Bengaluru: The blockbuster semaglutide class of diabetes and weight-loss drugs like Ozempic and Wegovy have made the hormone GLP-1 part of popular lexicon. But it’s only now that scientists and researchers are understanding how these drugs work — it’s not the gut, but the brain.
For nearly four years, it was thought that the drug molecules latch themselves to receptors in the gut or intestine. Turns out, it might actually be doing so in our brains.
As more research begins to confirm these findings, The Atlantic’s Sarah Zhang spoke to experts about how the drug works the brain, and other effects on the body it seems to have.
ThePrint explains what we know today about the “miracle” drug.
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What is semaglutide
Semaglutides like Ozempic are prescription drugs that were developed to treat people with type 2 diabetes, and also found to aid in weight loss. The molecule in the drug that causes it to produce these effects in our bodies is called semaglutide.
The semaglutide molecule mimics the Glucagon-like peptide-1 (GLP-1) hormone released by the gut after eating, which attaches itself to GLP-1 receptors in the body. The activated receptors help reduce blood sugar and curb appetite, besides preventing release of carbohydrates stored in the liver and production of glucose in the body.
Simultaneously, it lowers appetite and slows down the process of digestion, keeping a person feeling full longer.
It’s sold under the brand names Ozempic and Rybelsus for diabetes. For weight loss, it is sold as Wegovy. The drug can be taken orally or administered subcutaneously with an injection.
Semaglutide is contraindicated for use for those with a family history of thyroid cancer. Studies have also shown that those on the drug could have complications during surgery.
A similar molecule is tirzepatide, which is sold under the brand name Mounjaro and Zepbound.
A new drug called amycretin is also in trials, while another drug, MariTide (maridebart cafraglutide) has shown promising results.
Brain vs Gut
For the last 15 years of promising and positive trials, since the year 2008, it has been believed that semaglutide targets the GLP-1 receptors in the gut. However, The Atlantic reports, it in fact passes through the blood-brain barrier and enters the brain, which also hosts GLP-1 receptors.
The blood-brain barrier is a tight network of cells that make up a semi-permeable membrane, which protects harmful substances in the bloodstream from crossing over into the brain like parasites. It allows only limited substances like oxygen and water molecules, and medicines and anaesthesia.
Semaglutide lasts in the blood longer than the natural GLP-1 molecule; GLP-1 disappears in minutes, but semaglutide can stay in the body for up to five weeks, indicates research.
This enabled the drugs to penetrate deep into the brain, causing unanticipated, positive effects like curbing addiction.
The receptors in the brain are independent of those at the end of the small intestine, and animal experiments with rodents confirmed that removal of receptors in the brain affected the drug’s appetite-suppressing ability. These rodents were no longer able to lose weight.
On the other hand, in another study, rodents whose receptors in the brain were not removed were used. These animals were addicted to alcohol and cocaine. When they were given semaglutide, they were found to have consumed less alcohol and cocaine in experiments through the drug.
When genetically engineered mice had their brain receptors removed, scientists noticed that semaglutide did not seem to work as intended, and did not suppress appetite. On the other hand, when the drug was tested on rodents with their brain receptors intact, but with alcohol and cocaine addiction, the rats quickly became de-addicted and lost interest.
The Atlantic reports that people have also reported addiction to smoking or shopping disappearing with semaglutide.
Semaglutide does have side effects, which include nausea, headache, constipation, diarrhoea, flatulence, fatigue, and more.
What do we not know?
The drug has been found to be serious side-effect free for up to 18 months, with no increased risk of cancer or other complications.
However, longer-term effects are still unknown.
Zhang reports that Tirzepatide is known to activate the receptor of another hormone called GLP along with GLP-1. However, the new drug MariTide, seems to block the GLP receptors while simultaneously activating GLP-1 receptors. It is unclear how both drugs lead to the same outcome despite opposite actions on GLP receptors.
Meanwhile, the report also expounds on the role of the GLP-1 receptors in the intestine. Findings have suggested that the semaglutide class of drugs lowers inflammation, and could be used to treat diseases like Parkinson’s and Alzheimer’s.
Experts quoted in the report speculate from ongoing research that GLP-1 in the gut is primarily responsible for controlling inflammation, and could be used to treat inflammatory gut diseases like Crohn’s disease. However, those suffering from these diseases tend to already be underweight, and GLP-1 drugs make people lose more weight.
(Edited by Amrtansh Arora)