Treatment of Hypoglycemia Following Gastric Bypass Surgery
Condition: Hypoglycemia; Obesity; Surgery
MeSH terms: Hypoglycemia
Study type: Interventional
Phase: Phase 4

Summary: 
      Obesity is increasing worldwide and consequently the need for efficient treatment
      opportunities. Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed
      bariatric procedures used in the treatment of severe obesity. The surgery results in
      significant and sustained weight loss and has a beneficial effect on blood glucose
      regulation.

      However, some patients experience the syndrome postprandial hyperinsulinemic hypoglycemia
      years after the operation, with symptoms varying from mild dizziness to confusion, loss of
      consciousness and seizures. Larger insulin and glucagon-like peptide 1 (GLP-1) responses to
      an oral glucose load are believed to play a role in the syndrome, which is not yet fully
      understood. There are no current treatment guidelines beside dietary recommendations.

      The purpose of this study is to compare different pharmacological treatments on daily blood
      glucose variations as well as postprandial hormonal and autonomous changes in subjects with
      symptoms of postprandial hyperinsulinemic hypoglycemia after RYGB.
    

Detailed description: 
      Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed bariatric procedures
      used in the treatment of severe obesity. RYGB has in several studies been shown to result in
      significant and sustained weight loss. Moreover, RYGB has a beneficial effect on obese
      subjects with type 2 diabetes by improving blood glucose regulation, resulting in remission
      or partial remission of type 2 diabetes already days after surgery.

      The changes of the anatomy of the stomach and small intestine cause a faster and more abrupt
      increase in blood glucose after a meal. As a consequence of the changed glucose absorption
      after RYGB and the increased insulin secretion, some subjects experience the condition named
      postprandial hyperinsulinemic hypoglycemia. Postprandial hyperinsulinemic hypoglycemia is
      typically seen years after RYGB and the symptoms vary from mild dizziness to confusion, loss
      of consciousness and seizures. The condition is characterized by large postprandial blood
      glucose variations accompanied by exaggerated insulin and glucagon-like peptide 1 (GLP-1)
      responses. Continuous glucose monitoring (CGM) have shown that subjects suffering from
      postprandial hyperinsulinemic hypoglycemia presents large variations in blood glucose from
      values below 3.5 mmol/L to diabetic values above 11.1 mmol/L within the first hour after a
      meal.

      At present, there are no treatment guidelines beside dietary recommendations. Experimental
      treatment includes diet modifications, pharmaceutical treatments and surgical procedures.
      Several pharmaceutical agents have been attempted in the management of postprandial
      hyperinsulinemic hypoglycemia, but overall the existing studies consist of few case reports
      and case series evaluated primarily by relief of symptoms and not by CGM and hormonal
      analyses.

      The study is designed as a randomized, non-blinded cross-over study including five treatment
      arms. The pharmaceutical agents are: a) Glucobay, b) Januvia, c) Verapamil, d) Victoza and e)
      Signifor. The treatment duration is 1 - 3 weeks, except for Signifor, which is administered
      for one day only. Each treatment period is separated by a wash out period of 7-10 days.

      Sixteen none diabetic women are included in the study. They have undergone RYGB and have
      symptoms of postprandial hyperinsulinemic hypoglycemia. Moreover, former CGM has shown
      fluctuations in blood glucose of more than 5 mmol/L during daily living and with at least one
      blood glucose reading below 3.5 mmol/L.

      Six days continuous glucose monitoring will be performed at run-in and during each treatment
      arm, except for e) Signifor due to the short treatment period. At the end of the CGM
      measurement a meal tolerance test (MTT) will be performed. During the MTT blood samples for
      glucose measurements and hormone assessments (insulin, C-peptide, GLP-1, gastric inhibitory
      peptide (GIP), glucagon, insulin like growth factor (IGF-1), epinephrine, norepinephrine)
      will be drawn continuously as well as continuous pulse recording and blood pressure
      measurements.
    

Intervention name(s): Glucobay (acarbose); Januvia (sitagliptin); Verapamil HEXAL (verapamil); Victoza (liraglutide); Signifor (pasireotide); Continuous glucose monitoring (CGM); Meal tolerance test (MTT)
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Device; Dietary Supplement
Intervention description(s): Se arm description; Se arm description; Se arm description; Se arm description; Se arm description; Continuous glucose monitoring will be performed during 6 days of the treatment period.; A meal tolerance test will be performed at the end of the treatment period. The subjects will consume the liquid meal at baseline and blood will be drawn for continuous blood sampling.
Other intervention name(s): glucobay; Januvia; Verapamil HEXAL; Victoza; Signifor
Intervention MeSH terms: Sitagliptin Phosphate; Liraglutide; Acarbose; Verapamil; Pasireotide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment