = 1 Distal pancreatectomy (85%) • Symptoms resolved but elevated levels of GLP-1 persisted Ceppa et al. [122] Case report N = 1 Distal pancreatectomy • Hypoglycemia persisted and a total pancreatectomy was required Qintar et al. [123] Case report N = 1 Distal pancreatectomy (80%) • Full remission initially after surgery but hypoglycemia recurred after 6 months

• Hypoglycemia recurrence well-controlled by octreotide therapy

Lee et al. [107] Case report N = 1 Distal pancreatectomy • Distal pancreatectomy was followed by gastric bypass reversal

• Gastric bypass reversal was ineffective in reversing hypoglycemia

Vilarrasa et al. [66] Multicenter, retrospective, systematic case series N = 33 Partial pancreatectomy • Hypoglycemia resolved in 2 patients (67%) As shown in Table 5, approximately 24% of patients who underwent surgical re-intervention because of refractory severe post-Roux-en-Y gastric bypass hypoglycemia received a gastric bypass reversal [66, 103, 106-113] and approximately 9% had gastric pouch restriction [66, 114, 115]. Pancreatic resection, the most commonly reported procedure, was performed in approximately 67% of patients [66, 103, 105, 107, 114, 116-123]. Some patients underwent two or more consecutive surgical re-interventions or combined re-interventions for severe hypoglycemia. The proportion of patients with symptom resolution after each procedure was generally higher for gastric bypass reversal or gastric pouch restriction than for pancreatic resection. Complications of surgical re-intervention included recurrent symptoms, diabetes and weight gain. Most surgical re-intervention studies were relatively small and presumably included highly selected patients, mean follow-up was short, and the methodology used to evaluate hypoglycemia was not consistent. Furthermore, the effectiveness of one surgical re-intervention procedure relative to another has not been evaluated in adequately controlled clinical studies. Conservative management approaches should be pursued before attempting surgical re-intervention as patients with dumping syndrome may experience symptomatic improvement over time. Continuous enteral feeding (level of evidence: V; grade of recommendation: D)

An additional approach for the management of refractory dumping syndrome involves the provision of a constant supply of nutrients via a feeding jejunostomy. Anecdotal evidence suggests that continuous enteral feeding may be beneficial in avoiding dumping symptoms after meal ingestion; however, this approach is invasive and may impair quality of life [1, 126]. Restoring the original nutrient transit route via placement of a gastric tube in the remnant stomach was also reported to be effective [127]. Standardized liquid meal administration via a gastric tube demonstrated complete reversal of severe metabolic abnormalities including hypersecretion of insulin and incretin hormones such as GLP-1 compared with oral administration [127]. The authors of this publication also restored glucose homeostasis via the placement of a gastric tube in the remnant stomach of a patient who had undergone gastric bypass surgery (Dr. van Beek, unpublished observation). However, as these findings are based on individual case reports, clinical evidence supporting the use of continuous enteral feeding in the management of dumping syndrome is very limited.