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.

Lose Your Weight and Stomach Fat Fast With These 10 Diet Life Hacks

Ready to hear the dirty little secret no one tells you about how to lose stomach fat?

The secret is — you can’t. At least, not the way that you think.

Studies show that blasting your abs with tons of crunches won’t trim your belly fat, just like doing curls won’t give you tighter arms and squats won’t give you leaner legs.

Spot reducing fat or picking and choosing where you’d like to lose fat on your body, is a complete and utter myth.

The only way to get a leaner midsection is to shed fat from your entire body. To do this, you’ll need the right combination of diet strategy and exercise — something you can stick to long enough for your body to start tapping into the fat stores in your belly.

There are as many approaches to losing weight as there are people on this planet, but no matter who you are, here are 10 diet hacks to keep you on track as you lean down in your quest for a flat stomach.

1. Create a Consistent Calorie Deficit

Eating the right number of calories on a daily basis is the number one driver of fat loss. Don’t let the low-fat or low-carb gurus fool you!

What’s the right number of calories?

Well, a calorie is a unit of energy that our bodies primarily derive from food. Every day, we burn a certain number of calories depending on our size, age, gender, and activity levels. To burn fat, which is to say, to force our bodies to tap into our fat reserves and use them for energy instead of food, we need to eat fewer calories than we burn in a day.

The key is not to overcomplicate your diet by demonizing specific food groups or macronutrients. Aim for a deficit of about 500 calories per day. The easiest method to calculate this is to multiply by 12 calories per pound of bodyweight and eat that many calories every day. If you do nothing else on this list except consistently hit your daily calorie target, you WILL lose weight.

2. Eat Slower and Be Patient

Eating fewer calories to lose weight is really simple, but that’s not to say that it’s easy.Forcing your body to burn its fat stores for energy is an uncomfortable process that might leave you feeling drained and with less energy, while getting used to smaller meals may leave you feeling hungry at first.

One great workaround is to eat slower, chew more, and be patient. There is evidence to support the idea that eating more slowly can increase how satisfied and full some people feel after a meal, and decrease your desire to eat more. It simply takes time for your stomach to communicate to your brain that it’s full and satisfied! If you eat quickly, you might bypass this signal and wind up eating more than you really needed to feel full.

Not only that, but it takes a solid 2 to 3 hours for your body to convert food you’ve just eaten into actual, usable energy. Even after eating a large meal while dieting, you may still feel hungry, but that doesn’t mean you need to eat more.

If you’re patient enough and allow your body to do its work, you’ll usually feel a jolt of energy a few hours after eating.

3. Eat More Protein

If you hit the right number of calories every day, you’ll be well on your way toward losing your belly, regardless of the overall makeup of your diet.However, there is lots of evidence to suggest that people interested in fat loss should consider a diet high in protein.

People who eat more protein are generally more satisfied and tend to eat fewer calories overall. Plus, a healthy dose of protein every day will help you preserve more muscle mass and encourage your body to lose more fat.

Your protein needs will vary depending on your gender and activity levels, but most people should shoot for at least 40 to 50 grams of protein every day.

4. Delay Your First Meal

Ever heard of intermittent fasting? It’s an eating style wherein you drastically reduce your eating window during the day while remaining fasted the rest of the time. For example, you might be “allowed” to eat for 8 hours, from noon to 8pm, while the rest of the time you only drink water.

The health benefits of fasting are vast and go far beyond weight loss and include boosts in mood, energy, focus, longevity, and more. However, you needn’t jump right into long, extended fasts, though they can be extremely effective.

Try pushing your first meal back just a few hours after you wake up. You’ll likely trigger more fat burning than you would by eating right away, and surprisingly, you’ll probably be a lot less hungry eating nothing than you would after eating a small breakfast.

Even mild fasting can dramatically decrease your overall appetite and calorie intake throughout the day.

5. Work Your Core

I know I said you can’t force your body to lose stomach fat, but that doesn’t mean you shouldn’t be prepared for the day that it does!

Work your abdominal and core muscles 2 to 3 times per week to build strength in your midsection. As you begin to lose fat, you’ll discover better tone and definition in that area than if you ignored it.

What are the best core exercises? Leave the crunches on the bench and try some more challenging moves like:

· Hanging leg raises

· Planks

· Reverse sit ups

· Incline sit ups

· Ab wheel roll outs

You don’t need much, just 2 to 3 sets of 20 reps or so a few times per week should be plenty to build those abs and prepare them for their big reveal.

6. Do the Right Kind of Cardio

Believe it or not, exercise is completely optional when it comes to losing weight. If you eat the right number of calories, the fat will come off regardless.

However, it will be much easier to create your consistent calorie deficit if you’re active and burning extra calories at least a few times per week. Plus, exercising is a whole lot better for your health that not exercising.

Cardio can definitely help! But you’ll have a few choices for how to go about it:

• LISS (Low Intensity Steady State): Going for a long walk or light jog would be considered low intensity cardio. The benefits of this kind of exercise are that you’ll burn calories without taxing your body too badly and driving up your appetite. The downside? It can be kind of boring and lengthy, therefore difficult to incorporate on a consistent basis as a result.
• HISS (High Intensity Steady State): Think going for a long run. The plus side of HISS is that you’ll burn more calories a lot faster when compared to LISS, however these workouts are more draining and difficult to recover from. You may find yourself extremely hungry as a result of the exertion.
• HIIT (High Intensity Interval Training): HIIT refers to short bursts of intense exercise followed by stretches of rest or long intensity work. Imagine walking on a treadmill and occasionally working in high-speed sprints, or doing a circuit of pushups, air squats, lunges, etc. with rest intervals worked in. These workouts burn a ton of calories quickly and dramatically improve your conditioning, but they can also be difficult for your body to recover from and can drive up your appetite.

Each form of cardio has its place, but for fat loss, I’d recommend sticking mostly with LISS or HIIT workouts to burn extra calories a few times per week.

7. Eat More Filling Foods

Again, hitting a calorie target sounds simple, but that doesn’t make it easy!

If you find you’re consistently getting hungry throughout the day when trying to stick to a diet, you may need to change up your food choices.

Sure, you could technically lose weight by eating 1200 calories of Doritos every day, though I wouldn’t recommend it!Your best bet will be to eat lots of nutrient rich foods that satiate your body and take time to digest.

Simple carbs (white bread, sugar, etc.) are unquestionably delicious but offer little nutritional value, so your body churns through them quickly. They might briefly fill your stomach, but they won’t leave you satisfied for long.

Complex carbs (oatmeal, brown rice, sweet potatoes) and lean proteins (chicken, turkey) will keep you full for longer and better fuel your body for any workouts you might incorporate.

8. Utilise Strategic Refeeds and Diet Breaks

You likely won’t need these strategies when you first begin your diet, but as you start to see results and get to a lower body fat percentage, you might find your body needs a break every now and then.

After all, burning your own fat for energy is difficult on the body and mind. Long-term adherence to the diet is a lot more important than getting results as fast as possible.

Consider adding in one refeed day per week, where you eat an additional 500 calories or so (usually complex carbs). This will help restore your body’s energy and promote a healthy metabolism.

You can also take a 2 to 4 week diet break, where you eat your body’s maintenance calories (around bodyweight times 15 calories per day) and allow yourself to recover and rejuvenate.

Funny enough, you may find that eating more actually encourages your body to shed some of the fat it’s been desperately clinging to. Studies show that people who take strategic breaks from dieting now and then have better long-term fat loss results.

9. Get More Sleep

So much of adhering to a fat loss diet comes down to willpower and mental focus.

Know what the number one killer of willpower is? A lack of sleep.

Sleep deprivation can cause chaos with your hormonal balance and ability to regulate your appetite, but more importantly, it can leave you with very little self-control. People who don’t sleep enough find themselves snacking more and overeating more frequently.

Blue light from phones, computers, and TVs, for example, is known to disrupt sleep patterns. Opt for a book before bed if you’re having trouble getting to sleep on time.

10. Track Everything

An extra bite of your friend’s dessert here, a quick snack there, and another dollop of sauce or oil on your plate… It all adds up, and those extra calories can easily derail your diet if you’re not careful.

To be sure you’re hitting your calorie goal every day, it’s best to track everything, even if you’re only using your best estimation (though calorie counters can help, too).

Tracking meals is one thing, but for the best results you’ll want to write down every single thing you take into your body including sauce, oil, sides, snacks, drinks, and more.

Forgetting about that 300 to 500 extra calories you had during the day will be the difference between losing belly fat fast, and not.

The Bottom Line

I wish there was an easy way to quickly lose fat from your belly, believe me!

What more people need to understand is that, although targeted fat loss is impossible, fat doesn’t come off of your body completely evenly, either.

For many people, especially men, the stomach is their body’s absolute favorite place to store fat. You may need to lose a significant amount of weight before your body is ready to start tapping into its belly stores.

Remember to set your calorie target and focus on hitting it every single day. Exercising, getting lots of protein, and incorporate tricks to stay motivated can really help, but the energy deficit is the primary driver and fat loss and should be your main priority.

You’ll likely need to stick with the plan for a long time before that stomach completely flattens out.

Reference

		J Strength Cond Res.: The effect of abdominal exercise on abdominal fat
		Science Direct: Calories do count
		Science Direct: Slower eating rate reduces the food intake of men, but not women
		The American Journal of Clinical Nutrition: A high-protein diet induces sustained reductions in appetite …
		Trusty Spotter: I tried my first 24 hour fast. Here’s what happened.
		Science Daily: Taking a break from dieting may improve weight loss
		WebMD: Sleep and Weight Gain