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Jumping the Gun?

There is no question that semaglutide (Ozempic) is a major advance in the treatment of diabetes. But when it comes to using such GLP-1 agonists for weight loss, there are some lingering questions.
Image by Mario Tama/Getty.

Ready, Set, Go…. for Ozempic. That’s what the incessant television ads suggest. “Ask your doctor about Ozempic,” the ads advise, without mentioning what the drug is for. The marketer’s hope is that the doc, on seeing the few extra pounds on the questioner, will reach for the prescription pad. There is a good chance of that since the weight control effects of GLP-1 agonists, the class of drugs to which semaglutide belongs, have been a hot topic in the medical literature and are enthusiastically pointed out by pharmaceutical reps. And the ads work, as can be seen by the stunning demand for Ozempic, a demand that has resulted in a backlog of the drug.

Semaglutide was originally developed as a treatment for type 2 diabetes but its effect on body weight was a fortunate finding, certainly for Novo Nordisk, the Danish pharmaceutical company that produces the drug. GLP-1 is a hormone secreted by the intestine in response to the entry of food. It then travels through the bloodstream and delivers a message to the pancreas to release insulin. But as it turned out, semaglutide, a GLP-1 mimic, also affects hunger signals to the brain and slows the rate at which the stomach empties which results in a longer feeling of being full. Studies have shown that weekly injections of semaglutide can lead to as much as a 15% loss of body weight.

In terms of chemistry, GLP-1 is a “peptide,” a molecule composed of a short chain of amino acids, in this particular case, thirty. These days the sequence of amino acids in a peptide can be readily determined, and bonding the required amino acids together in the correct sequence is a routine task.

When triggered by food, GLP-1 is secreted on a continuous basis from the intestine since the molecule is readily broken down by an enzyme in the blood within a couple of minutes. This means that even though a synthetic version of the peptide is available, it cannot be used as a drug. Injection every few minutes is not a viable treatment for diabetes. Therefore, the pharmaceutical quest was to find a way to keep the peptide away from the clutches of the enzyme.

It took years of work and many trials to solve this problem. The solution was to surround the peptide with albumin, a protein naturally produced in the body. Albumin envelopes the peptide, protects it from the enzyme, but releases it as needed to bind with receptors on cells in the pancreas and stimulate the release of insulin. Because it fits the receptor just like the body’s natural GLP-1, this albumin protected peptide is referred to as a “GLP-1 agonist.”

Enveloping GLP-1 with albumin was a major challenge, but eventually a method to forge a link using a fatty acid and a string of glutamate molecules was found. Obviously, given the immense market potential of an effective weight control drug, the specifics of the technology are proprietary. The long-term research and the difficult chemistry involved in producing semaglutide account for part of high cost of about $1000 a month. Needless to say, there is a tidy bit of profit there as well.

The high price and lack of availability have generated a copycat industry staffed by compounding pharmacists who claim to be able to make the drug in their lab and provide it at a fraction of a price. “Compounding” is a legitimate segment of the pharmacy business in which pharmacists make special versions of drugs for people who may have allergies to an ingredient in the standard version, or perhaps require a liquid preparation instead of a pill. However, in the case of semaglutide, it is hard to know what they are actually compounding, since Novo Nordisk does not sell the active ingredient to outsiders and has not published details of the manufacturing process. It is unlikely that cheaper versions of semaglutide made by compounding pharmacies, or sold online, are equivalent to Ozempic.

Currently, Ozempic is approved as a treatment for type 2 diabetes but not for weight control. However, once a drug has been approved, physicians can prescribe it “off label,” and there is no doubt this has been happening. But recently a slightly higher dose of semaglutide was approved as Wegovy for weight control. As can be expected in the midst of an obesity epidemic, sales are rocketing. But so is concern among some doctors and scientists.

Long term effects, especially on the pancreas and the thyroid gland, are unknown for the simple reason that a long term has not passed since the drug was introduced. Nausea and vomiting are not infrequent side effects and can be serious. Curiously, there have also been reports of bizarre dreams. In one case an Ozempic user described playing baseball in front of a hostile crowd and being rescued by Oprah Winfrey in a go-kart.

The race for an effective weight control drug is understandable since obesity is a risk factor for diabetes, cardiovascular disease, and cancer. However, in the case of GLP-1 agonists for weight loss, the foot on the gas pedal may be a touch too heavy. Not all segments of the population have been represented in clinical trials and studies have not yet shown improved health outcomes in users. Physicians have to carefully weigh whether potential benefits for an overweight person outweigh the risks. While it is likely that someone with a body mass index over twenty-seven and having at least one risk factor for cardiovascular disease will benefit, the same cannot be assumed for someone who may be packing an extra 10-20 pounds without any risk factors. GLP-1 analogues are not for people trying to squeeze into last year’s bathing suit. Where a squeeze is needed, is on the overly enthusiastic promotion of Ozempic and its brethren as the silver bullet to deflate the obesity epidemic.


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