Patient involvement to inform the design of a clinical trial in postbariatric hypoglycaemia.

BACKGROUND: Bariatric surgery may lead to symptomatic postprandial hypoglycaemia as a major side effect without established therapy so far. We aimed to develop an evidence-based study design of a clinical trial that tests treatment options and can provide useful patient-relevant evidence. METHODS: We searched systematically for guidance of core outcome sets to determine the most relevant types of outcomes and duration of such a trial. Our search comprised literature databases, a database of core outcome sets and self-help organizations. We then developed a simple online questionnaire based on interviews with German-speaking patients with postprandial hypoglycaemia after bariatric surgery. We recruited participants by reaching out to all German speaking endocrinologists in Switzerland and large Swiss bariatric centres. We asked for preferences regarding outcome types and acceptable duration of being included in a corresponding clinical trial. RESULTS: The literature search did not identify evidence-based guidance for informing our study design. Experience of clinical and research routine as well as patient interviews helped in identifying potential outcomes and the design of an online questionnaire. Therein, a total of 29 persons started the questionnaire and 22 answered questions related to the primary outcome. Of these, 17 (77.3%) deemed quality of life more relevant as primary outcome than the rate of hypoglycaemic episodes. A trial length of four weeks or longer was regarded as acceptable for 19 of 21 respondents to this question (91.4%) and of six months or longer for 12 respondents (56%). CONCLUSIONS: In situations with no other guidance, a simple questionnaire may help to inform trial design decisions. This study identifies a patient preference for "quality of life" as a primary outcome and supports the evidence-based conception of a patient-centred clinical trial in postbariatric hypoglycaemia.

Critical role for GLP-1 in symptomatic post-bariatric hypoglycaemia.

AIMS/HYPOTHESIS: Post-bariatric hypoglycaemia (PBH) is a rare, but severe, metabolic disorder arising months to years after bariatric surgery. It is characterised by symptomatic postprandial hypoglycaemia, with inappropriately elevated insulin concentrations. The relative contribution of exaggerated incretin hormone signalling to dysregulated insulin secretion and symptomatic hypoglycaemia is a subject of ongoing inquiry. This study was designed to test the hypothesis that PBH and associated symptoms are primarily mediated by glucagon-like peptide-1 (GLP-1). METHODS: We conducted a double-blinded crossover study wherein eight participants with confirmed PBH were assigned in random order to intravenous infusion of the GLP-1 receptor (GLP-1r) antagonist. Exendin (9-39) (Ex-9), or placebo during an OGTT on two separate days at the Stanford University Clinical and Translational Research Unit. Metabolic, symptomatic and pharmacokinetic variables were evaluated. Results were compared with a cohort of BMI- and glucose-matched non-surgical controls (NSCs). RESULTS: Infusion of Ex-9 decreased the time to peak glucose and rate of glucose decline during OGTT, and raised the postprandial nadir by over 70%, normalising it relative to NSCs and preventing hypoglycaemia in all PBH participants. Insulin AUC and secretion rate decreased by 57% and 71% respectively, and peak postprandial insulin was normalised relative to NSCs. Autonomic and neuroglycopenic symptoms were significantly reduced during Ex-9 infusion. CONCLUSIONS/INTERPRETATION: GLP-1r blockade prevented hypoglycaemia in 100% of individuals, normalised beta cell function and reversed neuroglycopenic symptoms, supporting the conclusion that GLP-1 plays a primary role in mediating hyperinsulinaemic hypoglycaemia in PBH. Competitive antagonism at the GLP-1r merits consideration as a therapeutic strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02550145.

Postbariatric hypoglycemia, abdominal pain and gastrointestinal symptoms after Roux-en-Y gastric bypass explored by continuous glucose monitoring.

BACKGROUND: Abdominal pain and postbariatric hypoglycemia (PBH) are common after bariatric surgery. OBJECTIVES: This study aimed to explore the potential relationship between abdominal pain, gastrointestinal symptoms, and PBH more than a decade after Roux-en-Y gastric bypass (RYGB) and whether continuous glucose monitoring (CGM) with dietary intervention has an educational role in reducing symptoms. SUBJECTS: At two public hospitals in Norway (one University Hospital) 22 of 46 invited patients who reported abdominal pain more than weekly took part. Recruited from a prospective follow-up study of 546 patients 14.5 years after RYGB. METHODS: They used a CGM for two 14-day periods, with a dietary intervention between periods. The Gastrointestinal Symptom Rating Scale (GSRS) and the Dumping Severity Score (DSS) questionnaires were completed at the start and end of the study. RESULTS: The 22 women had preoperative age 39.6 ± 7.7 years and body mass index (BMI) 42.0 ± 4.0 kg/m2, present age 54.6 ± 7.7 years and BMI 29.8 ± 4.8 kg/m2. The total GSRS score and DSS of early dumping decreased after the diet intervention. The number of events with Level 1 (<3.9 mmol/L) or Level 2 (<3.0 mmol/L) hypoglycemia did not change in the second period. Half of the patients had fewer, three had unchanged, and eight had more frequent events with Level 1 hypoglycemia after the intervention. Ten patients had Level 2 hypoglycemia. CONCLUSION: Though inconclusive findings, a personalized dietary intervention reduces GSRS. This intervention was accompanied by lower mean absolute glucose in patients with recurrent abdominal pain after bariatric surgery. However, further studies are needed to explore the benefits of CGM in this setting.

Dumping Syndrome: Pragmatic Treatment Options and Experimental Approaches for Improving Clinical Outcomes.

Dumping syndrome is a common complication after esophageal, gastric and bariatric surgery and has a significant negative impact on the quality of life of patients. This narrative review describes the clinical syndrome, pathophysiology, diagnosis and reports on standard and pragmatic therapeutical treatment options in order to improve the clinical outcome of patients with dumping syndrome. Dumping syndrome consists of early and late dumping symptoms and can be diagnosed using clinical parameters with the help of the Sigstad's score, questionnaires or by provocative testing. The prevalence of dumping syndrome varies depending on the employed definition of dumping syndrome. Overall, dumping syndrome is more frequent nowadays due to increasing numbers of upper gastrointestinal and bariatric surgeries being performed. First treatment step includes dietary adjustment and dietary supplements, which are often sufficient to manage symptoms for the majority of patients. Next step of therapy includes acarbose, which is effective for late dumping symptoms, but the use is limited due to side effects. Somatostatin analogues are indicated after these two steps have failed. Somatostatin analogues are very effective for controlling early and late dumping, also in the long term. Glucagon like peptide-1 receptor agonists, endoscopic and surgical (re)interventions are reported as treatment options for refractory dumping syndrome; however, their use is not recommended in clinical practice due to the limited evidence on and uncertainty of outcomes. These alternatives should be considered only as last resort options in patients with otherwise refractory and invalidating dumping syndrome.

Predictors of Postprandial Hypoglycemia After Gastric Bypass Surgery: a Retrospective Case-Control Study.

BACKGROUND: Postprandial hypoglycemia after bariatric surgery is an exigent disorder, often impacting the quality of life. Distinguishing clinically relevant hypoglycemic episodes from symptoms of other origin can be challenging. Diagnosis is demanding and often requires an extensive testing such as prolonged glucose tolerance or mixed-meal test. Therefore, we investigated whether baseline parameters of patients after gastric bypass with suspected hypoglycemia can predict the diagnosis. METHODS: We analyzed data from 35 patients after gastric bypass with suspected postprandial hypoglycemia and performed a standardized mixed-meal test. Hypoglycemia was defined by the appearance of typical symptoms, low plasma glucose, and relief of symptoms following glucose administration. Parameters that differed in patients with and without hypoglycemia during MMT were identified and evaluated for predictive precision using receiver operating characteristic (ROC) areas under the curve (AUC). RESULTS: Out of 35 patients, 19 (54%) developed symptomatic hypoglycemia as a result of exaggerated insulin and C-peptide release in response to the mixed-meal. Hypoglycemic patients exhibited lower glycosylated hemoglobin A1c (HbA1c) and higher absolute and relative weight loss from pre-surgery to study date. HbA1c and absolute weight loss alone could achieve acceptable AUCs in ROC analyses (0.76 and 0.72, respectively) but a combined score of absolute weight loss divided by HbA1c (0.78) achieved the best AUC. CONCLUSIONS: HbA1c and weight loss differed in patients with and without symptomatic hypoglycemia during mixed-meal test. These baseline parameters could be used for screening of postprandial hypoglycemia in patients after gastric bypass and may facilitate the selection of patients requiring further evaluation.

Continuous Glucose Monitoring to Diagnose Hypoglycemia Due to Late Dumping Syndrome in Children After Gastric Surgeries.

Gastrostomy tubes (G-tubes) and Nissen fundoplication are common surgical interventions for feeding difficulties and gastroesophageal reflux disease in children. A potential yet often missed, complication of these procedures is dumping syndrome. We present 3 pediatric patients with postprandial hypoglycemia due to late dumping syndrome after gastric surgeries. All patients received gastrostomy tubes for feeding intolerance: 2 had Nissen fundoplication for gastroesophageal reflux disease, and 1 had tracheoesophageal repair. All patients underwent multiple imaging studies in an to attempt to diagnose dumping syndrome. Continuous glucose monitoring (CGM) was essential for detecting asymptomatic hypoglycemia and glycemic excursions occurring with feeds that would have gone undetected with point-of-care (POC) blood glucose checks. CGM was also used to monitor the effectiveness of treatment strategies and drive treatment plans. These cases highlight the utility of CGM in diagnosing postprandial hypoglycemia due to late dumping syndrome, which is infrequently diagnosed by imaging studies and intermittent POC blood glucose measurements.

A Case Report of Hypoglycemia Due to Late Dumping Syndrome After Jejunostomy Tube Insertion.

Dumping syndrome occurs when food moves to the small bowel faster than usual. Patients can report a variety of symptoms such as abdominal cramps, weakness, flushing, shakiness, and decreased consciousness. Dumping syndrome can be divided into early and late based on the onset of the symptoms after the ingestion of a meal. In the literature, cases of dumping syndrome have been reported, but rarely after jejunostomy tube insertion. We report a case of an 86-year-old female suffering from late dumping syndrome after jejunostomy tube placement. An 86-year-old Saudi female presented with decreased oral intake and gastrostomy tube placement was decided. Later, the multi-disciplinary team agreed to switch her to jejunostomy tube after she developed a couple of complications in the site of insertion. However, she developed hypoglycemia due to late dumping syndrome, which was managed with the addition of starch and switching her back to a gastrostomy tube feeding.

Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1ß.

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1ß leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n = 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo = 7/12, empagliflozin = 2/12, and anakinra = 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo = 2.4 mmol/L, 95% CI 2.18-2.62, empagliflozin = 2.69 mmol/L, 95% CI 2.31-3.08, and anakinra = 2.99 mmol/L, 95% CI 2.43-3.55, pvalLRT = 0.048). Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1ß in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Long-term self-reported symptom prevalence of early and late dumping in a patient population after sleeve gastrectomy, primary, and revisional gastric bypass surgery.

BACKGROUND: Early and late dumping are side effects of bariatric surgery. Almost no data are available on the prevalence of dumping after different surgical procedures. OBJECTIVES: Comparison of the relative risks of dumping in a large population of patients having undergone primary Roux-en-Y gastric bypass (pRYGB), sleeve gastrectomy (SG), or revisional RYGB (rRYGB; after removal of band). SETTING: Bariatric center of a teaching hospital. METHODS: In this descriptive cohort study, all patients who underwent a pRYGB (n = 615), SG (n = 157), or rRYGB (n = 274) between 2008 and 2011 were approached by mail and asked to complete and return a questionnaire of general and disease-specific questions related to dumping syndrome. Relative risks (RR) were calculated (mean with 95% confidence intervals) by comparing the prevalence of high suspicion for early and late dumping between different surgical procedure groups and primary gastric bypass surgery. RESULTS: The questionnaire was completed and returned by 593 (57%) of 1046 patients. Fewer patients with SG were at high suspicion of early dumping than after pRYGB (RR [95% confidence interval] .46 [.22-.99], P = .049). No differences for early dumping were seen between rRYGB and pRYGB (RR 1.21 [.77-1.91], P = .40). More patients were at high suspicion for late dumping after rRYGB compared with after pRYGB (RR 1.78 [1.09-2.90] P = .021). No differences for late dumping were seen between SG and pRYGB (RR .59 [.22-1.61], P =.30). CONCLUSION: Fewer complaints of early dumping are reported after SG, while patients report more complaints of late dumping after rRYGB compared with pRYGB.

The short- to mid-term symptom prevalence of dumping syndrome after primary gastric-bypass surgery and its impact on health-related quality of life.

BACKGROUND: Early and late dumping are complications of gastric bypass surgery. Early dumping occurs within an hour after eating, when the emptying of food into the small intestine triggers rapid fluid shifts into the intestinal lumen and the release of gastrointestinal hormones, resulting in gastrointestinal and vasomotor symptoms. Late dumping occurs between 1 and 3 hours after carbohydrate ingestion and is caused by an exaggerated insulin release, resulting in hypoglycemia. Almost no data are currently available on the prevalence of early and late dumping or their impact on health-related quality of life (QoL). OBJECTIVES: To study the prevalence of early and late dumping in a large population of patients having undergone a primary Roux-en-Y gastric bypass (RYGB) and its effect on QoL. SETTING: Cross-sectional study at a single bariatric department in the Medical Center Leeuwarden, The Netherlands between 2008 and 2011. METHODS: In 2013, this descriptive cohort study approached by email or post all patients who underwent a primary RYGB in the setting between 2008 and 2011 in one hospital. These patients were asked to fill in standardized questionnaires measuring their QoL (RAND-36), anxiety and depression (HADS), fatigue (MFI-20) and any disease specific indicators of early and late dumping syndrome. RESULTS: The questionnaire was completed and returned by 351 of 613 patients (57.1%) and 121 nonobese volunteers. Participants were mostly female (80%), aged 42 (40-54 years), with an excess weight loss of 76.8% [IQR 61-95] after RYGB surgery 2.3 [ IQR 1.6-3.4] years earlier. Self-reported complaints of moderate to severe intensity suggestive of early and late dumping were present in 18.8% and 11.7% of patients, respectively. Patients with early and late dumping demonstrated significantly lower scores on the RAND-36 and HADS compared with patients without dumping. No differences were seen in the MFI-20 scores between patients with or without early and late dumping. CONCLUSION: In this descriptive cohort, self-reported complaints suggestive of early and late dumping of moderate-to-severe intensity were, respectively, 18.8% and 11.7% in a cohort after primary gastric bypass surgery. These complaints were associated with markedly reduced health-related QoL.

Incretin Kinetics Before and After Miglitol in Japanese Patients With Late Dumping Syndrome.

BACKGROUND: In patients with late dumping syndrome following gastrectomy, it has been reported that hypoglycemia occurs due to inhibition of glucagon secretion as a result of excessive insulin production facilitated by an increase in glucagon-like peptide-1 (GLP-1). METHODS: To determine the kinetics of incretins in Japanese patients with late dumping syndrome, an oral glucose tolerance test was carried out before and after miglitol administration, and the kinetics of insulin and incretins were analyzed. RESULTS: After miglitol administration, there was improvement of hypoglycemia and early phase insulin secretion, with persistent excessive insulin secretion being minimized. These findings revealed that miglitol inhibited rapid excessive influx of carbohydrates into the blood and persistent elevation of GLP-1, resulting in improvement of early phase insulin secretion and minimizing persistent excessive insulin secretion. CONCLUSIONS: Eating frequent small meals is generally effective for late dumping syndrome, but patients often find it difficult to continue such a regimen. Based on the present analysis of incretin kinetics, miglitol may be a useful treatment option for late dumping syndrome.

Endoluminal Revision (OverStitch (TM) , Apollo Endosurgery) of the Dilated Gastroenterostomy in Patients with Late Dumping Syndrome After Proximal Roux-en-Y Gastric Bypass.

Dumping syndrome is a long-term postoperative complication of Roux-en-Y gastric bypass procedures. Morphologically, dumping syndrome usually correlates with a dilatation of the gastroenterostomy with accelerated pouch emptying. Conservative therapy includes diet changes, complementary pharmacotherapy and, if symptoms persist, surgical revision. Surgical options include endoscopic, endoluminal surgery to constrict the gastrojejunostomy using a novel endoscopic suturing device (OverStitch(TM), Apollo). In our study, we aimed to assess the viability, safety and efficacy of this procedure in patients with late dumping; 14 patients who had developed late dumping syndrome underwent surgery using an endoscopic suturing technique (OverStitch(TM), Apollo). Late dumping was confirmed by Sigstad score and an oral glucose tolerance test (OGTT). Prior to surgery, objective analysis of pouch emptying speed was assessed by gastric scintigraphy. Surgery was performed under general anaesthesia. None of the 14 patients suffered intra- or postoperative complications. No postsurgical increase in inflammation parameters was observed. The postinterventional pain scale (visual analogue scale) showed a mean score of 0.5 (range 0-10). In 13 of the 14 patients, no dumping was observed 1-month postsurgery. The postoperative Sigstad score (3.07 ± 2.06; range 1-9) showed an impressive reduction compared with the preoperative score (12.71 ± 4.18; range 7-24) (p < 0.001). Postoperative upper gastrointestinal gastrografin swallow revealed regular emptying in all the patients. The endoluminal endoscopic suturing technique-applied here for surgical revision of gastroenterostomy following Roux-en-Y gastric bypass-represents a promising, novel therapeutic option in late dumping syndrome involving minimal trauma and offering rapid reconvalescence.

Phytotherapy of chronic abdominal pain following pancreatic carcinoma surgery: a single case observation.

A patient with pancreatic carcinoma diagnosed in 2005 suffered from chronic abdominal pain 6 years later that did not respond to conventional pain treatment according to guidelines. Furthermore, several complementary medical approaches remained ineffective. In the long run, only an Iberis amara drug combination relieved pain sufficiently. The drug is registered in Germany for the indications irritable bowel syndrome and dyspepsia. The multi-target approach of this combination drug may account for the effectiveness under these fundamentally different pathophysiological conditions. No serious undesired effects have been described in the use of this drug for other indications and none were observed in this case.

Treatment with acarbose in severe hypoglycaemia due to late dumping syndrome / Tratamiento con acarbosa en la hipoglicemia severa debido al síndrome de dumping tardío

BACKGROUND: We present a case of recurrent loss of consciousness, which was finally accurately diagnosed as late dumping syndrome twelve years after subtotal gastrectomy and successfully treated with acarbose. A 66-year old lean male was found unconscious repeatedly within one year. Oral glucose tolerance tests performed before and after acarbose treatment verified the diagnosis of late dumping syndrome. Acarbose can be used as a successful treatment modality for reactive hypoglycaemia due to late dumping syndrome by influencing the release of hormone.

ANTECEDENTES: Presentamos un caso de pérdida recurrente de conciencia, que fue finalmente diagnosticado con precisión como síndrome de dumping tardío, doce años después de la gastrectomía subtotal, y tratado con éxito con acarbosa. Un hombre magro de 66 años de edad fue encontrado inconsciente repetidas veces en un año. Las pruebas orales de tolerancia a la glucosa realizadas antes y después del tratamiento con acarbosa verificaron el diagnóstico de síndrome de dumping tardío. La acarbosa puede utilizarse como una modalidad de tratamiento acertado para la hipoglicemia reactiva debido al síndrome de dumping tardío por la influencia en la liberación de hormonas.