GLP-1, GLP-2 & GLP-3: Complete Peptide Guide

Introduction

Over the past few years, a new class of research peptides has revolutionized treatments for obesity and type 2 diabetes. Notably, GLP-1 analogs such as semaglutide (a GLP-1 receptor agonist) have demonstrated unprecedented weight loss and glucose control in patients. Building on this success, next-generation peptide drugs combine multiple hormonal targets: tirzepatide (sometimes dubbed a “GLP-2” in this context) activates two gut hormone pathways, and the experimental retatrutide (“GLP-3”) targets three.

These therapies mimic or enhance hormones that naturally regulate appetite, metabolism, and blood sugar, offering new hope in tackling chronic conditions like obesity and diabetes. In this article, we’ll break down the mechanism of action for semaglutide, tirzepatide, and retatrutide – explaining what they do in the body, which receptors they act on, and how they influence appetite and metabolism. We’ll also summarize recent clinical trial results for each peptide, highlighting outcomes in weight loss, blood sugar (glycemic) control, and safety. Finally, we’ll compare their relative effectiveness and side effect profiles, all in clear terms for a general audience.

GLP-1 (Semaglutide): Mechanism and Effects

What is GLP-1?

Glucagon-like peptide-1 (GLP-1) is a hormone released from the gut after we eat. It binds to GLP-1 receptors in the body, triggering a cascade of effects: it signals the pancreas to release insulin (helping lower blood sugar), reduces glucagon secretion (glucagon is a hormone that raises blood sugar), slows down gastric emptying (so food leaves the stomach more slowly), and sends a “fullness” signal to the brain. In simpler terms, GLP-1 tells your body “we’ve got nutrients; let’s use them efficiently and stop eating.”

Semaglutide’s Mechanism of Action

Semaglutide is a GLP-1 receptor agonist – essentially a long-acting mimic of natural GLP-1. By activating GLP-1 receptors throughout the body, semaglutide enhances insulin release when you eat and curbs the appetite via the brain’s appetite centers. It “fakes” your body into feeling full and satisfied, while also slowing digestion, so you stay full longer. The result is that you tend to eat less and your blood sugar levels remain more stable.

Importantly, this insulin release is glucose-dependent – it happens mostly when blood sugar is high, which means semaglutide by itself typically does not cause dangerously low blood sugar (hypoglycemia) in patients. This selective action makes it safer than older diabetes drugs that could drop sugar regardless of meals.

Physiological Effects

By mimicking GLP-1, semaglutide has multiple beneficial effects on metabolism: it lowers blood glucose (by boosting insulin and suppressing glucagon), reduces appetite and calorie intake, and can even lead to improved cardiovascular markers in patients (blood pressure and cholesterol often improve secondary to weight loss). The most dramatic effect garnering public attention is weight loss. Patients on semaglutide often report feeling less hungry and having fewer cravings, which, along with its effect of keeping food in the stomach longer, leads to a significant reduction in calorie consumption.

Clinical Trial Outcomes (Weight Loss and Glycemic Control)

Semaglutide was initially developed for type 2 diabetes (under brand names like Ozempic for injection and Rybelsus for oral form). In diabetes trials, it showed powerful glucose-lowering – for example, one study found semaglutide lowered HbA1c (a marker of average blood sugar) by about 1.9 percentage points more than placebo. Many patients achieved much better blood sugar control on this drug.

But what really made headlines was semaglutide’s effect on body weight. A pivotal 68-week trial (STEP 1) in people with obesity showed an average weight reduction of ~15% of body weight with weekly semaglutide 2.4 mg (the higher dose marketed as Wegovy), compared to about 2% in the placebo group. In absolute terms, the semaglutide group lost roughly 15 kg (33 lbs) on average.

Notably, about 50% of patients lost at least 15% of their starting weight with semaglutide, a degree of weight loss previously achievable mainly with surgery. Alongside the weight loss, patients saw improvements in blood sugar (many with prediabetes returned to normal glucose levels), blood pressure, and cholesterol – all signs of a healthier metabolic profile. These impressive results led to semaglutide’s approval specifically for chronic weight management in 2021 (Wegovy), making it a groundbreaking medical obesity treatment.

Safety and Side Effects

Semaglutide’s side effect profile is well-characterized, and most issues are related to its gastrointestinal actions. Because it slows digestion and reduces appetite, common side effects include nausea, diarrhea, constipation, and occasionally vomiting or abdominal discomfort, especially when first starting the medication or increasing the dose.

In the STEP 1 trial, for instance, nausea and diarrhea were the most frequently reported side effects. These symptoms are usually mild to moderate and tend to improve over time as the body adapts. To help minimize stomach-related side effects, doctors start patients on a low dose and gradually titrate up. A small percentage of people (around 4–5% in trials) do stop semaglutide due to intolerable GI symptoms. Aside from tummy troubles, semaglutide is generally well tolerated; it does not typically cause low blood sugar by itself because it won’t trigger insulin unless glucose is elevated.

Rare but serious safety considerations include the risk of pancreatitis (inflammation of the pancreas) and gallbladder issues (rapid weight loss can sometimes precipitate gallstones). Such events are uncommon, but patients are monitored for any severe abdominal pain. Additionally, all GLP-1 based drugs carry a warning about thyroid C-cell tumors observed in rodent studies. In those animal studies, extremely high doses caused thyroid tumors. Importantly, no increased thyroid cancer risk has been seen in human trials so far, but out of an abundance of caution, people with a personal or family history of a specific thyroid cancer (medullary thyroid carcinoma) or MEN2 syndrome are advised not to use GLP-1 agonists.

Overall, for most individuals, semaglutide’s benefits in controlling appetite, weight, and diabetes outweigh these theoretical risks, and it’s now widely used as a safe and effective therapy for both diabetes and obesity.

GLP-2 (Tirzepatide): Dual Receptor Targeting with GIP/GLP-1

What is Tirzepatide?

Tirzepatide is a next-generation peptide drug that activates two hormone receptors: the GLP-1 receptor and the receptor for GIP (Glucose-Dependent Insulinotropic Polypeptide). GIP is another hormone released from the gut when you eat, and like GLP-1, it prompts the pancreas to release insulin. In fact, GIP was the first “incretin” hormone discovered – incretins are gut hormones that tell the body to lower blood sugar after meals.

However, GIP on its own has complex effects on metabolism and appetite, and by itself it hasn’t been a successful drug target for weight loss. Tirzepatide cleverly combines GIP and GLP-1 actions in one molecule, and the result is synergistic – it amplifies insulin release, powerfully lowers glucose, and produces even greater appetite suppression and weight loss than a GLP-1 agonist alone.

Mechanism of Action

Tirzepatide is often referred to as a “dual agonist” or even a “twincretin” because it binds and activates both GIP receptors and GLP-1 receptors. Once-weekly tirzepatide injection essentially mimics two natural gut hormones simultaneously. By activating GIP receptors, tirzepatide further boosts meal-time insulin secretion and may have direct effects on fat tissue that complement GLP-1’s actions. Meanwhile, through GLP-1 receptors it continues to provide the potent appetite reduction, slower gastric emptying, and glucagon suppression.

In practice, tirzepatide causes a cascade: more insulin output, less sugar production by the liver, and a greater feeling of fullness with reduced cravings. Patients often report that on tirzepatide they feel satisfied with smaller portions and have less desire for snacks or sugary foods. Interestingly, by slowing stomach emptying, tirzepatide can make you feel full for longer after meals – which helps with weight loss but can also be why some people experience nausea or indigestion on the drug.

It’s worth noting that tirzepatide was engineered with a ratio of activity at the two receptors (it isn’t a 50/50 activator of GIP and GLP-1 – it has a bit more activity on GIP). This balance was chosen to maximize metabolic benefits. The precise reason why adding GIP action leads to more weight loss is still being studied. Some hypotheses are that GIP might counteract the body’s tendency to fight weight loss or might improve the function of fat cells. Whatever the case, the clinical results made it clear that this dual approach is extremely effective.

Physiological Effects

In people taking tirzepatide, the combined effect is significant weight loss and improved metabolic health. Tirzepatide lowers fasting and post-meal blood glucose even more than semaglutide (GLP-1 alone) can, and it causes a dramatic decrease in appetite and food intake. Many patients on tirzepatide experience rapid improvements in diabetes control – often needing to reduce or discontinue other diabetes medications.

Beyond blood sugar, tirzepatide helps reduce overall body fat. In a study of body composition, most of the weight lost on tirzepatide was fat mass rather than muscle (about 75% of weight lost was fat). This is encouraging, as preserving lean muscle is important for health during weight loss. Additionally, like GLP-1 drugs, tirzepatide may have beneficial effects on the heart and kidneys (trials are ongoing to confirm cardiovascular benefits).

Clinical Trial Outcomes

Tirzepatide has shown remarkable results in clinical trials, both for type 2 diabetes and obesity. In the diabetes-focused SURPASS trials, tirzepatide at its highest dose (15 mg weekly) lowered HbA1c by roughly 2.3 percentage points from baseline – significantly more than a standard dose of semaglutide (-1.9 percentage points in the same trial). In fact, tirzepatide was found superior to semaglutide for glucose lowering and produced greater weight loss in diabetic patients as well. Many participants on tirzepatide were able to reach near-normal blood sugar levels; one study noted that a majority of patients on 10 mg or 15 mg tirzepatide achieved an HbA1c under 7% (the general target for diabetes control).

For obesity (in people without diabetes), the results have been even more eye-opening. The SURMOUNT-1 trial tested tirzepatide in adults with obesity over 72 weeks. The highest dose, 15 mg, led to an average weight reduction of about 20% of body weight. To put that in perspective, someone who weighed 100 kg (220 lbs) would lose around 20 kg (44 lbs) on average. In fact, many individuals lost over 22% of their weight on tirzepatide in that trial. The results noted patients losing between 16% and 22.5% of their starting weight depending on the dose. At the 15 mg dose, participants lost an average of ~52 pounds (≈24 kg) over the ~1.5 year study.

These are unprecedented numbers for a medication – approaching the kind of weight loss seen with bariatric surgery. Substantial weight loss was seen even at lower doses (5 mg and 10 mg groups lost about 35 lbs and 49 lbs on average, respectively). It’s important to highlight that these participants were also following diet and exercise advice, but the drug effects drove much greater losses than lifestyle changes alone. Along with weight, tirzepatide improved waist circumference, blood pressure, and lipid levels in trials, indicating broad health benefits.

Given these outcomes, tirzepatide earned FDA approval in 2022 for type 2 diabetes (brand name Mounjaro) and in late 2023 for chronic weight management in obesity (brand name Zepbound). It represents a new class of therapy for obesity – one that many are calling a game-changer in the field.

Safety and Side Effect Profile

Because tirzepatide activates the GLP-1 pathway, it shares many of the same side effects as semaglutide and other GLP-1 agonists. The most common side effects are gastrointestinal – notably nausea, diarrhea, constipation, vomiting, and indigestion. In trials, these GI symptoms were generally mild to moderate and tended to occur during the initial dose-escalation phase (when doses are gradually increased).

As with GLP-1 therapies, starting at a low dose and titrating up helps improve tolerability. For example, in SURMOUNT-1, nausea was often reported when participants were upping their dose, and then it usually subsided. An American Diabetes Association release noted that tirzepatide’s overall safety and tolerability were similar to other incretin-based therapies (like GLP-1 drugs) used for obesity. Rates of side effects such as nausea, diarrhea, etc., on tirzepatide are comparable to those seen with semaglutide – for instance, about 1 in 5 people might experience some nausea. A small percentage of patients discontinue the medication due to side effects, but in trials, dropout rates due to adverse events were only a bit higher than with semaglutide.

There are some additional side effects worth mentioning. People on tirzepatide (and GLP-1 RAs) sometimes report taste changes or diminished appetite for certain foods, which are actually part of how the drug works to reduce intake. Some individuals have also noted hair loss or thinning during rapid weight loss on these medications. While hair loss is not due to the drug’s chemical effect on hair follicles, losing weight quickly (over 15–20% of body weight in a short time) can cause temporary hair shedding in some people. The prescribing information for tirzepatide’s obesity indication (Zepbound) does list hair loss as a reported side effect, alongside things like fatigue, injection-site reactions, and burping/heartburn. It’s generally a transient issue and can be managed with proper nutrition and supplements.

Serious adverse events with tirzepatide were rare in trials. Like GLP-1 drugs, there’s a low risk of pancreatitis (patients are advised to stop the drug if they get severe abdominal pain) and a risk of gallbladder problems (due to weight loss-related gallstones). Tirzepatide also carries the same thyroid tumor warning (based on rodent data) as other GLP-1 therapies.

In summary, tirzepatide’s safety profile does not reveal any new major concerns beyond what is already known for GLP-1 agonists – it mostly causes stomach-related side effects that are manageable for most people. Given its dramatic efficacy, most patients and clinicians find these temporary discomforts an acceptable trade-off for the health benefits. Ongoing studies are monitoring long-term safety, but so far tirzepatide appears to be a generally safe medication in line with its GLP-1 cousins.

GLP-3 (Retatrutide): Triple-Agonist on the Horizon

What is Retatrutide?

Retatrutide is an investigational peptide that represents the next wave of metabolic therapy – it’s a triple hormone receptor agonist. Retatrutide can bind to and activate three key receptors: GLP-1, GIP, and the glucagon receptor. In essence, it packs the actions of three natural hormones into one weekly injection.

We’ve discussed GLP-1 and GIP; the new addition here is glucagon. Glucagon is a hormone produced by the pancreas (from alpha cells) that typically has the opposite effect of insulin – it signals the liver to release stored sugar, thus raising blood glucose. It also plays a role in breaking down fat for energy. At first glance, activating glucagon receptors might sound counterintuitive for a diabetes/obesity drug (since glucagon raises blood sugar). However, researchers hypothesized – and early studies suggest – that a little glucagon activation can actually increase metabolic rate and promote fat burning, especially when combined with the insulin-boosting, appetite-curbing effects of GLP-1 and GIP.

The idea is to attack obesity on multiple fronts: decrease food intake (GLP-1, GIP) and increase energy expenditure (glucagon), all while keeping blood sugars in check with enhanced insulin. Retatrutide is the first triple agonist of this kind to be tested in humans, and it has shown striking results in mid-stage trials.

Mechanism of Action

Retatrutide’s mechanism combines everything we’ve described for semaglutide and tirzepatide, plus the added effect of glucagon receptor activation. Through GLP-1 and GIP receptor agonism, retatrutide will boost insulin secretion when needed and strongly suppress appetite, causing individuals to eat much less. It will also slow gastric emptying, similar to the other drugs.

Meanwhile, by agonizing the glucagon receptor, retatrutide likely increases the utilization of energy stores – essentially telling the body “burn more calories.” Low doses of glucagon (or glucagon agonists) have been found to raise metabolic rate and promote weight loss by increasing fat breakdown. The challenge is balancing that effect so as not to cause high blood sugar; but with GLP-1 and GIP on board stimulating insulin, the net effect of retatrutide still leans toward lowering glucose. Indeed, in early studies retatrutide lowered blood sugar in people with obesity, suggesting the mix of hormones was well-balanced.

Researchers at Eli Lilly (the company developing retatrutide) believe that it’s precisely this combination of glucagon, GIP, and GLP-1 actions that yields unprecedented weight loss – essentially more than the sum of its parts. In Lilly’s words, “combining glucagon receptor agonism with GIP and GLP-1 receptor agonism” appears to be a key reason for the level of weight reduction seen with retatrutide.

Physiological Effects

In trials so far, retatrutide has demonstrated the kinds of effects one would expect from a triple agonist: dramatic weight loss, improved glycemic measures, and changes in body composition. Patients report reduced appetite and quicker satiety (fullness) during meals, similar to GLP-1 agonists, but possibly even more pronounced. The glucagon component might also contribute to feelings of warmth or slight increases in heart rate, as metabolism revs up.

Since retatrutide is still in clinical trials, we have data primarily from a Phase 2 study in people with obesity (many of whom had metabolic syndrome or prediabetes but not frank diabetes). In that study, retatrutide not only slashed body weight (more on that below) but also significantly improved markers like fasting blood glucose, insulin resistance, and liver fat. A subset of patients with fatty liver disease saw major reductions in liver fat content on retatrutide, presumably due to the combination of weight loss and the direct effects of glucagon signaling on the liver. Moreover, retatrutide likely has the same benefits on blood pressure and cholesterol that we see with other incretin therapies, simply as a consequence of weight loss and improved insulin sensitivity.

Clinical Trial Outcomes

Although retatrutide is not yet on the market, the Phase 2 trial results (published in 2023) have generated a lot of excitement. This trial tested multiple doses of retatrutide versus placebo in adults with obesity over 48 weeks. The amount of weight loss achieved was unprecedented for a medication in a trial of this length.

At the highest dose (12 mg weekly), retatrutide produced an average –24.2% change in body weight after 48 weeks. That’s nearly a quarter of one’s body weight gone in roughly 11 months. For context, someone weighing 250 lbs could lose about 60 lbs on average. The 8 mg dose wasn’t far behind, with about a –22.8% change. Even the moderate doses (4 mg) saw ~17% weight reduction, far above the placebo group which lost only ~2%.

These results were dose-dependent and suggest that with higher doses or longer treatment, weight loss might continue. In fact, the weight loss curves were still trending downward at 48 weeks, meaning some patients hadn’t even plateaued yet. To put it plainly, retatrutide induced weight loss approaching that of bariatric surgery in just one year of treatment.

A noteworthy portion of patients on retatrutide achieved very large weight reductions – according to the publication, 83% of those on the 12 mg dose lost at least 15% of their body weight, and over 75% achieved ≥20% weight loss by week 48. These are extraordinary figures in obesity pharmacotherapy.

While the Phase 2 trial was primarily focused on weight outcomes (and included only people without diabetes), it also reported improvements in glycemic measures. Many participants had prediabetes at baseline, and retatrutide significantly reduced blood glucose levels and improved insulin sensitivity during the trial. In fact, the triple-agonist properties suggest that if a person with type 2 diabetes took retatrutide, they would likely see substantial glucose lowering – similar to tirzepatide or even better, though formal trials in diabetes are ongoing.

Lilly has initiated Phase 3 trials (named TRIUMPH) to test retatrutide in various populations, including those with type 2 diabetes and those with cardiovascular disease. So far, the early data indicate that retatrutide could be a true all-in-one metabolic treatment, addressing obesity, diabetes, and even fatty liver disease simultaneously. It’s hard to overstate the potential impact if these results hold up in larger studies.

Safety and Side Effects

With great power, of course, can come side effects. Retatrutide’s side effect profile in Phase 2 was broadly similar to that of GLP-1 and dual agonist therapies, with gastrointestinal symptoms being the most common. Almost all the usual suspects were observed: nausea, vomiting, diarrhea, constipation – and these were generally dose-related (higher doses had more frequent GI issues). Most of these effects were mild or moderate in severity and tended to occur during the dose-escalation period, just as seen with semaglutide/tirzepatide.

The study actually tested two different titration regimens (some groups started at a lower initial dose of 2 mg vs others at a higher 4 mg) to see if side effects could be mitigated. The findings suggested that starting at a lower dose helped reduce GI side effect severity – which is good news, because it means a slow ramp-up could make retatrutide better tolerated. Only a small number of participants dropped out due to side effects, indicating most people managed to continue the medication despite some nausea or GI discomfort.

One side effect more unique to retatrutide (and potentially related to its glucagon activity) was a slight increase in heart rate observed in some patients. In the trial, they noted dose-dependent increases in resting heart rate, which peaked by about 24 weeks and then declined thereafter. This transient rise in heart rate has also been noted with pure GLP-1 agonists, but it appeared a bit more pronounced with retatrutide initially. By the end of the study, the heart rate had come back down closer to normal, suggesting the body might adapt over time. Nonetheless, this will be something for longer-term studies to watch, especially in patients with heart conditions. The exact cause isn’t certain, but it may relate to glucagon’s effect (glucagon can increase heart rate and blood flow as part of its metabolic stimulation).

Beyond that, retatrutide would carry the same precautions as the other drugs – e.g., avoid in those with a history of medullary thyroid carcinoma (until more is known), use caution if a patient has pancreatitis history, etc. Thus far, no new safety red flags have emerged. It’s encouraging that side effects were manageable and mostly temporary in the Phase 2 trial, given the magnitude of benefit. Of course, retatrutide is still investigational – it will likely be a couple of years before it could be approved (pending successful Phase 3 outcomes). But if it does get approved, patients will need careful monitoring at the start to ensure tolerability.

In summary, retatrutide looks like a powerful triple-threat against obesity: it powerfully curbs appetite, significantly boosts calorie burn, and improves metabolic health. Its clinical trial results so far suggest a potential for even greater efficacy than the dual-agonist tirzepatide. The side effect profile, while significant (notably GI issues), appears manageable with proper dosing strategies. Many in the medical community are watching retatrutide’s development closely, as it could represent the next big leap in peptide therapy for obesity and diabetes – truly pushing the envelope of what’s achievable without surgery.

Comparative Efficacy and Side Effects of Semaglutide, Tirzepatide, and Retatrutide

Each of these GLP-analog therapies has shown remarkable results in clinical trials, but there are important differences in their potency and profiles. Below is a comparative look at how GLP-1 (semaglutide), “GLP-2” (tirzepatide), and “GLP-3” (retatrutide) stack up:

Weight Loss Efficacy

All three peptides lead to significant weight loss, but retatrutide appears to be the most potent to date. Semaglutide 2.4 mg (GLP-1 alone) helped people lose about 15% of body weight on average over ~68 weeks. Tirzepatide (dual GIP/GLP-1) showed roughly 20% average weight loss at the highest dose over ~72 weeks – with some individuals losing over 22% of their weight. Retatrutide (triple agonist) upped the ante further, with about 24% average weight loss at 48 weeks (12 mg dose) and ~22% at 8 mg.

It’s plausible that with a longer duration (say 72 weeks or more), retatrutide’s numbers could climb even higher, potentially reaching the high-20s in percentage weight loss. In short, semaglutide < tirzepatide < retatrutide in terms of average weight impact, based on trial data so far. Another way to look at it: semaglutide helped many lose 10–15% of weight, tirzepatide pushed that to the 15–20%+ range, and retatrutide is moving towards 20–25%+ loss in a year. All of these are hugely beneficial from a health standpoint – even a 5–10% weight loss can improve metabolic health – so these drugs are achieving 2–5 times that benchmark for many patients.

Glycemic Control

For people with type 2 diabetes, all three therapies can dramatically improve blood sugar control, but tirzepatide has shown the greatest impact in head-to-head comparisons. Semaglutide is a powerful glucose-lowering agent – it can bring down HbA1c by ~1.5–1.9% and often gets patients to goal (HbA1c <7%). Tirzepatide, with its dual action, typically lowers HbA1c even further (in one trial, –2.3% on tirzepatide 15 mg vs –1.9% on semaglutide over 40 weeks). In fact, tirzepatide was shown to be superior to semaglutide in reducing HbA1c and body weight in a large diabetes trial.

A higher proportion of patients on tirzepatide achieved rigorous targets like HbA1c <6.5% (near normal levels) compared to those on semaglutide. Tirzepatide’s ability to stimulate insulin via both GIP and GLP-1 means it can effectively lower both fasting and post-meal glucose.

Retatrutide has not yet been tested in a large diabetes trial, but Phase 2 results in non-diabetic individuals showed improved fasting glucose and insulin sensitivity. Given retatrutide’s mechanism, we expect robust glucose lowering as well – likely on par with tirzepatide – but with a caution: the glucagon receptor activation could raise blood sugar if the insulin effect doesn’t balance it. So far, in the obesity trial, retatrutide did lower blood glucose, suggesting the balance is right. Upcoming trials in diabetes (TRIUMPH-2) will clarify how it compares. Overall, semaglutide and tirzepatide are already proven diabetes drugs, with tirzepatide having an edge in efficacy. Retatrutide is poised to join them, potentially offering similar or even better glycemic control if the triple-agonist synergy works as intended.

Appetite Suppression and Metabolic Effects

All three peptides work on the brain’s appetite control centers to reduce hunger, but patients often describe a stronger appetite suppression with tirzepatide than with semaglutide, and potentially even stronger with retatrutide. This aligns with the incremental addition of hormone pathways.

Semaglutide significantly curbs appetite – many people on it feel full faster and have reduced cravings, which is a big factor in its weight loss effect. Tirzepatide users frequently report an even greater effect: feeling full on smaller meals and sometimes even forgetting to eat, as the drive to snack diminishes. With retatrutide, early reports suggest a profound dampening of appetite plus a sense that the body’s engine is revving higher (some patients in trials noted feeling warmer or having a higher resting heart rate, consistent with increased thermogenesis from glucagon).

Another metabolic effect is energy expenditure – semaglutide mainly works by decreasing intake, and doesn’t significantly increase how many calories you burn (in fact, the body tends to reduce energy expenditure slightly with weight loss). Tirzepatide’s impact on energy expenditure isn’t fully clear; it likely doesn’t drastically increase it either (most of its effect is also via intake reduction). Retatrutide, on the other hand, may uniquely increase caloric burning thanks to the glucagon component, helping counteract the body’s natural tendency to resist further weight loss. This could be a crucial difference, helping patients overcome weight-loss plateaus.

Side Effect Profiles

There is a lot of overlap in side effects among the three drugs, given their shared pathways, but a few distinctions:

Gastrointestinal Side Effects

Nausea, vomiting, diarrhea, constipation, and indigestion are common to all. Semaglutide and tirzepatide have very similar rates of these GI side effects. Retatrutide also causes GI symptoms, and at higher doses a greater proportion of patients experienced these (as expected with more potent effects). However, using a gradual dose escalation dramatically helps – for instance, starting retatrutide at 2 mg instead of 4 mg reduced nausea incidence.

In practice, all these medications are introduced slowly (over weeks to months) to improve tolerability. By the time patients reach full dose, many of the early GI side effects have diminished. It’s important to note that individual tolerance varies: some people feel only mild nausea for a short time, others might have more persistent stomach issues. Staying hydrated, eating smaller meals, and avoiding very rich or greasy foods can help manage symptoms.

Other Common Side Effects

Some patients on these peptides experience headaches, fatigue, or a slight dizziness occasionally, especially early on. These tend to be transient. With tirzepatide and retatrutide (less so with semaglutide), a portion of patients report mild injection-site reactions (redness or itching where the shot was given) and sometimes short-lived immune reactions (like a runny nose or minor cold-like symptoms) – possibly due to the body reacting to a foreign peptide. These effects are generally minor. As mentioned, hair thinning has been reported with the rapid weight loss from tirzepatide and retatrutide (and to some extent semaglutide as well), but this is usually temporary and can be managed.

Unique to Retatrutide

Increased heart rate was noted with retatrutide at higher doses. While GLP-1 drugs can raise heart rate by ~2–3 beats per minute, retatrutide’s glucagon activity might amplify this initially. Fortunately, it seems to level off over time, but patients on retatrutide might notice their heart beating slightly faster at rest during the first months. This will need monitoring in long-term studies, especially for those with cardiovascular conditions.

Risk of Hypoglycemia

Interestingly, even though these drugs improve blood sugar, when used alone (without other diabetes meds), they have a low risk of causing hypoglycemia. This is because they only boost insulin in the presence of nutrients/glucose. Semaglutide and tirzepatide in trials had hypoglycemia rates similar to placebo, unless combined with a sulfonylurea or insulin (which can cause lows). Retatrutide, by virtue of also having glucagon activation, might actually have an inherent safeguard against low blood sugar (glucagon raises sugar if it dips). So, paradoxically, retatrutide may have very low hypoglycemia risk on its own – though if someone is on insulin or other meds, careful adjustment is needed to avoid lows as their blood sugar improves.

Serious Rare Risks

All three drugs will have the class warning about thyroid C-cell tumors from rodent studies (again, no evidence in humans so far). Pancreatitis is a rare risk; a history of pancreatitis is usually a precaution for these drugs. Gallbladder issues (like gallstones or inflammation) can occur from rapid weight loss; in fact, the more rapid the weight loss (as with tirzepatide and retatrutide), the more one has to be mindful of gallstone formation. Doctors sometimes check in on gallbladder symptoms or use medications like ursodiol for prevention in high-risk patients losing weight fast.

Lastly, there have been isolated reports of mood changes (some people report improved mood/energy with weight loss, while a few have noted feelings of apathy or slight changes in how food reward is perceived – since these drugs interact with brain areas related to reward and appetite). These are areas of ongoing observation, but no clear causal link to serious mood disorders has been established.

Availability and Use

Semaglutide and tirzepatide are already available by prescription (with semaglutide approved for both diabetes and obesity, and tirzepatide for diabetes and very recently for obesity). Retatrutide is still in clinical trials, so it’s not yet accessible outside of a trial setting. Experts anticipate that if Phase 3 trials are successful, retatrutide could be up for regulatory approval in a couple of years.

In terms of how they’re used: all are once-weekly injections, typically into the abdomen or thigh, with tiny needles. Semaglutide is also unique in that it has an oral tablet form (Rybelsus) for type 2 diabetes, taken daily – though the injection is more effective for weight loss. Tirzepatide and retatrutide, due to their larger molecule size and multi-receptor action, are injections only. When comparing convenience, all weekly shots are similar; patient preference may come down to how easy the pen device is to use and, of course, availability/insurance coverage. Cost can be a factor: these are advanced biologic medications and can be expensive, though insurance often covers them for approved indications (diabetes, and increasingly obesity as it’s recognized as a chronic disease).

Comparative Bottom Line

Semaglutide, tirzepatide, and retatrutide form a trio of increasingly potent peptide therapies. Semaglutide (GLP-1 agonist) set the stage with robust weight loss and glucose control, tirzepatide (dual GIP/GLP-1 agonist) built on that with even greater results (earning nicknames like the “game changer” in obesity treatment), and retatrutide (triple agonist) is emerging as possibly the most powerful yet, pending further research.

Side effects are a consideration for all, but largely manageable, and the risk/benefit tilts in favor of significant health improvements. Choosing between them in the future may come down to how much weight loss is needed, patient tolerance, and access. Some people may achieve their goals with semaglutide and not need the “big guns” of a triple agonist, whereas others with severe obesity or harder-to-control diabetes might benefit from the extra boost of tirzepatide or retatrutide. It’s truly a remarkable time in medicine, as we now have tools to induce weight loss and metabolic changes that were once thought to be only possible through surgery.

Conclusion: The Peptide Therapy Revolution and Valor Sciences’ Mission

The advent of GLP-1 analogs and their successors marks a revolution in peptide therapy for metabolic diseases. By harnessing hormones that naturally regulate appetite and blood sugar, drugs like semaglutide, tirzepatide, and retatrutide are enabling patients to achieve health outcomes that were previously unattainable with medications alone. These aren’t magic bullets or standalone cures – patients still benefit from healthy diets and exercise – but they dramatically improve the biological playing field, allowing individuals to lose substantial weight, keep blood sugars in check, and reduce risks of complications.

The ripple effects are enormous: better control of diabetes, lower rates of heart disease, potential improvements in fatty liver and even reduced wear-and-tear on joints from weight reduction. This is why there’s such tremendous excitement and research investment in this area.

The success of semaglutide, tirzepatide, and retatrutide underscores a broader lesson: by targeting the body’s own cellular communication system (hormones and receptors), we can unlock new levels of therapy. As we move forward, Valor Sciences remains committed to driving such breakthroughs and educating the public about them. These GLP-1 related peptides are just the beginning; many more innovative peptides are in development for a range of conditions. With each discovery, we get closer to safer, more effective solutions for health challenges that have long plagued society.

In summary, the rise of GLP-1, GLP-2, and GLP-3 analogs is a shining example of the promise of peptide science – a promise that Valor Sciences is proud to be a part of, as we look toward a healthier future powered by peptides.

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Sources

1. Wilding J.P.H. et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity – New England Journal of Medicine
2. Frias J.P. et al. (2021). Tirzepatide versus Semaglutide in Type 2 Diabetes (SURPASS-2 Trial) – New England Journal of Medicine
3. American Diabetes Association Press Release (2022). SURMOUNT-1: Tirzepatide in Obesity – ADA Newsroom
4. Jastreboff A.M. et al. (2023). Triple-Hormone Receptor Agonist Retatrutide for Obesity – Phase 2 Trial – New England Journal of Medicine
5. Sanyal A.J. et al. (2024). Retatrutide for Fatty Liver Disease (MASLD) – Nature Medicine (sub-study of retatrutide Phase 2 trial)
6. Lilly Investor/Press Statement (2023). Quoted comment by Dr. Dan Skovronsky on Retatrutide’s triple agonism and weight reduction
7. GoodRx Health (2025). “Tirzepatide’s Mechanism of Action: 7 Ways It Works” – K. Carter, PharmD
8. Nature Review (2024). GLP-1 Receptor – mechanisms and therapy – highlights GLP-1 actions (insulin release, glucagon suppression, appetite)
9. Fred Hutch News Service (2024). “The new weight-loss drugs and cancer” – D. Mapes. (Explains how semaglutide mimics GLP-1 and induces fullness, and notes FDA boxed warnings)