Study Reviewed: Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. Jastreboff et al. (2023)

You’ve likely seen headlines about weight loss drugs over the last year or two. They’ve been all over the news, and I’ve heard that they’re the talk of the town on TikTok. We don’t often discuss prescription drugs in MASS, and for good reason. None of the MASS authors can prescribe medication, very few of our readers can prescribe medication, and there aren’t that many prescription drugs that get studied for sport science applications. As a result, we rarely encounter opportunities to discuss prescription drugs in a manner that will actually yield actionable information or conclusions. Having said that, weight loss drugs are an exception to the rule. They have fueled considerable discussion within the fitness industry and are likely to make a considerable impact on the space moving forward, so it makes sense to address them in MASS.

This new wave of weight loss drugs goes by many names, such as Ozempic, Wegovy, semaglutide, Mounjaro, and tirzepatide. This list is not exhaustive, but those are the most recognizable names in the current chatter about this class of drugs. As it turns out, Ozempic, Wegovy, and semaglutide are all the same drug. Semaglutide is the generic name, Ozempic is the brand name drug approved for diabetes, and Wegovy is the brand name drug approved for weight loss (with a slightly different dosing schedule than Ozempic). Similarly, Mounjaro is simply the brand name version of the generic drug tirzepatide.

This category of weight loss drugs is broadly known as “incretin mimetics.” This means that they mimic incretins, which are hormones released by the intestines in response to nutrient ingestion (2). Upon binding to their receptors, these incretins play a major role in regulating insulin and glucagon release. Incretins produced endogenously (by our own bodies) include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; also known as gastric inhibitory peptide). Semaglutide is a GLP-1 agonist, meaning it binds to GLP-1 receptors and produces a similar physiological response. Tirzepatide also mimics GLP-1, in addition to mimicking GIP. The use of incretin mimetic drugs, typically administered in the form of once-weekly injections, leads to enhanced glycemic control, slower gastric emptying rate, reduced hunger, and reduced food cravings. As a result considerable weight loss is observed. For example, research has documented losses of 15-20% of initial body mass for both semaglutide (3) and tirzepatide (4). In other words, these drugs yield magnitudes of weight loss that aren’t too far off from bariatric surgery, while offering a far less invasive intervention with a much more favorable risk profile.

Now there’s a new incretin mimetic drug on the block: the presently reviewed study by Jastreboff and colleagues (1) examines the effects of retatrutide. Based on the previous paragraph, you might wonder why we’d bother looking into yet another incretin mimetic (after all, we’ve got two that both seem to work really well). However, retatrutide differs from both semaglutide and tirzepatide because it adds another mechanism to the mix: retatrutide is an agonist of GLP-1, GIP, and glucagon. In theory, this should make retatrutide even more effective than its predecessors. In this study, the researchers enrolled 338 weight-stable adults between the ages of 18 and 75 with overweight or obesity. The sample was an approximately even split of males and females, and the average BMI of participants at baseline was just above 37. Participants were divided into seven different groups; one was a placebo group, and the other six were retatrutide groups with different dosing protocols of retatrutide. One group used 1mg/week of retatrutide for the duration of the 48-week intervention, and one group used 4mg/week for the entire intervention. The other groups worked their way up to higher doses of retatrutide, increasing the dosage every 4 weeks until reaching the final dosage by week 12 (at the latest). One group started at 2mg/week and worked up to 4mg/week, one group started at 2mg/week and worked up to 8mg/week, one group started at 4mg/week and worked up to 8mg/week, and one group worked their way up from 2mg/week to 12mg/week. So, in summary, the groups were as follows:

• Placebo
• 1mg/week
• 4mg/week (starting at 2mg/week)
• 4mg/week (starting at 4mg/week)
• 8mg/week (starting at 2mg/week)
• 8mg/week (starting at 4mg/week)
• 12mg/week (starting at 2mg/week)

All participants also received a comprehensive lifestyle intervention that included regular counseling sessions from a dietitian or healthcare professional, with guidance based on US guidelines for physical activity and nutrition. Participants were not required or encouraged to achieve any specific energy deficit for the study. After 48 weeks, participants lost a considerable amount of weight in a dose-dependent manner (Figure 1), with the highest-dose group (12mg/week) losing an average of 24.2% of their initial body mass. In addition, retatrutide was well-tolerated; adverse events were generally mild to moderate in severity, and most commonly involved gastrointestinal symptoms. The researchers noted that adverse events were partially attenuated by using a lower starting dose (2mg/week instead of 4mg/week). This class of drugs also tends to cause dose-dependent increases in resting heart rate, which was observed in the presently reviewed study. Heart rate peaked at 24 weeks, then declined after that point.

In summary, retatrutide was extremely successful in this trial. Previous studies tend to report 15-20% weight loss with semaglutide and tirzepatide, which suggests that retatrutide is as effective, and potentially even more effective, than these popular predecessors. Having said that, we’ll need some head-to-head trials before we make any definitive conclusions about comparing one weight loss drug to another, whether we’re talking about effects on weight loss, cardiometabolic health outcomes, or side effect prevalence and severity.

Surprisingly, the positive findings from studies on these weight loss drugs have prompted considerable backlash. Some people have downplayed the significance of these weight loss drugs by noting that they may not reduce an individual’s body weight enough to reach the “normal” BMI category if they aren’t combined with lifestyle interventions including exercise and dietary changes. That may be true, but I think just about everyone is on board with the idea that the preferred course of treatment would combine these drugs with simultaneous lifestyle interventions whenever possible. It’s also important to recognize that considerable weight loss (for example, at least 5-10% of body mass) can yield meaningful health improvements, even if the individual’s BMI remains above 25. In addition, this general concept is par for the course when it comes to drugs that aim to improve cardiometabolic outcomes. For example, if you’re trying to manage hypertension a combination of exercise and medication is often implemented. The fact that exercise and medication have additive effects does not render the medication’s independent effect any less helpful. 

Others have downplayed the significance of these weight loss drugs by noting that weight regain is often observed when patients stop taking them. For example, Figure 2 shows results from a recent semaglutide trial published by Wilding and colleagues (3). While patients lost about 17% of their baseline weight after 68 weeks of treatment, they had regained about two-thirds of the weight within one year after treatment ended. So, a large percentage of the weight tends to come back when you stop treatment, but that’s pretty much how it goes – progress you get from diets, training programs, and even anabolic steroids regress upon cessation.

Some folks have publicly voiced concerns that weight loss drugs cause disproportionately large losses of fat-free mass, which is certainly less favorable than fat loss when it comes to a wide range of outcomes related to health and physical function. It’d be valuable for researchers to look closely at this claim in future studies; unfortunately many studies in this area report weight and BMI changes without more direct measures of fat mass and fat-free mass (including the presently reviewed study). Having said that, the cardiometabolic pros would almost certainly outweigh the cons associated with modest loss of lean mass for a large percentage of patients who would be using these drugs. More importantly, it seems very reasonable to suggest that any such effect could be largely or fully attenuated by a combination of resistance training and adequate protein intake. Finally, some people have criticized weight loss drugs because of a collection of so-called “side effects” that have gotten attention in the lay press. “Ozempic finger” refers to the observation that some peoples’ fingers are shrinking to the extent that their rings no longer fit. “Ozempic face” refers to looking older due to loose skin on one’s face. “Ozempic butt” refers to having flatter glutes. I don’t mean to minimize the very real impact of body image concerns, but these “side effects” aren’t actually side effects. They are direct consequences of the primary effect, which is weight loss. When you lose fat, you don’t get to control where it comes from; losing fat from one’s fingers, face, and glute area is far from unusual and not unique to weight loss drugs. 

That’s not to say that there aren’t any notable side effects from weight loss drugs. I’m no physician, but it appears that the most common side effects reported are gastrointestinal in nature. For example, it seems fairly common to see reports of nausea, vomiting, abdominal discomfort, and diarrhea in studies. There are also anecdotal reports of “smelly” burps, which may be indicative of some acid reflux symptoms, and some evidence of gallbladder issues (which is common for interventions that induce large amounts of rapid fat loss, including bariatric surgery). Nonetheless, symptoms of these side effects appear to go away over time, and the safety profile of these weight loss drugs seems to be strong when used correctly. There are also some legitimate concerns about the cost and availability of these drugs. They’re really expensive, and demand seems to be quite high. As a result, I’ve seen lay press articles stating that some folks with diabetes are concerned that they’ll be unable to get their medication because it’s being used by people who don’t really need it. So, there are some legitimate reasons for people to carefully consider whether or not they should explore the use of these drugs. Nonetheless, these drugs shouldn’t be demonized or categorically dismissed, and any decisions about prescription drug options should be discussed with a qualified medical professional.

Finally, I want to address one last element of the weight loss drug conversations: some folks seem to suggest that utilizing these medications for weight loss purposes is “unfair,” or represents the “wrong way” to do weight loss by presenting some sort of crutch or shortcut. From a human perspective, the emergence of safe and effective drugs to prevent or reverse obesity is categorically good. Obesity presents one of the largest public health challenges of our time, and tools that boost the success and self-efficacy of people with weight loss goals are tremendously valuable. When someone is diagnosed with hypertension, type 2 diabetes, or high cholesterol, interventions typically involve a combination of lifestyle interventions and pharmaceutical interventions. I see no reason to view weight reduction through a different lens if safe and effective drugs are available. 

It also seems like some fitness professionals are a bit concerned that their ability to offer products and services might be negatively impacted by the emergence of effective weight loss drugs. Even if we set aside the troubling idea of hoping people stay in a state of compromised health so your business can benefit (ironically, a common accusation that some fitness enthusiasts hurl at medical and pharmaceutical entities), I believe this line of thinking is flawed. I may be naive, but I believe it’s beneficial for the fitness industry to move away from the concept that exercise is for weight loss. Frankly, exercise interventions tend to yield underwhelming weight loss results anyway (one, two). In contrast, exercise (independent of weight loss) is great for mental health, athletic performance, stamina, strength, body composition, performance of activities of daily living, musculoskeletal pain and injury, sleep, a variety of cardiometabolic risk factors, and more. Exercise is a pretty lackluster weight loss intervention, and a pretty incredible intervention for overall health and wellness. I think the fitness industry will benefit from reframing exercise accordingly.

On top of that, I believe that discouragement and disappointment are key factors that remove people from the potential pool of fitness industry consumers. There are so many people who try to lose weight, fall short of their goal (or promptly regain the weight after achieving it), and experience substantial threats to their confidence and self-efficacy. In many cases, these individuals lose confidence in their ability to achieve fitness-adjacent goals and temporarily (or permanently) stop pursuing them. In a hypothetical (and very plausible) future world with safe, affordable, and widely accessible weight loss drugs, these individuals (who represent an enormous percentage of the global population) begin their fitness journey with a higher probability of success. I wonder how many of them, after successfully losing 10-20% of their body weight, will explore new ways to engage with exercise and physical activity once they can exercise more confidently and comfortably. I suspect that many will want to build some muscle after losing fat, or exercise to bolster their mental health, or build up a base of fitness to join a recreational sport league, or run some races for fun, or take up strength training to enjoy the thrill of chasing new PRs, or build up their fitness level to keep up with their children and grandchildren. Assuming that research continues to support the safety and efficacy of weight loss drugs, I think they offer an opportunity to reframe exercise as what it really is: a wellness-inducing, quality-of-life-improving intervention, not a weight loss intervention. And while that’s clearly a great thing for the health and wellness of our population, I think that’s a great thing for fitness as well.

References

1. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023 Jun 26. Epub ahead of print.
2. Seino Y, Fukushima M, Yabe D. GIP and GLP‐1, The Two Incretin Hormones: Similarities And Differences. J Diabetes Investig. 2010 Apr 22;1(1–2):8–23.
3. Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, et al. Weight Regain And Cardiometabolic Effects After Withdrawal Of Semaglutide: The STEP 1 Trial Extension. Diabetes Obes Metab. 2022 Aug;24(8):1553–64.
4. Sinha R, Papamargaritis D, Sargeant JA, Davies MJ. Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management. J Obes Metab Syndr. 2023 Mar 30;32(1):25–45.