Every every now and then, scientists develop treatments that find yourself being much more popular for one more condition entirely. Think of Viagra, originally for hypertensionnow used for erectile dysfunction. Or thalidomide, a dangerous morning sickness treatment that’s now a worthwhile cancer treatment.
The blockbuster drug Ozempic was originally developed to treat type 2 diabetes, a condition that leads to an excessive amount of glucose, or sugar, within the blood. This is since the body can’t effectively use the insulin it produces.
In the Eighties, medications to treat type 2 diabetes would often result in weight gain, which could worsen the condition. Patients would find yourself needing insulin substitute therapy.
But the category of medicine Ozempic belongs to would change this and generate A$21 billion of sales in 2023 alone for its maker.
The start of the journey
In the nineteenth century, French physiologist Claude Barnard sought to elucidate why large amounts of glucose (the foremost sugar in your blood) will be taken orally, whereas if glucose is given intravenously, small amounts overload the body’s systems.
In 1922 Frederick Banting and Charles Best discovered the hormone insulin, which controls glucose use. But this didn’t explain the difference between oral and intravenous glucose tolerance.
In 1932, Belgian Jean La Barre identified there was a hormone within the gastrointestinal tract answerable for stimulating insulin secretion. La Barre named this “incrétine” (incretin), a mixing of ingestion and secretin, and suggested it could be a diabetes treatment.
In the Sixties, researchers showed the incretin effect was answerable for about two-thirds of individuals’s insulin response. New and sensitive ways to measure blood hormone levels then allowed researchers to indicate a hormone called GIP (glucose‐dependent insulinotropic polypeptide) was partly answerable for the incretin effect.
This meant there have to be one other hormone, whose discovery had to attend until the age of cloning within the Eighties. Cloning the GLP-1 (glucagon-like peptide 1) gene, biochemist Svetlana Mojsov demonstrated it stimulated pancreatic insulin secretion at 1/one centesimal of the concentration needed for GIP. So GLP-1 was identified as the opposite incretin answerable for people’s insulin response.
The glucose-lowering effects of GIP and GLP-1 excited scientists, but they couldn’t be used as medicines because they metabolised too quickly within the body.
Enter a toxic lizard
In the Eighties John Pisano, a biochemist with a penchant for venoms, and a young gastroenterologist Jean-Pierre Raufman were working with poisonous lizard venom from the Gila monster, a slow-moving reptile native to the south of the United States and north of Mexico. By the Nineteen Nineties, Pisano, Raufman and colleague John Eng identified a hormone-like molecule they called exendin-4. This stimulated insulin secretion via motion at the identical receptor as GLP-1.
Excitingly, exendin-4 was not quickly metabolised by the body, and so is likely to be useful as a diabetic therapeutic.
Eng was convinced this might work, but pharmaceutical firms didn’t want to offer people a hormone mimic from a venomous lizard. Even the medical centre where Eng was working wouldn’t help fill the patent.
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Eventually he and Raufman convinced a small start-up called Amylin Pharmaceuticals. Amylin quickly showed synthetic exendin-4 rapidly normalised blood glucose in type 2 diabetic mice. Exendin-4 then proved secure and effective in humans, resulting in the 2005 US Food and Drug Administration (FDA) approval of exenatide, under the name Byetta.
It soon became evident that many taking Byetta were experiencing sustained weight-loss (around 5%but with some experiencing far more), with the advantage of reversing their diabetic symptoms.
News of this weight-loss effect spread and inside six months Byetta was getting used off-label for weight-loss, foreshadowing the widespread use of Ozempic.
From a lizard toxin to Ozempic
Meanwhile, Danish pharmaceutical company Novo Nordisk had been developing a long-acting GLP-1-mimicking drug, because it had done for insulin up to now. Its research showed high levels of GLP-1 could correct diabetes in mice and they’d drop some weight.
During the Nineteen Nineties, there was controversy over how GLP-1 led to weight reduction, nevertheless it later became clear there have been GLP-1 receptors within the brain that suppressed the will to eat.
Novo Nordisk’s latest GLP-1 drug had been designed to be long-acting. One consequence of this design was it was higher at accessing brain GLP-1 receptors.
This latest drug, liraglutide, approved as Victoza in 2010 within the United States, was higher for weight-loss than Byetta (typically 10% weight-loss), but still needed each day injections.
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Daily injections aren’t popular, and Novo Nordisk’s team had been working on an excellent longer acting drug, semaglutide, approved as Ozempic in 2017 as a once-weekly injection. It had improved brain GLP-1 receptor targeting, further enhancing weight reduction.
Due to its safety profile and weight-loss efficacy (of around 15%), the next dose of semaglutide gained FDA approval as Wegovy in 2021 as a stand-alone obesity treatment.
So how do these drugs actually work?
Your gastrointestinal tract comprises specialised cells that measure the quantities and qualities of incoming food (in addition to the absence of food) and communicates this with the remainder of your body, including your brain.
You may remember Pavlov’s dogs, which were conditioned to expect a meal on the sound of a bell, form of like what happens if you’re presented with a delicious plate of food. Not only does your brain make you salivate, it also starts the strategy of releasing digestive juices and even causes insulin levels to rise.
Ozempic and other GLP-1-mimicking drugs slow gastric emptying, which increases your sense of fullness.
Insulin secretion increases because there are nerves with GLP-1 receptors near the wall of your gastrointestinal tract. This sends messages to the unconscious a part of your brain that interpret these and send messages back (via nerves) to your gastrointestinal tract and pancreas to secrete insulin.
What concerning the latest drug, Mounjaro?
Remember the opposite incretin hormone, GIP? GIP also suppresses appetite and might stimulate insulin secretion, but not in addition to GLP-1.
Unlike GLP-1, GIP increases the secretion of one other hormone, glucagon. Glucagon promotes energy use but additionally increases blood glucose during times of fasting. Many felt the actions of glucagon needed to be blocked for effective anti-diabetic and weight-loss medications. But this doesn’t appear to be the case.
German physician and scientist Matthias Tschöp and American chemist Richard DiMarchi, who had met at Eli Lilly, were working on synthetic versions of glucagon to treat sudden drops in blood glucose once they unexpectedly found long-term dosing caused weight-loss in obese mice. Since GLP-1 and GIP are closely related, they thought it is likely to be possible to focus on each receptors with a single drug.
In 2013, they showed a dual-acting drug was effective in obese mice. This led to the event of tirzepatide (Mounjaro and Zepbound, which is a rather higher dose). Compared with GLP-1 drugs, it also stimulated metabolism, particularly fat use.
Clinical trials of Zepbound showed it to be more practical than Ozempic for weight-loss (typically 18% of body weight). Mounjaro was approved for type 2 diabetes in 2022 and Zepbound was approved for obesity in 2023.
GIP and GLP-1 are much like glucagon so Tschöp and DiMarchi got down to develop a drug targeting all three. In 2014 they showed that a triple-targeting drug, which might turn out to be retatrutide, was superior in obese mice. Now in mid-stage clinical trialsEli Lilly’s drug retatrutide (once-weekly injection) leads to a weight reduction of around 24% in obese adults.
Why can’t you’re taking them in a pill?
These current drugs are big molecules (peptides) and for that reason have to be injected as they’re not absorbed effectively within the gut.
In 2019, Novo Nordisk managed to reformulate semaglutide so some would make it through the stomach intact and enough got absorbed (about 1%) to be clinically effective. It repackaged this as Rybelsus.
But although enough of the drug gets into circulation to help with type 2 diabetes, it requires 100 times the dose for weight-loss.
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Both Pfizer and Eli Lilly have small-molecule drugs targeting the GLP-1 receptor. These are designed to be taken orally, are formulated for once-a-day, and can be inexpensive than Ozempic or Mounjaro.
Pfizer’s drug, Danuglipron, has had mixed success in clinical trials. One formulation has been discontinued due to high clinical-trial drop-out rates (as a consequence of gastrointestinal side-effects resembling nausea, vomiting, diarrhoea and pain). But each formulations do control type 2 diabetes and result in about 10% weight-loss.
Eli Lilly’s trials of Orforglipron have shown promising weight-loss for obese participants of about 10%.
Plenty of weight-loss drugs have failed, too
Anti-obesity drugs with other targets – resembling those sold under the brand names Qsymia, Contrave, Reductil and Accomplia – resulted in weight reduction (typically lower than 10%) but were accompanied by uncomfortable side effects resembling increased heart rate, heart disease and psychological safety concerns resembling anxiety and suicidal thoughts.
This resulted in market withdrawals and scared participants away from clinical trials.
Ozempic’s safety profile and effectiveness has reversed this, though there are numerous potential uncomfortable side effects (mainly gastric upsets) and folks who stop taking Ozempic typically have big weight rebounds. Clinical trial recruitment is becoming easier and lots of pharmaceutical firms are playing catch up.
