A successful gastric bypass should be easy on blood sugar. At least that’s the promise for some patients. For others, it’s the opposite: decades later, things start going wrong.
A lunch may go smoothly — then, suddenly, 90 minutes later, palms begin to sweat, the hands tremble, and words fumble. Glucose tablets are available, and the risk of driving after a large meal grows a serious concern.
The condition is called post-bariatric hypoglycemia, or PBH. It is rare, understudied outside of academic and specialty settings, and potentially disabling. There is no FDA-approved medication for it.
Avexitide may change that.
In August, Amylyx Pharmaceuticals announced that testing of its investigational new drug showed a 55% reduction in clinically meaningful hypoglycemic episodes from placebo in a late-stage trial and projected to seek FDA approval for the new agent by the end of 2026.
Why does a gastric bypass cause low blood sugar?
Roux-en-Y gastric bypass — among the most common forms — physically shunts food from the stomach, bypassing some intestines and significantly lowering caloric intake over time.
But there is another, more immediate effect of the surgery as far as blood sugar is concerned, which has to do with the speed of food transit.
A patient on a high-carb diet experiences a rapid increase in levels of glucose in the blood after eating. The body responds by releasing GLP-1, a hormone secreted by the gut that tells the pancreas to release insulin. But in PBH, this mechanism appears to be overly active.
The first spike in glucose is soon followed by a precipitous drop, also induced by the surplus of insulin, explained Dr. Mary Bowers, medical director at the Center for Internal Medicine and Endocrinology. «The whole cascade takes place with a time delay from fasting.»
In PBH, this can happen when eating normally — the problem occurs one to three hours after a meal, as, for example, the patient is already returning to work, driving a car, or walking the pet.
Mild episodes of PBH are associated with a sensation of hunger, tremoring and increased heart rate. As blood sugar drops further, the brain can also be affected — leading to confusion, dizziness, fainting and even epileptic seizures.
Diet changes are the typically the first line of therapy. Patients are advised to eat smaller meals, avoid excessively large amounts of simple carbohydrates and consume them with protein or fat. Sometimes that is not enough.
Drugs that prevent or treat episodes of PBH work on different principles. Ozempic, Wegovy and similar medications are GLP-1 agonists, meaning that they stimulate the same nerve receptors that are triggered by the hormone. Avexitide is a GLP-1 antagonist.
It would seem that such a medication is almost designed to provoke PBH — but that ignores the crucial difference between it and other similar substances.
An overproduction of GLP-1 relative to blood glucose concentration is part of the PBH mechanism. Ozempic or Wegovy may exacerbate that, as a result of stimulation of the GLP-1 receptor. Meanwhile, «avexitide inhibits the GLP-1 receptor, counteracting the excess insulin», said Dr. Bowers. That should keep glucose levels from dropping too fast.
The medication is injected once per day, with no appreciable effect on body weight. As a result, it is not officially classified as an obesity drug. The study participants, however, did see a benefit.
Results from its LUCIDITY Phase III trial for AD
LUCIDITY: a phase III trial (NCT05222801) followed 78 patients with PBH following Roux-en-Y bypass surgery who continued seeing episodes of low blood sugar despite dietary restrictions. One-half of them received 90 mg of avexitide per day while the other-half got a placebo. Neither patients nor evaluators knew which group was which.
According to the results posted on the Amylyx website, the treatment produced a 55% reduction in Level 2 and Level 3 hypoglycemic episodes, compared with the placebo.
Level 2 hypoglycemia is a reading of fewer than 54 mg/dL of glucose. Level 3 implies impairment so severe that the person needs the assistance of another. Finger sticks and continuous glucose monitoring also detected lower rates of Level 2 hypoglycemia, as well as less severe episodes.
Still, although the drug worked, «55% fewer events is not 0 events.
We were still getting the hypoglycemia just not as frequently or severely», cautioned Dr. Bowers. In addition, because Amylyx has not yet shared the results of the study in journals it has not yet published all of the data. Side effects included diarrhea, which is relatively common, and a rash or bruising at the site of the injection. All were generally mild or moderate, and no one in the blinded trial reported a serious adverse event.
That is reassuring, but 78 patients is a fairly small sample to analyze — and rare complications would still be difficult to attribute definitively to the drug. The same goes for whether the initial positive results are consistent over a longer period of use. The study is being extended to 32 weeks total. All participants will receive avexitide.
What can PBH patients do now?
Food plans that control the amount of glucose and allow for regular monitoring are the first line of defense. For more aggressive cases, drugs such as acarbose may be used. They interfere with the action of enzymes that break down carbohydrates in the digestive tract. Patients also utilize continuous glucose monitoring tools to detect decreasing trends. Those, meanwhile, cannot stop an episode of PBH — only prepare for it.
For the most severely ill, more intensive measures are required. One option is a gastric bypass revision, or another operation to slow the movement of contents through the digestive system. Another is enteral nutrition — placing a catheter into the stomach to provide sustenance directly. All of these are major procedures, and only recommended if nothing else works.
Avexitide has received both Breakthrough Therapy and Orphan Drug designations from the Food and Drug Administration. While that will presumably expedite the approval process, neither means that the drug has actually been approved or is on the market. It does not yet appear in the pharmacy catalogs.
Individuals with PBH should consult an endocrinology or their original surgery team if they have symptoms including confusion, tremors or fainting following meals long after a bariatric procedure or surgery. Other underlying causes need to be ruled out, and repeated severe episodes of hypoglycemia are not safely managed with dietary adjustments alone.
The key advantage of Avexitide — and why it is discussed approvingly among doctors — lies in its mechanism of action. It was developed precisely for this indication: when patients begin experiencing PBH after a gastric bypass. If the FDA confirms that the benefits outweigh the risks, such persons will soon have a treatment that actually targets the cause.
