In trials and in real-world settings, medications that reduce excess weight associated with chronic health issues have produced impressive results.
When Susan Yanovski arrived, the hotel ballroom was nearly to full with scientists. She had to manoeuvre to one of the few open seats at the rear despite arriving 10 minutes early. In November 2022, attendees at the Obesity Week conference in San Diego, California, eagerly awaited the findings of a highly anticipated medication trial.
Researchers from the Danish pharmaceutical company Novo Nordisk, with headquarters in Bagsvaerd, delivered an engaging presentation. They discussed the specifics of an examination of a potentially effective anti-obesity drug in teenagers, a population known for being resistant to such therapy. The results shocked the researchers: a weekly injection for over 16 months, combined with modest dietary and lifestyle modifications, caused more than one-third of the subjects to lose at least 20% of their body weight. The medicine, semaglutide, had previously demonstrated that it was equally effective in adults.
Yanovski, co-director of the Office of Obesity Research at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, claims that the presentation’s conclusion was unlike any other at the conference. She said there was continuous applauding that made the atmosphere “feel like you were at a Broadway musical.”
Over the past few years, this energy has permeated the field of obesity medicine. Researchers are now seeing results after decades of work: a new line of anti-obesity drugs that significantly reduce weight without the severe side effects that have dogged earlier attempts.
These medications are being developed at a time when obesity is increasing dramatically. Since 1975, the global rate of obesity has tripled; in 2016, the World Health Organization reported that 13% of adults were obese and 40% of individuals were judged to be overweight (WHO). Weight gain frequently increases the risk of diseases like type 2 diabetes, heart disease, and several malignancies. The WHO advises healthy diets and exercise to prevent obesity, although medication may be necessary if lifestyle improvements are insufficient. The brand-new medications mimic incretin hormones, which reduce blood sugar and suppress appetite. Several have already been approved for treating type 2 diabetes, and they are starting to earn approval for inducing weight loss.
The fact that weight can be lost by altering biology lends support to the theory that obesity is an illness. In the past, researchers and the general public frequently believed that people who were obese lacked the willpower to lose weight. But there is mounting proof that the majority of people’s bodies have a natural size that can be challenging to alter. According to Richard DiMarchi, a chemist at Indiana University Bloomington, “the body will defend its weight.”
Several academics are concerned that these medications contribute to some societies’ fixation with thinness. Health can’t always be predicted by body size. Sarah Nutter, a psychologist at the University of Victoria in Canada who specialises in weight stigma and body image, says she is “very hesitant to be thrilled about something that I think is potentially damaging from a weight stigma standpoint.”
There are many unanswered research questions, such as who will react to treatment and if patients would need to take these medications forever, which would be a major barrier to access given that the injections frequently cost over US$1,000 per month.
Nonetheless, these advancements are being praised by obesity researchers. According to German physician-scientist Matthias Tschöp, CEO of Helmholtz Munich, for the first time, scientists may pharmacologically change weight in a safe manner. It truly is “the” revolutionary breakthrough.
Hormone Search
The foundation for today’s achievement was laid decades ago, when Jeffrey Friedman was scrambling to identify the gene mutation causing the lab mice to overeat and become obese. The defective gene encoded leptin, a hormone that is produced by adipose tissue and causes a feeling of fullness, as was discovered in 1994 by Friedman, a molecular geneticist at The Rockefeller University in New York City. Mice without leptin had less appetite and weight gain after receiving leptin supplementation.
Yanovski claims that this “truly altered our understanding” regarding the biological causes of obesity and appetite control.
Research into the causes of obesity as well as research into pharmaceutical therapies exploded after that. However, these early medications had severe adverse effects, particularly on the heart, and only little weight loss.
Prior to the discovery of leptin, scientists had been searching for hormones that control blood glucose levels and had discovered one called GLP-1 (glucagon-like peptide 1). According to Jens Juul Holst, a medical physiologist at the University of Copenhagen who discovered and defined GLP-1, it appeared to have the opposite impact of type 2 diabetes—GLP-1 improved insulin production and decreased blood sugar—making it an interesting strategy for treating obesity.
In order to treat type 2 diabetes, the US Food and Drug Administration (FDA) started to approve medications in the 2000s (see “Weight busters”). However due to GLP-1’s impact on appetite-controlling brain and digestion-slowing gut receptors, researchers discovered that clinical trial participants also lost weight. Companies started testing these diabetes drugs for weight loss over time. By the middle of the 2010s, one of these medications, liraglutide, was capable of causing an average body weight loss of about 8%, which was 5 percentage points greater than for those taking a placebo.
Yet in early 2021, a phase III clinical trial involving a brand-new medication of the same class, semaglutide, astounded researchers. According to DiMarchi, the molecule, a modified form of liraglutide, works on the same pathways but stays in the body longer and is still active. He continues that it might also have easier access to brain areas that control eating.
After 16 months of treatment, participants receiving semaglutide injections on a weekly basis lost, on average, 14.9% of their body weight, while those receiving a placebo lost, on average, 2.4%. The FDA granted semaglutide approval for weight loss in 2021, four years after the drug was given the go-ahead for diabetic treatment.
Timo Müller, a scientist and the head of the Helmholtz Munich Center for Diabetes and Obesity, claims that historically, it has not been possible to safely reduce body weight by more than 10% by pharmaceutical means. But, he continues, these more recent therapies also enhance cardiovascular health, the opposite of earlier ones.
Tirizepatide may now be a more potent medication available. Tirzepatide targets the GLP-1 receptor as well as the glucose-dependent insulinotropic polypeptide, another hormone implicated in insulin production (GIP). This therapy, created by Indianapolis, Indiana-based Eli Lilly, was approved in 2022 for type 2 diabetes. At the maximum dose, it caused an average 21% decrease in body weight, compared to 3% for placebo.
Why duplicating both hormones is more effective than just one is unknown. Müller claims that GIP may help to lessen the negative effects of GLP-1, enabling bigger doses, and that tirzepatide may be a more effective activator of the GLP-1 receptor. Moreover, GIP may result in modest weight loss on its own.
Notwithstanding the unknowns, weight loss levels after tirzepatide treatment are comparable to those generally only possible through bariatric surgery. After six months, this therapy reduces body weight by 30% or more, and the weight loss lasts for the next year or two.
According to Ruth Gimeno, group vice-president of diabetes, obesity, and cardiometabolic research and early clinical development at Eli Lilly, “ten years ago, if you had told me we have something that puts us quite near [to bariatric surgery], I would have said that’s not conceivable.” The business intends to submit an application for the drug’s approval awaiting the conclusion of a second phase III trial in April 2023.
Device Mysteries
Researchers are baffled by tirzepatide despite its encouraging outcomes. GLP-1’s contribution to weight loss is obvious, while GIP’s function is unexpected. Since mice with malfunctioning GIP receptors are resistant to fat, scientists have long believed that GIP actually promotes obesity. Researchers therefore believed that the receptor should be turned off to cause weight loss. The opposite is true for tirzepatide.
According to Müller, who works with Novo Nordisk, “We were the first who came up with this ridiculous idea.” “And in the field, we received quite a bit of criticism.”
Müller claims that he and his colleagues, including DiMarchi and Tschöp, were aware that GIP, like GLP-1, promotes the release of insulin based on blood glucose levels. They therefore created compounds that imitated the two hormones. Pharmaceutical companies developed their own compounds to achieve the same results after initial research showed that activating both the GIP and GLP-1 receptors produced weight reduction, thereby validating the efficacy of the approach.
In Spain, a woman is weighed by a doctor as part of a weight loss challenge. The best ways to lose weight are through diet and lifestyle modifications, but a new class of medications may also be useful. Miguel Riopa/AFP/Getty Images.
Not everybody has, however, altered their opinions of GIP. According to Holst, tirzepatide is merely a GLP-1 imitator that is incredibly potent.
It can also mimic GIP, but according to Holst, “with individuals with diabetes and obesity, it doesn’t really matter because the GIP element doesn’t really do anything.” According to Holst, Eli Lilly is doing early-stage clinical trials with medications that only target GIP, which will end the controversy.
The Thousand Oaks, California-based biopharmaceutical company Amgen is also working on a medication that inhibits the GIP receptor while activating the GLP-1 receptor. Early clinical study findings indicate that, after 12 weeks, this therapy lowered body weight by up to 15%.
Another tactic is the use of “triple agonists,” substances that mimic the actions of the hormones GLP-1, GIP, and glucagon, a third hormone that also stimulates the release of insulin. Moreover, studies are being conducted on additional gut hormones, such as peptide YY, that influence appetite. Moreover, bimagrumab, a monoclonal antibody that increases lean muscle mass while decreasing fat, is being studied by some researchers.
Unique Questions
Whether patients will need to take these medications forever to maintain their weight is one of the primary questions that experts are currently addressing. After a year, a subset of clinical trial participants who stopped taking semaglutide and the lifestyle modifications they had been receiving gained back around two-thirds of the weight they had lost.
Who will respond to these medications and who won’t is another unknowable. Although it is yet too soon to say, type 2 diabetics appear to respond to the medications less favourably than those who do not. According to Tschöp, diseases like fatty liver disease and visceral body fat, which is fat that surrounds the organs, may also alter how individuals react to various medications.
Some experts are also concerned that by providing a weight-loss option in cultures that value thinness, these medications may unintentionally strengthen the debatable relationship between obesity and health. According to one study, 30% of those who are deemed obese had healthy metabolisms. Nutter points out that another study found that characteristics other than weight need to be taken into account when assessing health because they tend to be stronger predictors of someone’s risk of death than weight.
A person’s health should not be pathologized based just on their body weight, she continues.
Nutter worries that rather than starting these medications to address a genuine health need, people may do so to avoid the weight stigma. These treatments can have serious side effects, such as nausea and vomiting.
Others are concerned that these medications promise a speedy treatment. According to Leslie Heinberg, a clinical psychologist at the Cleveland Clinic in Ohio who specialises in bariatric behavioural health and body image, this is a typical misperception concerning bariatric surgery. ‘Oh, now folks can just take this drug and that’s the easy way out of obesity,’ some people who still cling to those false notions will assert,’ she says.
Yet, there is a substantial need. In addition, not everyone who need these treatments will have access even if they are entering the market.
Semaglutide for weight loss, sold under the trade name Wegovy, costs about $1,300 per month. In addition, many insurance companies in the United States refuse to cover the cost, largely because they do not understand the reasons of obesity and see the therapies as “vanity medications.”
According to Patty Nece, head of the board of directors of the Obesity Action Coalition (OAC), a Tampa, Florida-based advocacy organisation, “people talk about some of these treatments as being game-changers.” For a specific patient, though, “it’s never going to be a game-changer if they can’t afford it or don’t get access to it,” she continues.
Pharmaceutical companies are being pressured by groups like the OAC to develop programmes that are affordable. For instance, Eli Lilly offers a “bridging programme” for its type 2 diabetic medicine Mounjaro, which costs as little as $25 for the first three months. For Wegovy, Novo Nordisk operates a similar programme.
Notwithstanding the initial expenses, some scientists emphasise that by eliminating a number of illnesses that are linked to the disease, tackling obesity could enable health-care systems to save huge sums of money.
Many scientists agree that biology plays a substantial role in obesity, despite the fact that researchers are still working to understand the intricate interplay of factors that contribute to it, including genetics, environment, and behaviour. Treatment will always include healthy eating and exercise, but experts believe that these medications are a promising addition. Additionally, some experts believe that because these medications work through biological pathways, they will help people realise that it is frequently impossible to regulate one’s body weight just by dietary and lifestyle modifications. According to Gimeno, “Tirzepatide very clearly demonstrates that it’s not about willpower.”
This article, which was first released on January 4th, 2023, is being reprinted with permission.
Source: By McKenzie Prillaman, Nature magazine on January 10, 2023.