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The Promise and Impact of the Next Generation of Weight Loss Drugs

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Metaculus Journal

Neuroscientist Stephan Guyenet writes about and researches eating behavior and health. He is the author of The Hungry Brain and is the founder and director of Red Pen Reviews.

Obesity is a burden on individuals and on society, but it has historically been hard to treat. Until recently, weight loss approaches based on diet/lifestyle and drugs struggled to produce safe and sustainable weight loss of greater than 5% of body weight on average. That is changing with the development of highly effective, and apparently safe, new weight loss drugs. Which drugs will make it to patients, when will they arrive, who will have access to them, and how will they impact public health?

Obesity is common and has historically been hard to treat

Forty-three percent of US adults have obesity, and this number has continued to increase over the last four decades, despite the fact that two-thirds of this group attempts weight loss each year. Although US obesity rates are higher than most other countries, obesity is common in the majority of wealthy countries and its prevalence is increasing nearly everywhere.

Weight loss interventions based on diet and lifestyle changes struggle to produce sustainable weight loss of greater than 5% of body weight on average. For example, the Diabetes Prevention Program trial was a large, multi-center randomized controlled trial that used a particularly intensive diet and lifestyle intervention to try to prevent progression to type 2 diabetes in people with overweight or obesity and pre-diabetes. At 6 months, volunteers had lost about 7% of body weight, but they slowly regained weight over time, and by four years they were only about 4% below their initial weight on average. 

Nevertheless, they enjoyed a 58% reduction in the risk of progressing to type 2 diabetes relative to the control group, illustrating that even modest weight loss is valuable and implying that greater weight loss may provide even larger benefits.

The history of weight loss drugs is no more distinguished. Prior to 2014, weight loss drugs with regulatory approval also struggled to exceed a safe and sustainable loss of body weight greater than 5% on average, and they often had undesirable side effects. The weight loss drugs rimonabant, fen-phen, and sibutramine lost approval from American and/or European regulatory agencies over serious safety concerns. 

Among obesity treatments, one stands out as particularly effective: bariatric surgery. The most common variants of this procedure durably reduce body weight by about one quarter

They also appear to offer remarkable long-term health benefits. Relative to people of similar weight who do not undergo bariatric surgery, those who do undergo surgery experience: 

These benefits would be transformative for public health if they could be applied to all people with obesity. However, fewer than 1 in 400 American adults with obesity undergo bariatric surgery each year. Compounding the problem, most doctors don’t have the resources to offer best-practice behavioral or drug treatment for this condition, and most Americans do not have access to obesity specialist MDs who do have the resources. A safe, effective weight loss drug that could be easily prescribed might change this.

The new weight loss drug Wegovy is effective, and apparently safe

This grim situation began to change in 2014 with the approval of the drug liraglutide for weight loss by the US Food and Drug Administration (FDA), and its subsequent approval by the European Medicines Agency (EMA) in 2015. It is a once-daily injected drug based on the gut hormone glucagon-like peptide-1 (GLP-1), whose biology has turned out to be a goldmine for the medical management of obesity and type 2 diabetes. Liraglutide, which was developed by Novo Nordisk, causes about 7% loss of body weight in people with obesity when paired with diet and exercise advice. Better, but still not revolutionary.

By tweaking the design of GLP-1-based drugs, Novo Nordisk discovered another drug that had a much longer half-life in the blood and a substantially larger impact on body weight: semaglutide. Semaglutide only requires one injection per week and produces average weight losses of 15-18% in people with obesity when paired with diet and exercise advice. Initially approved at lower doses for the treatment of type 2 diabetes, the FDA approved a higher dose (2.4 mg) for the treatment of obesity this year (June 2021). It’s marketed under the brand name Wegovy.

According to several obesity medicine specialists I’ve spoken with, doctors and patients tend to be very satisfied with Wegovy due to its effectiveness and minimal long-term negative side effects. The Canadian physician David Macklin, for example, has treated more than one thousand patients with the drug “off-label” for the last two years and reports that it is “extremely rewarding for patients and for doctors”. 

Given the checkered history of weight loss drugs, it’s reasonable to be cautious about their safety. Semaglutide and related drugs often cause unpleasant gastrointestinal side effects like nausea, heartburn, diarrhea, constipation, fatigue, and headache, but these are typically mild and transient if the dose is started low and escalated slowly. Few people discontinue semaglutide due to side effects.

Some studies have suggested that this class of drugs may increase the risk of thyroid and pancreatic cancer in lab rodents. Yet randomized controlled trials including 64,000 people with type 2 diabetes have not observed an increased risk of cancer, overall or at any specific site in humans. These trials are limited in duration and don’t yet have enough people to reliably identify modest increases in the risk of low-frequency outcomes like thyroid and pancreatic cancer. Observational monitoring data are mixed but have not provided a clear signal of increased risk. 

Importantly, trials suggest that semaglutide reduces major cardiovascular events by about one quarter, similar to cholesterol-lowering statin drugs. Furthermore, across seven trials in people with type 2 diabetes, semaglutide and related drugs reduce the overall risk of dying by 12%. These findings are reassuring, but monitoring is ongoing and some concern remains

Wegovy is only the beginning

Semaglutide is a (modified) protein, which creates technical challenges. First, it’s expensive to produce and requires specialized facilities. Second, it’s most naturally administered as an injection, because if a person ingests it, it gets digested and inactivated just like the proteins in a piece of cheese. However, Novo Nordisk has developed technology that lets the protein be absorbed intact from the digestive tract into circulation, allowing it to be delivered in pill form. The oral semaglutide pill is FDA approved for the treatment of diabetes and marketed as Rybelsus.

Oral semaglutide is convenient for patients, but it has not yet been approved for the treatment of obesity. Novo Nordisk plans to initiate a phase 3a trial of oral semaglutide for obesity this year (2021), suggesting that the company will probably seek regulatory approval for the treatment of obesity. The trial will last 68 weeks.

Ultimately, non-protein “small molecule” drugs that activate GLP-1 receptors may offer advantages over proteins like semaglutide. These advantages include potentially lower cost of production in less specialized facilities, good oral availability, and longer shelf-life. In June of 2020, Pfizer presented promising results from a phase 1 trial of a small molecule GLP-1 receptor activator, PF-06882961, in people with type 2 diabetes. Over 28 days of treatment, the drug substantially improved blood glucose control and reduced body weight by 2-9%, depending on dose. Novo Nordisk may be working in the area as well.

The research pipeline has produced several other drugs and drug combinations for the treatment of obesity that are not yet approved, but are showing tremendous potential in human trials. Novo Nordisk recently completed a phase 1b trial pairing semaglutide with the amylin analog cagrilintide. Over 20 weeks, the addition of cagrilintide nearly doubled the rate of weight loss caused by semaglutide alone, suggesting that in a longer trial the combination may equal the weight loss caused by bariatric surgery. The combination caused somewhat more gastrointestinal side effects than semaglutide alone, but there was no indication of serious adverse events.

Eli Lilly has developed an injected drug based on GLP-1 and gastric inhibitory polypeptide (GIP) called tirzepatide. Tirzepatide has performed well in diabetes trials and appears poised to gain FDA approval for that condition. Experts believe it is probably more potent than semaglutide for the treatment of both type 2 diabetes and obesity, and Eli Lilly is currently conducting a phase 3 weight loss trial in people with obesity and overweight that promises to yield results in April of 2022. Importantly, tirzepatide may provide much-needed competition for semaglutide, potentially lowering drug costs.

So far, the drugs I’ve described are all based on brain-acting gut hormones, which has been the most productive biology for recent drug development in obesity. However, other biology may also hold promise. In January of this year (2021), Novartis published a phase 2 trial of its interesting drug bimagrumab in people with type 2 diabetes and obesity or overweight. Bimagrumab inhibits an inhibitor of muscle growth, causing muscles to grow. Over 48 weeks, people treated with bimagrumab lost one-fifth of their fat mass and increased their lean mass by 4%, along with gaining notable improvements in blood glucose control. 

Versanis Bio secured funding this year (2021) to develop bimagrumab for the treatment of obesity.

Who will have access to the new weight loss drugs?

The primary drawback of Wegovy is its cost. It has a wholesale cost of $1,349 a month in the US, although it will likely cost about a quarter of that in other countries. Wegovy costs so much because it’s expensive to produce, Novo Nordisk has to recoup substantial development costs, and of course, the company would like to turn a profit.

This high cost is likely to decline over time. One reason is competition from other drugs, like tirzepatide, which I believe will likely be approved by the FDA for obesity in the next few years. Wegovy currently does not have much competition. Another reason is the eventual expiration of patents and introduction of generic versions of the drug.

Generic Wegovy is not guaranteed however, since the chemistry behind semaglutide is specialized and expensive. In speaking with experts, it is not clear that generics manufacturers will have the ability and appetite to produce generic semaglutide. Wegovy has several patents associated with it, but I have not been able to get a clear sense of when generic entry may be possible.

Along with wholesale cost, another factor that determines access to drugs is health insurance coverage. 9% of Americans do not have health insurance, and obesity drugs are often not covered by insurance plans. Early signs suggest that Wegovy will be covered by at least some large insurance companies.

While high-income countries currently tend to have higher obesity rates than lower-income countries, that situation is changing rapidly. Many lower-income countries are experiencing an explosion of obesity rates, and it will probably be harder for them to access effective new weight loss drugs. I’m not sure how to compose an effective forecasting question about this, but I think it’s worthwhile to ponder how much access lower-income countries will have to these drugs.

What impact will the new weight loss drugs have on public health?

People with obesity typically do not want to have obesity, as demonstrated by the fact that two-thirds of American adults with obesity attempt to lose weight each year. It stands to reason that there will be a high demand for safe and effective weight loss drugs. Demand for Wegovy currently exceeds supply. If these drugs become widely available and affordable, one might predict that a substantial fraction of people with obesity will use them.

As more people with obesity use these drugs, one might predict that the prevalence of obesity will decline. However, this is hard to predict because it may (or may not) be superimposed on a baseline trend of increasing obesity rates. 

Given the impact of weight loss and GLP-1 based drugs on health, one might further expect that as the use of these drugs becomes more common, the prevalence of type 2 diabetes may decline. Type 2 diabetes is particularly sensitive to changes in body fat mass.

These drugs may also impact other deadly diseases like cardiovascular disease and cancer, but I believe the impact of weight loss drugs on these diseases will be more difficult to discern due to the fact that they are not as tightly linked to body weight as type 2 diabetes, and the determinants of their incidence and mortality are more complex. I think it would be challenging to design an effective forecasting question around this, but suggestions are welcome.

The future is bright for the medical management of obesity. Perhaps if we put our minds together, we can catch a glimpse of it.

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