The New Obesity Breakthrough Drugs

There are many holy grails in medicine, with failure after failure, like finding a way to prevent Alzheimer's disease or a non-invasive means for accurately measuring ambulatory blood pressure. But one of the biggest and most daunting has been finding drugs that can tackle obesity — achieving a substantial amount of weight loss without serious side effects. Many attempts to get there now fill a graveyard of failed drugs, such as fen-phen in the 1990s when a single small study of this drug combination in 121 people unleashed millions of prescriptions, some leading to serious heart valve lesions that resulted in withdrawal of the drug in 1995. The drug rimonabant, an endocannabinoid receptor blocker (think of blocking the munchies after marijuana) looked encouraging in randomized trials. However, subsequently, in a trial that I led of nearly 19,000 participants in 42 countries around the world, there was a significant excess of depression, neuropsychiatric side-effects and suicidal ideation which spelled the end of that drug's life.

 

In the United States, where there had not been an anti-obesity drug approved by the FDA since 2014, Wegovy (semaglutide), a once-weekly injection was approved in June 2021. The same drug, at a lower dose, is known as Ozempic (as in O-O-O, Ozempic, the ubiquitous commercial that you undoubtedly hear and see on TV) and had already been approved in January 2020 for improving glucose regulation in diabetes. The next drug on fast track at FDA to be imminently approved is tirzepatide (Mounjaro) following its approval for diabetes in May 2022. It is noteworthy that the discovery of these drugs for weight loss was serendipitous: they were being developed for improving glucose regulation and unexpectedly were found to achieve significant weight reduction.

Both semaglutide and tirzepatide underwent randomized, placebo-controlled trials for obesity, with marked reduction of weight as shown below. Tirzepatide at dose of 10 to 15 mg per week achieved >20% body weight reduction. Semaglutide at a dose of 2.4 mg achieved ~17% reduction. These per cent changes in body weight are 7-9 fold more than seen with placebo (2-3% reduction). Note: these levels of per cent body weight reduction resemble what is typically achieved with the different types of bariatric surgery, such as gastric bypass.

 

Another way to present the data for the 2 trials is shown here, with an edge for tirzepatide at high (10-15 mg) doses, extending to >25% body weight reduction.

 

 

The results with semaglutide were extended to teens in a randomized trial (as shown below), and a similar trial with tirzepatide is in progress.

 

How Do These Drugs Work?

 

These are peptides in the class of incretins, mimicking gut hormones that are secreted after food intake which stimulate insulin secretion.

 

These 2 drugs have in common long half-lives (~ 5 days), which affords once-weekly dosing, but have different mechanisms of action. Semaglutide activates (an agonist) the GLP-1 receptor, while tirzepatide is in a new class of dual agonists: it activates (mimics) both the GLP-1 receptor and GIP receptors (Gastric inhibit polypeptide is also known as glucose-dependent insulinotropic polypeptide.) The potency of activation for tirzepatide is 5-fold more for GIPR than GLP1. As seen below, there are body wide effects that include the brain, liver, pancreas, stomach, intestine, skeletal muscle and fat tissue. While their mode of action is somewhat different, their clinical effects are overlapping, which include enhancing satiety, delaying gastric emptying, increasing insulin and its sensitivity, decreasing glucagon, and, of course, reducing high glucose levels. The overlap extends to side effects of nausea, vomiting, abdominal pain, constipation and diarrhea. Yet only 4 to 6% of participants discontinued the drug in these trials, mostly owing to these GI side effects (and 1-2% in the placebo group discontinued the study drug for the same reasons).

In randomized trials among people with Type 2 diabetes, the drugs achieved HbA1c reduction of at least an absolute 2 percentage points which led to their FDA approvals (For semaglutide in January 2020, and for tirzepatide in May 2022). The edge that tirzepatide has exhibited for weight loss reduction may be related to its dual agonist role, but the enhancement via GIP receptor activation is not fully resolved (as seen below with GIP? designation). The Amgen drug in development (AMG-133) has a marked weight loss effect but inhibits GIP rather than mimics it, clouding our precise understanding of the mechanism.

 

The gut-brain regulation of food intake with the many gut hormones (including leptin, gherlin, PYY, amylin) and targets in the body and brain regions. From Muller et al, Nature Reviews Drug Discovery March 2022. 

Nevertheless, when the two drugs were directly compared in a randomized trial for improving glucose regulation, tirzepatide was superior to semaglutide, as shown below. Of note, both drugs achieved very favorable effects on lipids, reducing triglycerides, LDL and raising HDL cholesterol, along with reduction of blood pressure, an outgrowth of the indirect effect of weight reduction and direct metabolic effects of the drugs.

 

While there has been a concern about other side effects besides the GI ones noted above, review of all the trials to date in these classes of medication do not reinforce a risk of acute pancreatitis. Other rare side effects that have been noted with these drugs include allergic reactions, gallstones (which can occur with a large amount of weight loss), and potential of medullary thyroid cancer (so far only documented in rats, not people), which is why they are contraindicated in people with Type 2 multiple endocrine neoplasia syndrome.

How They Are Given and Practical Considerations

 

For semaglutide, which has FDA approval, the indication is a BMI of 30 kg/m2 or greater than 27 kg/m2 and a weight related medical condition (such as hypertension. hypercholesterolemia or diabetes). To reduce the GI side effects, which mainly occur in the early dose escalation period, semaglutide is given in increasing doses by a prefilled pen by self-injection under the skin (abdomen, thigh or arm) starting at 0.25 mg for a month and gradual increases each month reaching the maximum dose of 2.4 mg at month 5. The FDA label for dosing of tirzepatide has not been provided yet but in the weight loss trial there was a similar dose escalation from 2.5 mg up to 15 mg by month 5. The escalation is essential to reduce the frequent GI side effects, such as seen below in the tirzepatide trial.

 

Semaglutide is very expensive, ~$1500 per month, and not covered by Medicare. There are manufacturer starter coupons from Novo Nordisk, but that is just for the first month. These drugs have to be taken for a year to 18 months to have their full effect and without changes in lifestyle that are durable, it is likely that weight will be regained after stopping them.

What Does This Mean?

 

More than 650 million adults are obese and 13% of the 8 billion world's population (including over 340 million ages 5-18) is obese — that sums us to over 1 billion people. The global obesity epidemic has been relentless, worsening each year, and a driver of "diabesity," the combined dual epidemic. We now have a breakthrough class of drugs that can achieve profound weight loss equivalent to bariatric surgery, along with the side benefits of reducing cardiovascular risk factors (hypertension and hyperlipidemia), improving glucose regulation, reversing fatty liver, and the many detrimental long-term effects of obesity such as osteoarthritis and various cancers. That, in itself, is remarkable. Revolutionary.

 

But the downsides are also obvious. Self-injections, even though they are once a week, are not palatable for many. We have seen far more of these injectables in recent years such as the PCSK-9 inhibitors for hypercholesterolemia or the TNF blockers for autoimmune conditions. That still will not make them a popular item for such an enormous population of potential users.

That brings me to Rybelsus, the oral form of semaglutide, which is approved for glucose regulation improvement but not obesity. It effects for weight loss have been modest compared to Wegovy (5 to 8 pounds for the 7 and 14 mg dose, respectively). But the potential for the very high efficacy of an injectable to be achievable via a pill represents an important path going forward—it could help markedly reduce the cost and uptake.

The problem of discontinuation of the drugs is big, since there are limited data and the likelihood is that the weight will be regained unless there are substantial changes in lifestyle. We know how hard it is to durably achieve such changes, along with the undesirability (and uncertainty with respect to unknown side-effects) of having to take injectable drugs for many years, no less the cost of doing that.

The cost of these drugs will clearly and profoundly exacerbate inequities, since they are eminently affordable by the rich, but the need is extreme among the indigent. We've already seen celebrities take Wegovy for weight loss who are not obese, a window into how these drugs can and will be used without supportive data. As one physician recently observed, "Other than Viagra and Botox, I've seen no other medication so quickly become part of modern culture's social vernacular." Already there are concerns that such use is preventing access to the drugs for those who qualify and need them.

 

There are multiple agents in the class under development which should help increase competition and reduce cost, but they will remain expensive. There is private insurance reimbursement, often with a significant copay, for people who tightly fit the inclusion criteria. Eventual coverage by Medicare will markedly expand their use, and we can expect cost-effectiveness studies to be published showing how much saving there is for the drugs compared with bariatric surgery or not achieving the weight loss. But that doesn't change the cost at the societal level. Even as we've seen with generics, which will ultimately be available, the alleviation of the cost problem isn't what we'd hoped.

 

This is not unlike the recent triumphs of gene therapy, as in $3.5 million for a cure of hemophilia that just got FDA approval, but instead of a rare disease we are talking about the most common medical condition in the world. We finally get across the long sought after (what many would qualify as miraculous) goal line, but the economics collide with the uptake and real benefit.

 

These concerns can't be put aside in the health inequity-laden world we live in, that will unquestionably be exacerbated. However, we cannot miss that this represents one of the most important, biggest medical breakthroughs in history. This may signify the end or marked reduction in the need for bariatric surgery. These drugs will likely become some of the most prescribed of all medications in the upcoming years. While there are many drawbacks, we shouldn't miss such an extraordinary advance in medicine—the first real, potent and safe treatment of obesity.

Intermittent fasting may change how your DNA is expressed

Mice who only ate at specific times of the day experienced “profound” changes in genetic expression, leading to health benefits like reduced risk of obesity and inflammation, new research found.

To an extent, it’s not about  what you eat as much as when you eat it — so says recent research that sheds new light on the benefits of intermittent fasting. 

The study, published Tuesday in journal Cell Metabolism, found that mice fed only during certain blocks of time experienced “profound” changes in gene expression. Nearly 80 per cent of all genes were impacted in some way, the paper reads.

The changes resulted in a plethora of health benefits, the authors wrote, including: improved blood sugar regulation, decreased risk of obesity and even a reversal of certain hallmarks of ageing.
You can think of a gene as the blueprint for a specific protein, written in DNA. When a gene is expressed, the blueprint is converted into its protein product by cellular machinery. Because proteins are responsible for most cellular functions from fat metabolism to immune response, even slight changes in gene expression could leave a massive impact.

According to the research, restricting when mice could eat reshaped when and to what extent certain genes were expressed — for example, some organs learned to switch on the genes for regulating blood sugar when it came feeding time, and to repress them when it was time to fast.

The researchers say their findings opened the door for further research into how dietary interventions might impact our genes and what this means for those suffering from issues like diabetes, heart disease and cancer.

What is time-restricted eating?

Shaunak Deota, first author of the study and a post-doctoral fellow at the Salk Institute for Biological Studies in San Diego, explained time-restricted eating as “eating consistently in a narrow window of 8 to 10 hours” when one is most active and fasting the remainder of the day. Intermittent fasting is a form of this practice, he said.

By feeding and fasting at the same time every day, we are reinforcing a biological rhythm in our bodies, Deota said: “Our body is getting the food at the same time every day, so all our organ systems know when the food is going to come and they’re prepared for it.”

Previous studies have shown that time-restricted eating may reduce the risk of obesity and diabetes, help to improve cardiovascular health, provide benefits for gut function and cardiovascular health and more.

Deota’s research now contributes, to his knowledge, the first “holistic” look at how time-restricted eating impacts the body as a system.

To achieve their results, the researchers put two groups of mice on the same high-calorie diet. One group was only allowed to eat during a nine-hour window when they were most active. The other could feed whenever they wanted.

After seven weeks, the mice on a time-restricted diet gained less weight than their counterparts, despite eating the same amount of food. 

The researchers then killed 48 of the mice — 24 from each group — to investigate the diet’s impact on the body. They sacrificed two mice from each group every two hours over a 24-hour period, noting how their organ systems changed over time.

How time-restricted eating changes the body

After studying the mouse organs, Deota and his team made a “pretty surprising” discovery; mice on the time-restricted diet had synchronized their gene expression with their feeding schedules.

“That is important because these genes will get translated into proteins,” Deota said. “Those proteins are helping our body to anticipate that there is food coming.”

According to their paper, roughly 70 per cent of all mouse genes fell into rhythm with the feeding schedule. Come mealtime, individual organs could promote genes in charge of nutrient metabolism while suppressing those responsible for inflammatory signalling and immune activation.

Moreover, the scientists found the diet reversed several hallmarks of aging, leading to reduced inflammation, increased cellular housekeeping, improved RNA and protein balance and more.

“Molecularly speaking, we saw a lot of pathways which are activated by (the time-restricted diet) in multiple organ systems. And a lot of these pathways actually have been implicated in improving health and leading to a longer, healthy life,” Deota said.

The limitations

All that being said, we need to remember these results were seen in mice, not humans — we’re still a long way off from demonstrating the same phenomenon happens in people, said Dani Renouf, a registered dietitian at St. Paul’s Hospital in Vancouver. For now, these results represent a “wonderful start to a conversation.”

“We’re just prototyping at this point because we’re using animal models and looking at things on a cellular level,” she said. “In order to now make conclusions in human beings, we need to take several steps before we can definitively do that with time restricted-eating.”

Renouf also noted the experiments took place in a tightly controlled environment. Real life is messy and chaotic, she said, and will likely influence results.

On the flip side, Deota believes “most of these benefits can be translated to humans” because his lab’s findings line up with what clinical studies into time-restricted eating have discovered.