Japan’s First Over-the-counter Anti-obesity Drug to Hit Stores in April

TOMOKO OTAKE wrote . . . . . . . . .

Taisho Pharmaceutical announced Monday that it will start marketing in April anti-obesity drug orlistat, the first such drug to become available without a prescription in Japan.
The drug, which will be available from April 8 under the brand name Alli, is expected to reduce fat stored around internal organs and prevent obesity-related diseases. It is intended for overweight people age 18 or older with a waist circumference of 85 centimeters for men and 90 cm for women.

Taisho Pharmaceutical secured the rights to develop and sell the drug from GlaxoSmithKline in Japan in 2009, and won approval from the health ministry to market it as an over-the-counter drug in February 2023. Alli has been available over the counter in more than 70 countries since it was first approved in the United States in 2007.

Orlistat prevents fat from food from being absorbed into the body by blocking the work of an enzyme called lipase. Lipase breaks down fat in food to be absorbed into the intestines.

A double-blind, randomized clinical trial covering 200 people in Japan has shown that people who took orlistat lost 14.1% of their visceral fat area in 24 weeks; in contrast, those who took a placebo lost 5.78%, according to Taisho Pharmaceutical.

Since Alli suppresses the absorption of fat in the diet, the firm says that users may experience difficulty controlling the release of stool. The firm also notes that flatulence may occur when passing motion and that stool may become oily. It recommends users to wear pads over their underwear, keep a change of underwear ready and go to the toilet immediately when they experience bowel movements.

Though the drug is not due to hit stores for at least another month, Alli has already created a lot of buzz among people looking for ways to lose weight. To prevent nonobese people from abusing the drug, Taisho Pharmaceutical requires people who want to buy the product to receive prior guidance from licensed pharmacists at designated drugstores.

So far, around 26,000 pharmacists at 10,000 drugstores nationwide have undergone Taisho Pharmaceutical’s training so they can sell the product, it said.

Overweight individuals who wish to buy the capsules must start working to change their lifestyle three months before purchase. Then they must log their diet and workouts as well as their weight and waist circumference for a month on a check sheet to present to the pharmacist before buying the product, Taisho spokesperson Tadahiro Haba said.

The drug, to be taken three times a day, will cost ¥2,530 (US$17) for 18 capsules (enough for six days) and ¥8,800 for 90 capsules (enough for 30 days).

Source : The Japan Times

Obesity in China: The Miracle and Mirage of Weight Loss Drugs

From Caixin Global . . . . . . . . .

Liu Ping, a 25-year-old living in Beijing, is queuing up outside the obesity clinic of the Peking University People’s Hospital early one morning, seeking a doctor’s prescription for the so-called “skinny jab” — a weight loss drug that has created a buying frenzy in China, where half the adults out of a total population of 1.4 billion are either overweight or obese.

Like millions of others around the world striving to lose weight, Liu is holding out hope for the medication semaglutide, the generic name for a medicine better known globally as Ozempic. Heralded as a “miracle drug” in the war on weight, it has won praise from Western celebrities as diverse as Tesla’s Elon Musk and TV reality star Khloé Kardashian.

Made by Danish pharmaceutical company Novo Nordisk, Ozempic belongs to a class of medications known as glucagon-like peptide-1 receptor agonists, or GLP-1. It mimics the GLP-1 hormone, released in the gut in response to eating and has been used to regulate blood sugar levels to treat Type 2 diabetes.

Liu wasn’t always overweight. For him, the lockdowns that affected countless millions in China during the COVID-19 pandemic led to frequent overeating, a lack of exercise, and irregular work and life routines resulting in spiraling weight gain and Liu’s body mass index elevating to 28.

BMI is derived by dividing the weight in kilograms by the square of the person’s height in meters and is a key measurement in determining a healthy weight.

A figure of 28 puts Liu in the obese category, according to China’s public health guidelines, which define “normal” weight as a BMI of 18.5 to 23.9. Between 24 and 27.9 is “overweight,” and 28 and above is “obese,” according to the Chinese standards, which are a little lower than those set by the World Health Organization.

At least 2.8 million people die each year globally as a result of being overweight or obese, while an estimated 35.8 million or 2.3% global disability-adjusted life years (DALYs) — the loss of the equivalent of one year of full health — are caused by being overweight or obese, according to the WHO.

In China, expanding waistlines are the result of rapid urbanization and large-scale population migration, which have reshaped work and lifestyle habits, with labor-intensive jobs such as farming replaced by low physical exertion jobs in the manufacturing and service sectors, according to a July report in the Journal of Global Health.

That socioeconomic change has translated into the proportion of overweight and obese adults in China reaching 50.7% in 2022, according to the report, which cited the Chinese Nutrition Society.

Obesity ‘inevitable’

“Obesity is not the sin of an individual, rather it is almost inevitable in the development of society and the rise in economic levels,” said Li Guangwei, an endocrinologist at the China-Japan Friendship Hospital in Beijing.

Keen not to become a statistic, Liu has tried various methods to lose weight, but all have failed. In desperation, he’s turning to medicine.

“I can’t control my eating habits, and I struggle to exercise. What else can I do?” Liu lamented as he waited in line.

His BMI puts him squarely in the category recommended for drug intervention under medical supervision, according to guidelines from the Chinese Nutrition Society and Preventive Medicine Association.

Enter Ozempic. Approved for use in China in 2021 for Type 2 diabetes, it is a prescription medicine, although widely available to purchase online. The drug is administered by a subcutaneous injection once a week. A 2 milligram dose produced a weight reduction of 6.9 kilograms over 40 weeks, according to Novo Nordisk in a June 2021 study, which involved participants with a mean baseline body weight of 99.3 kilograms.

Designed primarily to treat adults with Type 2 diabetes by lowering blood sugar and reducing the risk of heart attack and stroke with heart disease, GLP-1 drugs could also help with weight loss, according to scientists, as they suppress the appetite and lengthen the amount of time food stays in the stomach.

The drugs have also shown promising results in areas such as treating kidney damage and non-alcoholic fatty liver disease.

“It is a miraculous rarity in the field of drug development,” said Ding Sheng, a professor at the school of pharmaceutical sciences at Tsinghua University in Beijing.

Several people on the medication told Caixin that they had lost about 10 kilograms one month after starting injections, with a greater amount of weight shed among those starting from a higher baseline weight.

GLP-1 is a game changer for traditional methods to treat obesity, said Alyssa Dominguez, an endocrinologist at the Keck Medical Center of the University of Southern California.

Doctors around the world have long believed a controlled diet and regular exercise are the keys to treating people who are overweight and obese, but with the addition of the medication, those efforts are more effective, said Dominguez.

Compared to lifestyle changes, which can require a significant investment of time and willpower, a seemingly one-stop fix-all medication offers a far more appealing route.

Cheap alternative

And then there is the cost advantage. While consulting a dietician will require three to six months of expensive consultations for weight loss of 5%-10%, a prescription for a GLP-1 drug can achieve similar results in the same period at a fraction of the cost, said Liu.

A three-to-six-month dietary plan issued by a doctor for Liu costs 7,000 yuan ($977) per month, compared with the 813 yuan per injection, he said.

Currently, the most popular GLP-1 shot used globally for weight loss besides semaglutide is liraglutide, which is also made by Novo Nordisk and marketed as Victoza and Saxenda.

American drugmaker Eli Lilly’s experimental drug tirzepatide has delivered promising data to compete with Novo Nordisk, with participants in a clinical trial losing up to 15.7% of body weight over 72 weeks, equivalent to 15.6 kilograms, according to results released in April.

And in China, Huadong Medicine Co. Ltd.’s liraglutide biosimilar injection and Shanghai Benemae Pharmaceutical Co.’s beinaglutide have recently been approved for the treatment of obese or overweight patients, becoming the only locally made GLP-1 available for that use, according to pharmaceutical news site BaiPharm.

The demand speaks for itself, with liraglutide in short supply.

“Significant demand for weight-management medicines has impacted the availability of Novo Nordisk obesity medications, including Saxenda,” according to the company’s website. “We continue to produce and ship all available Saxenda, but unfortunately, you may still have difficulty filling Saxenda prescriptions for the remainder of 2023 and beyond.”

The increasing popularity of GLP-1 drugs for weight loss has triggered a surge in capital markets, causing stock prices of many pharmaceutical and material suppliers to soar.

Driven by GLP-1 drug sales, stocks of Novo Nordisk and Eli Lilly have surged 43% and 51%, respectively, during the first 10 months of this year. That has made the pair the most valuable pharmaceutical firms in Europe and the U.S., respectively, according to a report last week by industry news site Fierce Pharma.

However, some market analysts have cautioned investors to remain calm, noting that an influx of new players into the market may reduce profit margins.

Meanwhile, health experts have warned against excessive use of the drug for weight control, especially with people of “normal” weight seeking injections for aesthetic purposes. Indeed, the Ozempic website makes it clear that weight loss is not the intended primary aim of the treatment.

“Ozempic is a medicine for adults with Type 2 diabetes that, along with diet and exercise, may improve blood sugar,” said the site. “While not for weight loss, Ozempic may help you lose some weight.”

But, as with all medicines, GLP-1 drugs can also cause side effects like nausea, vomiting, and indigestion, which could diminish tolerance among certain patients.

And as the body gradually adapts to the dosage, the appetite-suppressing effects of the medication will gradually diminish and eventually disappear, according to Ji Linong, director of the endocrinology department at Peking University People’s Hospital.

Some individuals attempting to lose weight by using the medication might end up heavier than before, said Ji, adding that GLP-1 drugs simultaneously reduce both fat and muscle.

Investor frenzy

The frenzy has also led to a surge in pharmaceutical stocks on China’s domestic markets, prompting regulators to issue several warnings regarding excessive speculation.

Since mid-September, a Wind Info index tracking stocks related to weight loss drugs in China’s A-share market has gained 31%. Companies like Shenzhen-listed Hebei Changshan Biochemical Pharmaceutical Co. Ltd., which is conducting clinical trials for experimental GLP-1 drugs, has seen its stock skyrocket more than threefold.

GLP-1 is not new. It was discovered in the 1980s and the world’s first GLP-1 receptor agonist, exenatide, was approved by the U.S. Food and Drug Administration in 2005 for the treatment of Type 2 diabetes.

The watershed moment came in 2021, when weight loss was added as a new indication for semaglutide in the U.S. and Novo Nordisk’s Wegovy — targeted specifically at helping people shed kilos — was launched in the U.S. with Denmark, Norway, Germany, U.K., and Iceland since following suit.

The company last week reported sales in the first nine months of diabetes and obesity products had increased 36% to $22 billion, mainly driven by GLP-1 diabetes sales growth of 45% and obesity care surging by 167%. The volume growth of the global branded obesity market was 93.6%, it said.

Such is the demand that JPMorgan in September revised its prediction for the global GLP-1 market for obesity, forecasting that by 2032, it will reach $71 billion, more than double the previous projection of $34 billion. At that time, the overall global GLP-1 market size is expected to reach $100 billion, it said.

The market for GLP-1 used as a weight loss treatment could grow into a market worth tens of billions of yuan in China in the coming years, analysts from Chinese brokerages like Caitong Securities and Citic Securities have predicted.

The medical projections support the forecast. By 2030, it’s anticipated that overweight and obese Chinese adults will reach 65.3% of the population, according to the Chinese Nutrition Society and Chinese Preventive Medicine Association

Consequently, by 2031, the market for GLP-1 drugs in obese patients in China will exceed 20 billion yuan, Sinolink Securities predicted in a research report published at the end of 2022.

Competition heats up

Some market analysts have sounded concerns over bubbles in the GLP-1 weight loss drug market as more players flood in.

Caixin calculates, based on data from DXY.cn-backed drug research database Insight that a total of 371 GLP-1 projects have been approved globally, 143 of which are specifically related to obesity indications to date.

Semaglutide is currently the most commonly used GLP-1 drug in treating obesity and was approved in 2021 for adult Type 2 diabetes patients in mainland China, where it was subsequently included under state medical insurance coverage.

The patent for semaglutide in China will expire in 2026, which is shaping up to be a key year for the drug’s sales in the country, as many domestic pharmaceutical companies line up to produce generic versions.

Within three to five years, numerous similar products are likely to be launched successively, potentially leading to a price war, a pharmaceutical industry investor told Caixin.

Chinese biotech firms are also actively involved in their own research and development of new GLP-1 candidates.

According to the Insight database, there are a total of 42 ongoing GLP-1 projects in China conducted by both domestic and international pharmaceutical companies, including clinical trials related to obesity indications. Most of these projects still prioritize the development for diabetes, including biosimilars of liraglutide and semaglutide.

Currently, there are only around 10 domestic companies, including Innovent Biologics Inc., Hangzhou Sciwind Biosciences Co. Ltd., and Jiangsu Hengrui Pharmaceuticals Co. Ltd., that have progressed obesity and weight reduction indications to phase 2 clinical trials or beyond.

Innovent Biologics is one of the fastest movers and is set to complete all three phases of clinical trials by 2024, with product launch expected in 2025, according to Gu Nan, a manager of a pharmaceutical investment fund.

For a “considerable length of time into the future,” the domestic weight loss market will be dominated by Novo Nordisk, Eli Lilly, and Innovent, a foreign pharmaceutical company sales agent told Caixin.

But carving out market share will not necessarily lead to profit as the prices of GLP-1 drugs have been brought down in China after they were included into the state insurance system.

For instance, Ozempic is priced at 813.96 yuan ($112) in China for the 1milligram dose. In the U.S., a product with the same specifications retails for $994.86, as per online pharmaceutical encyclopedia Drugs.com

“After the emergence of more semaglutide biosimilars, everyone can imagine what the prices will be like,” said Gu, who added that leading companies will engage in price wars that will make it difficult for enterprises with slower product development timelines to generate profits.

Diminishing returns

Diminishing returns from using the drugs for weight loss may also dent profits going forward.

Tian Xiao has lost 10 kilograms after taking liraglutide injections for 103 days, but the gains have been dropping off.

“The effects of the drug have been diminishing, while I have encountered side effects such as indigestion and hair loss,” Tian told Caixin.

Despite Tian’s BMI decreasing to 22.5, which is considered to be within a normal weight range, she has not stopped taking the medication as she is concerned about her weight rebounding.

Endocrinologist Dominguez confirmed the ephemeral benefits of the drugs: “The effectiveness of the drug is limited to the period of medication. After stopping the medication, weight gain often recurs,” she said.

The global medical community and regulatory agencies are still closely monitoring the risks associated with GLP-1 medications. Health experts including Dominguez and the People’s Hospital Ji have warned people who want to use the drug despite their BMI not meeting the criteria for weight loss.

“Being overweight is a lifestyle disease,” said China-Japan Friendship Hospital’s Li. “Without changing one’s lifestyle, no amount of medication will be effective.” Li added that obesity is associated with many severe conditions such as diabetes, coronary heart disease, and cancer.

Ji agreed. Controlling obesity requires the joint participation of the government and society to improve and create an environment that promotes healthy living for people, he said.

“We can’t create a problem and then try to solve it with drugs. That’s not a long-term solution,” said Ji.

Source : Sixth Tone

The Future of Obesity Drugs Just Got Way More Real

Yasmin Tayag wrote . . . . . . . . .

A wild idea recently circulated about the future of aviation: If passengers lose weight via obesity drugs, airlines could potentially cut down on fuel costs. In September, analysts at Jefferies Bank estimated that in the “slimmer society” obesity drugs will create, United Airlines could save up to $80 million in jet fuel annually.

In the past year, as more Americans have learned about semaglutide, which is sold for diabetes under the brand name Ozempic and for obesity under the name Wegovy, hype has become completely divorced from reality. For all the grand predictions, just a fraction of Americans who qualify for obesity drugs are on them. With a list price of roughly $1,350 a month, Wegovy is far too expensive, under-covered by insurance, and in limited supply to be a routine part of health care.

But that possibility is beginning to seem very real. The results of a highly anticipated study published on Saturday indicate that Wegovy can have profound effects on heart health, which potentially opens up the drug to even more patients. A few days earlier, the FDA approved Zepbound, an obesity drug that is a bit cheaper and appears more potent than Wegovy. If there was any doubt before, now it is undeniable: Obesity drugs “are here to stay,” Kyla Lara-Breitinger, a cardiologist at the Mayo Clinic, told me. “There’s only going to be more and more of them.” They are now poised to become deeply entrenched in American health care, perhaps eventually even joining the ranks of commonly used drugs such as statins and metformin.

Considering that obesity is linked to all sorts of major heart ailments, it is no big surprise that a weekly shot for weight loss might have some cardiovascular benefits. But because this class of obesity drugs, known as GLP-1 agonists for the hunger hormone they target, is so new, doctors did not know that for sure. Starting in 2018, Novo Nordisk, the company that manufactures semaglutide, began to look for answers in a study of more than 17,600 people with obesity and cardiovascular disease. In this group, results of a trial named SELECT show that Wegovy reduced the risk of major cardiac events—stroke, heart attack, death—by 20 percent. Even compared with studies on common heart medications such as Praluent and Repatha, the Wegovy results are “impressive,” Eugene Yang, a cardiologist and professor of medicine at the University of Washington, told me.

How exactly the drug prevents major cardiac events isn’t fully understood. Some of the effects can likely be chalked up to weight loss itself, which is associated with improvements in metrics that influence heart health, such as blood pressure, Yang said. But mechanisms independent of weight loss may also be at work. In the trial, lower rates of cardiovascular events began showing up before participants lost weight. One explanation is the drug’s impact on inflammation, which is associated with heart disease: C-reactive protein, a rough proxy for inflammation, dropped by nearly 40 percent in study participants.

Regardless of how Wegovy works, Yang said, “it has the potential benefit of being very significant” as a new line of treatment for heart disease, the leading cause of death nationwide. Novo Nordisk has already applied for expanded FDA approval and anticipates receiving it within six months. Approval would also show that Wegovy has a medical benefit beyond weight loss, pressuring insurers to cover it. Right now, for instance, Medicare does not, in part because obesity has long been viewed as a cosmetic issue, not a medical one. Even with private coverage, the drug is still frequently out of reach. The SELECT trial makes it “unequivocally clear” that obesity is a health condition that can be treated with drugs, Ted Kyle, an obesity-policy expert, told me. Still, the study leaves room for pushback: The absolute risk reduction of cardiovascular events was 1.5 percent, which is, by some reckonings, quite small. A higher risk reduction would have “put more pressure” on insurers and manufacturers to make the drugs more affordable for Americans, Lara-Breitinger said.

Still, the findings are robust enough that it seems likely that the heart benefits of obesity drugs will lead more Americans to take them—if not immediately, then eventually. The approval of a new drug could do the same. Tirzepatide, which Eli Lilly has sold as a diabetes drug under the name Mounjaro, will be marketed as Zepbound for obesity—and it is coming for Wegovy’s throne. In one study, people on tirzepatide lost an average of 18 percent of their body weight; for comparison, in another study patients on Wegovy lost an average of 15 percent. At a little over $1,000 a month, Zepbound is not cheap, but its list price is hundreds of dollars lower than that of Wegovy. (The manufacturers of both drugs have said that most insured patients pay far less than that.)

Zepbound’s approval is just the beginning. Unlike semaglutide, which targets only one hormone, GLP-1, to exert its effects on appetite and fullness, tirzepatide targets two. Other drugs that target two or even three hormones are in the works, as are versions that come in a more appealing pill format rather than as an injection. Generic versions of these drugs, likely beginning with liraglutide, a predecessor to semaglutide sold as Saxenda, could become available soon, Yang said. This competition will help bring down costs, but it will go only so far. Drug pricing is “a little bit screwy,” Kyle said, complicated by the wide gap between the list price and the net price created by manufactures, insurers, and intermediaries between them.

Each new competitor and new study is a step toward a future in which a substantial proportion of Americans with obesity are routinely prescribed these drugs. In a single week, obesity drugs leapt a new era—one in which they are about to become significantly more mainstream. No doubt that future is a bright one for millions of people who might benefit from treatment. Still, many questions about the drugs remain unanswered, such as their long-term safety and endless supply shortages.

But the potential for obesity drugs to truly change America has never felt closer—with all of the dizzying questions this creates about what “a slimming society” might mean for exercise, the food industry, and apparently even airline jet fuel.

Source : The Atlantic

A Little Drinking Won’t Help Prevent Obesity, Diabetes

Steven Reinberg wrote . . . . . . . . .

Having a couple of drinks a day won’t protect you from obesity or diabetes, a new study suggests.

Everybody knows that heavy drinking isn’t good for your health, but whether moderate alcohol consumption is protective or harmful is still open for debate, researchers say.

“Some research has indicated that moderate drinkers may be less likely to develop obesity or diabetes compared to non-drinkers and heavy drinkers. However, our study shows that even light-to-moderate alcohol consumption (no more than one standard drink per day) does not protect against obesity and type 2 diabetes in the general population,” said lead researcher Tianyuan Lu, of McGill University in Montreal, Canada.

“We confirmed that heavy drinking could lead to increased measures of obesity (body mass index, waist-to-hip ratio, fat mass, etc.) as well as increased risk of type 2 diabetes,” Lu added in a news release from the Endocrine Society.

For the study, Lu’s team collected data on alcohol use from nearly 409,000 men and women in the UK Biobank (a large-scale biomedical database and research resource). The researchers found that people who had more than 14 drinks per week had higher fat mass and a higher risk of obesity and type 2 diabetes.

The links were greater among women than men, the researchers noted. They found no association between moderate drinking and better health in people consuming up to seven drinks per week.

“We hope our research helps people understand the risks associated with drinking alcohol and that it informs future public health guidelines and recommendations related to alcohol use,” Lu said. “We want our work to encourage the general population to choose alternative healthier behaviors over drinking.”

The report was published in the Journal of Clinical Endocrinology & Metabolism.

Source: HealthDay

 

 

 

 

What the Scientists Who Pioneered Weight-Loss Drugs Want You to Know

Matt Reynolds wrote . . . . . . . . .

THE HISTORY OF weight-loss drugs is littered with failures. Some were outright dangerous: In the 1950s and ’60s, amphetamine-based diet pills were popular, but their prominence faded after being linked to addiction and other severe side effects. In 1997 the drug cocktail fen-phen was removed from the US market after it became clear it caused heart valve damage. Other attempts at treating obesity with drugs hit scientific dead ends. The history of anti-obesity drug discovery is for the most part “a bottomless pit into which people shove money and time,” wrote Derek Lowe in Science.

The new crop of much-hyped weight loss drugs seems to be different. These work by mimicking a hormone called glucagon-like peptide 1 (GLP-1), which regulates blood sugar levels and slows down the rate at which food leaves the stomach, making people fuller for longer. GLP-1-mimicking drugs seem to be a powerful tool for weight loss: Some people lose 15 percent of their body weight or more after 68 weeks on semaglutide, which is approved in the US for weight loss as Wegovy and for type 2 diabetes under the brand name Ozempic.

But the history of GLP-1 goes back more than 40 years—before obesity became the health crisis it is today. To get a sense of where these drugs came from—and where they might go next—WIRED spoke to two scientists who did some of the earliest work on the GLP-1 hormone, and who have played an important role in the development of these drugs.

Jens Juul Holst is a professor in the Department of Biomedical Sciences at the University of Copenhagen in Denmark. Joel Habener is a professor at the Mass General Research Institute in Massachusetts. In 2021, Habener, Holst, and Daniel Drucker were awarded the Warren Alpert Foundation Prize for their work discovering and developing treatments based on the GLP-1 hormone.

Holst and Habener were interviewed separately. This interview has been edited for length and clarity.

---

WIRED: Jens, you got involved with this research in the 1970s. Rather than diabetes or obesity, the history of GLP-1 starts with a completely different disease. Tell us about that.

Jens Holst: This was duodenal ulcer disease—people have forgotten about that disease completely. Diabetes was just something for old people, and you couldn’t do a lot about it anyway, and it was not interesting. So people were talking about duodenal ulcer disease—that was the problem.

And this meant looking at the hormones that are secreted when people eat. You started taking GLP-1 from pigs and pumping it through pig pancreases to see what it did—and that’s when you realized GLP-1 seemed to be a particularly powerful hormone.

Holst: We found that not only did GLP-1 stimulate insulin secretion, it also inhibited glucagon secretion. This was interesting, because people with diabetes have too much glucagon and that glucagon causes high blood sugar. So by stimulating insulin and inhibiting glucagon, you could have a double mechanism on the blood glucose. And now it was beginning to look like something interesting, and we were beginning to think of diabetes.

That pig pancreas study was published in 1988. Were drug companies paying much attention then?

Holst: I have always had friendly relationships with [Ozempic and Wegovy manufacturer] Novo Nordisk. It’s in Denmark, just up the street, and we were interested in the same things, so I kept telling them about what we were doing.

They were obviously interested in anything that could stimulate insulin secretion, but I must say that when we showed Novo Nordisk that [a different but related hormone] does not stimulate insulin secretion in people with diabetes, they withdrew some research support we had received because they said it wouldn’t work.

This is true. This is what happened. They were listening politely, but they weren’t really interested.

But by the early 1990 things started to change?

Holst: The real turning point was a study by Michael Nauck in 1993. We worked together, and we finally infused GLP-1 into people with type 2 diabetes and could show that the blood glucose came to completely normal levels in four hours, while insulin was stimulated and glucagon was inhibited. This demonstrated to everybody that this was really doing something in people with type 2 diabetes, completely unlike other hormones.

At that point, did you have a sense of how much potential these drugs might have, for treating obesity as well as diabetes?

Holst: We were finding these things out step by step. First, it was stimulating insulin secretion. That’s interesting but not really exciting. Then it’s stimulating glucagon secretion—that’s more interesting, put that on top. Then it’s also inhibiting the GI tract and gastric emptying.

Then we find out it’s inhibiting food intake as well. Wow, amazing. Amazing. It’s building up on top of each other all the time.

Joel Habener: We thought this might be a potential treatment for diabetes, type 2 diabetes. But we and others were finding with treating human subjects with GLP-1 in the very early days that you had to be very careful to keep the dose low, because many patients felt ill when they were eating. They were supposed to eat a meal, and then within 30 minutes we’d measure the blood insulin to check how effective it was.

Many of the subjects noted they were unable to finish their meal. It was messing up the experimental protocol because they were getting full and feeling nauseated and saying they didn’t want to eat any more food. Today, we’re between 10 to 15 percent of adults in the world who have a BMI at or above 30; in the US it’s around 40 percent. And obesity is clearly a very serious metabolic disease.

And that means a huge number of people will meet the FDA’s requirements for Wegovy treatment. Some projections put the future value of obesity drugs at $100 billion annually. Did you ever suspect that your work on GLP-1 could make you rich?

Holst: I’m so old, you know! I’m from ’68 and all of that; I was walking around in the street with signs saying: “Research for the people, not for the profit.” We didn’t even think of patenting or getting money out of this or anything. We were interested in publishing, doing something and moving this ahead.

Right, but you have close links with Novo Nordisk—it supported some of your research on GLP-1—and you also work at the metabolic research foundation it established at the University of Copenhagen. The company must be pretty grateful for your work?

Holst: I have been treated very nicely by them. I’ve been hired as a consultant [by Novo Nordisk] for some years, but otherwise I’ve never received a penny from them. Actually, when we found GLP-1 inhibited food intake and demonstrated this in 1998, we tried to make a patent with Novo Nordisk on the treatment of obesity. We were very interested in appetite regulation and treatment of obesity.

They said yes, and we thought we’d have a good patent, together with Novo Nordisk’s experience. Of course, eventually it turned out that the things we patented were not the things that they developed, so nothing came out of that after all.

The wider world really started to realize the potential of these drugs for weight loss in 2021, when The New England Journal of Medicine published a study showing that weekly semaglutide injections led to an average 14.9 percent weight loss in overweight and obese people. A lot of people in the industry were really impressed by this result—did it come as a surprise to you?

Holst: We already knew since 2001 that the dose of GLP-1 you were able to give people would determine its effect on food intake, so you could make the deduction that this would work. The problem was the side effects. Throughout the development of these GLP-1 drugs, the main problem has been finding a balance between the two. One of the really important observations was when Novo Nordisk created a fixed combination of long-acting insulin and GLP-1 called Xultophy. That was given to people with severe diabetes and it worked beautifully, but it turned out that to get to a steady dose with Xultophy it took 14 weeks of [gradually upping] the dose. And the more carefully you can up these drugs, the less side effects you can get eventually.

And a 15 percent weight reduction is pretty remarkable too, right?

Holst: It’s exceptional for two reasons. One is that it has not been possible with any other means to make a similar drug-induced weight loss. It’s simply not been possible; you can’t do it. This in itself is remarkable.

With low-calorie diets you can make 12 percent decreases in eight weeks, you could do that. But you can’t continue that kind of low-calorie diet. But now to have 15 percent or perhaps even up to 20 percent weight loss in a year or so is really remarkable.

The other reason is shown by studies like the DIRECT studies from Scotland, where they managed to make people lose weight by dieting and lifestyle interventions, and they could look at weight loss in categories. Those who were able to lose 15 percent of their body weight in that study had 86 percent diabetes remission. If you can lose 15 percent body weight, then a lot of people can get rid of their diabetes, apparently. If they can maintain it, the same is true. And this, of course, is supported from bariatric surgery results—they show exactly the same results.

But one of the problems is that these drugs aren’t always being taken by the people who are most in need of them—just look at Ozempic’s popularity as an off-label drug among celebrities. Derek Thompson in The Atlantic has written that these drugs could be a public health revolution, but in early 2023 they represent “an elite cultural makeover more than a medical intervention.”

Holst: I am a doctor. I am an MD all the way through. And my interest is in the complications of diabetes and obesity, and so I’m thinking constantly of people with obstructive apnea, and people with arthritis who can’t move, and I’m thinking about all the cardiovascular disease in these people. This year we will have the results of the SELECT study looking at semaglutide’s effects on heart disease and stroke in patients with obesity.

There are so many terrible problems. Have you ever visited a diabetes hospital? It’s really deplorable. People come in with amputated limbs and compromised cognitive functions and heart problems or they can barely move—they’re miserable and depressed. It’s really serious. There is so much you can improve with a drug that is not only a weight-loss drug but is also an anti-diabetic.

Habener: I think it’s important at this stage that the use of GLP-1 drugs is under medical supervision. The drugs should not be available over the counter, for example. It needs to be a prescription carefully followed by a physician who will be looking for troublesome side effects. But it’s hard to know where it’s gonna go.

I’d say the most satisfying thing right now about the drugs is the fact they are very effective at controlling type 2 diabetes for the most part.

Activists have warned that the rise of weight-loss drugs could deepen social stigma against fatness; that it will entrench the idea that anyone could—and should—have a skinny body. Does this worry you?

Holst: I don’t consider the shape of people at all in this. I only talk about complications. If people are completely healthy, I’m not interested. Let them be, that’s not a problem for me. But if they start to develop cardiovascular disease or cancer or depression, then there’s something to do. Then I’m a doctor or a surgeon and have to do something about it.

And this also underlines the importance of making sure the right people have access to the drug.

Habener: It’s not going to be available for poorer people unless things change. And currently a lot of insurance companies won’t cover [Wegovy] because obesity is still seen as a cosmetic problem, and they think that people are obese because they eat too much or don’t exercise enough or don’t have any willpower. But obesity is a disease, a metabolic disorder that has genetic and environmental inputs. It’s a complex trait.

It’s also partly to do with big problems with our food system: access to healthy food, poverty, the dominance of big corporations over our diets. Drugs like Wegovy can’t address any of these root causes, so I wonder if there’s this dynamic where we have this terrible food environment, but we also have these drugs that undo some of those effects, so we end up ignoring all of these fundamental problems with our diets.

Holst: I don’t think it works that way, actually. What happens is that you lose your appetite and also the pleasure of eating, and so I think there’s a price to be paid when you do that. If you like food, then that pleasure is gone. The craving for food for some people is taken away when they take GLP-1 drugs.

So you don’t eat through GLP-1 therapy because you’ve lost interest in food. That may eventually be a problem, that once you’ve been on this for a year or two, life is so miserably boring that you can’t stand it any longer and you have to go back to your old life.

So there might be a problem with getting people to stay on GLP-1 drugs?

Holst: GLP-1s have been on the market since 2005. Do people stay on them? No, they don’t. It’s just like every other drug, they don’t stay on it for many reasons. One of the reasons, as I said, is that once you have tried it and you realize you’ve lost interest in food, then that may be enough. We don’t know why people stop taking these drugs, but we know for a fact that they do stop. They do that all over the world.

It’s not the question of money. It’s simply because something happens that makes you uninterested in going on. Maybe you think everything is alright now, and then it turns out later that it is not alright and maybe you come back on the therapy. But I don’t see that a huge part of the population will be put on Wegovy and will stay on Wegovy for the rest of their lives—I simply don’t see that picture, because this hasn’t happened with other GLP-1 drugs.

Source: WIRED