A New Potential Treatment for Postprandial Hypoglycemia Following Bariatric Surgery

Sophia M. Rössner; Daniel P. Andersson


J Clin Endocrinol Metab. 2021;106(8):e3264-e3265. 

Bariatric surgery has been shown to be the most effective treatment of obesity for sustained weight reduction. In addition, studies have shown that bariatric surgery leads to long-term remission of type 2 diabetes and also a reduction in cardiovascular events, stroke, and cancer.[1,2] With the increasing number of obese individuals undergoing bariatric surgery, there is also an increasing number of patients experiencing side effects.

Already in the 1940s, Custer et al described dumping syndrome in patients undergoing gastroenterostomy for treatment of duodenal ulcers.[3] This type of surgery is similar to the later-developed Roux-en-Y gastric bypass (RYGB). These patients experienced severe symptoms soon after oral nutrient intake, such as nausea, weakness, palpitations, warmth throughout the body, and sometimes hypermobility of the bowel with diarrhea. Later it was recognized that postbariatric patients sometimes presented with similar symptoms caused by hyperinsulinemic hypoglycemia and that this might be an effect of altered glucagon-like peptide 1 (GLP-1) secretion.[4] Whereas dumping typically is experienced within 30 minutes following a meal, postbariatric hypoglycemia (PBH) often occurs 1 to 3 hours after a meal and is, in contrast to dumping, seldom reported during the first 6 months postoperatively. A diagnosis of PBH requires documented low venous glucose accompanied by neuroglycopenic symptoms that are improved by glucose correction (Whipple triad).

Initial management of PBH has been similar to the treatment of dumping symptoms, with a diet low in carbohydrates or containing high-glycemic index carbohydrates divided into multiple small meals. If this is insufficient, medical treatment with acarbose, diazoxide, somatostatin/octreotide, and calcium channel blockers has been used off-label to reduce and slow breakdown of carbohydrates in the intestine and reduce insulin and GLP-1 secretion. However, clinical trials evaluating different medical treatments have so far been missing. Keeping in mind that PBH is reported in more than 25% of patients after RYGB,[5] the present study[6] in this issue of the Journal of Clinical Endocrinology & Metabolism, "PREVENT: A Randomized, Placebo-Controlled Crossover Trial of Avexitide for Treatment of Post-Bariatric Hypoglycemia" by Craig et al provides an important contribution to the research field. Craig and colleagues have previously shown in a small, nonrandomized pilot study that a GLP antagonist, avexitide (exendin 9–39), can prevent hyperinsulinemic hypoglycemia and its associated symptoms.[7] In the present work they have further investigated avexitide treatment in a randomized, placebo-controlled phase 2 trial of 18 female patients with PBH performed at 5 US academic centers. The included individuals experienced severe PBH, reflected in the baseline characteristics that all patients were refractory to dietary treatment, all but one woman reported daily or weekly hypoglycemic symptoms, and most had previously attempted off-label use of medication to treat PBH. The primary outcome was glucose nadir and insulin peak after a mixed-meal tolerance test, but the crossover study design with avexitide administered as subcutaneous injections once (60 mg) or twice (30 mg ×2) daily also allowed the authors to evaluate the effects of different dose regimens.

Avexitide significantly reduced the occurrence of hypoglycemia in both dose regimens. This was seen not only during the mixed-meal test, but also on continuous glucose monitoring in the home setting throughout the study period. The twice-daily regimen gave a more sustained pharmacokinetic exposure, whereas the once-daily regimen was more effective during daytime than the lower dose given twice. These results suggest that a higher dose combined with prolonged exposure might lead to even greater clinical improvements. In addition, the present trial showed that avexitide was well tolerated with few side effects and importantly without a clinically relevant increase of percentage time with glucose greater than 250 mg/dL. With the results presented by Craig et al in mind, it is likely that treatment of PBH with avexitide may not only have a substantial impact on hypoglycemia, but may also lead to improved well-being in general. PBH has been associated with increased weight regain due to overeating to avoid hypoglycemia. Thus, with decreased hypoglycemic symptoms, avexitide may also affect future weight regain.

The results from the PREVENT study are promising and in concurrence with previous smaller nonrandomized studies. It is clear that future larger studies with avexitide are warranted, but given the lack of scientific evidence from clinical trials for treatment of PBH until now, the present study may have a direct impact on PBH treatment strategy.