Just when we all thought Tirzepatide (Mounjaro) was an amazing weight & fat loss peptide, medicine continues to evolve & here we are at the new and improved version called Retatrutide & Pemvidutide. These medications have all the benefits of Tirzepatide, including the weight/fat loss component. In addition, Retatrutide offers anti-aging properties. Yes! You heard us correctly; anti-aging! This triple effect will help with appetite suppression, weight/fat loss, & anti-aging! Do we have your attention now? Pemvidutide has the capability to significantly reduce body weight, liver fat content & serum lipids are an unmatched profile relative to other obesity & MASH drugs. Let’s work through the differences between Semaglutide, Tirzepatide, & now Retatrutide & Pemvidutide.
Retatrutide & Pemvidutide are a triple agonist, which means they act on GLP-1R, GIP-R, & glucagon receptors (GCGR). Structurally, they are nearly identical to Tirzepatide. Retatrutide is also a 39 amino acid modified GIP molecule, but with changes to the amino acid structure to allow for activity at the GCGR site to achieve triple agonist activity at the GLP-1R, GIP-R, & GCGR. Here is a more in-depth explanation of each one:
- Glucagon-like Peptide Receptor-1 (GLP-1R): When this receptor is activated, it slows the speed at which the stomach empties. Slower stomach emptying signals the brain to eat less, helping to manage weight.
- Gastric Inhibitor Peptide Receptor (GIP-R): This receptor, also known as the glucose- dependent insulinotropic polypeptide receptor, is found in the brain & throughout the digestive system. It plays a vital role in controlling hunger by telling the brain when the stomach is full.
- Glucagon Receptor (GCGR): This receptor is mostly found in the liver & kidneys. Retatrutide and Pemvidutide can boost the production of glucagon, a hormone that helps break down stored energy like fat & sugar. This increases the body’s basic metabolism, even when sleeping, leading to overall weight loss, specifically targeting fat.
Retatrutide is 8.9-fold more potent at GIP-R than human GIP!! This drug is significantly more potent than Tirzepatide at GIP-R agonism which means it further enhances any of the GIP-R AND GLP-1 effects in a synergistic manner.
Continuing on, it is 2.9-fold less potent than human glucagon & 2.5-fold less potent than human GLP-1. Therefore, this drug is an imbalanced GIP agonist, but balanced when comparing GLP-1 & GCGR activation. This is important for multiple reasons including fewer side effects, positive cardiovascular effects, & allowing GLP-1R & GCGR to work together.
Now let’s focus on the GLP-1 component. Comparisons to Semaglutide are not necessarily going to be accurate & the research has not been done yet. However, we could speculate that about 6mg of Retatrutide would have the same level of GLP-1 agonist as 1mg of Semaglutide. We need someone to actually do that research first,which probably won’t happen until the Phase 3 Trials for Retatrutide are over, but even that isn’t a fair comparison because of the GCGR activity.
The GCGR part, along with the heavy GIP-R potency, are probably the real secret sauce here. Let’s quickly review what glucagon does in our body. If you took any high school or college level biology class, you know that glucagon is the ying to insulin’s yang; the two counterbalance each other. When your blood sugar drops, your body will start cranking out glucagon, & vice versa. When blood sugar is high, glucagon is suppressed. However, we are discovering that it does FAR more than that.
Glucagon increases heart rate & cardiac output/contractility while lowering pulmonary vascular resistance. If this sounds like a performance enhancement for exercise, you are correct, except that native glucagon is rapidly degraded by our body within minutes. The catch is that you don’t want high doses of glucagon because it will crank your heart rate up. This is why every drug company running a trial with GCGR agonism is being so hypervigilant about cardiac side effects. It is also why it’s not a bad thing that Retatrutide is less potent than glucagon. Allowing dose escalation to happen slowly allows tachyphylaxis to occur & allows our bodies to adjust to it. Tachyphylaxis is why most people eventually have less side effects with GLP-1 drugs; their body quite literally gets used to the drug so you don’t experience the side effects at the same intensity. It may also explain why some folks switching between these drugs may not notice the “effects” as intensely as when they first took a GLP-1 drug.
Like GLP-1, it increases satiety by slowing gastric emptying & changing our appetite preferences. Just like GLP-1, it can cause nausea. This is why the anti-nausea effects that occur from the GIP-R agonism found in Retatrutide are so critical.
Most importantly, glucagon has a multitude of effects on the liver as well as brown and white adipose tissue (aka fat). In the liver, it increases liver cell survival while increasing lipolysis. This process creates free fatty acids, which our body then turns into ketones for energy. In fat cells, it increases thermogenesis and lipolysis, further driving the conversion of free fatty acids to ketone bodies. It’s literally FORCING your body to burn excess fat. Most studies will tell you this effect is probably in the neighborhood of an extra 150-200 calories of excess energy expenditure per day. It is likely why people in the Phase 2 study were still dropping weight. Just think, 200 calories a day is nothing to sneeze at. That is 1400 calories a week! This is probably why we are seeing such substantial weight loss with Retatrutide. The synergistic effect of the imbalanced agonism is working in such a way that it maximizes the benefits of each incretin hormone while significantly reducing the side effects.
Pemvidutide is another peptide-based GLP-1/glucagon dual receptor agonist. It is in development for the treatment of obesity & metabolic dysfunction-associated steatohepatitis (MASH). What is MASH you ask? The Cleveland Clinic states this: Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of your liver caused by excess fat cells in it (steatotic liver disease). Chronic inflammation causes progressive liver damage. MASH resembles hepatitis caused by alcohol use, but it stems from something else. It’s most often associated with overweight, high blood lipids, & high blood sugar.
Activation of the GLP-1 & glucagon receptors in Pemvidutide is believed to mimic the complementary effects of diet & exercise on weight loss, with GLP-1 suppressing appetite & glucagon increasing energy expenditure. As we have said before, glucagon has a direct effect on hepatic fat metabolism, leading to rapid reductions in levels of liver fat & serum lipids. Trials have shown compelling weight loss, robust reductions in triglycerides, LDL cholesterol, liver fat content, & blood pressure. This medication will progress to late-stage trials, the last step before its maker seeks FDA approval.
In clinical trials, Pemvidutide helped subjects drop more than 15% of their body weight, with less muscle loss than rival GLP-1 drugs. Those taking Pemvidutide experienced no changes in fasting blood sugar or A1C. That makes Pemvidutide different from Semaglutide & Tirzepatide, which were originally developed to treat type 2 diabetes. It’s the glucagon component! Glucagon, by making the liver make glucose, raises blood sugar. The GLP-1 reduces sugar. The two hormones appear to cancel each other out.
Health Benefits of Retatrutide & Pemvidutide:
- Weight management: obesity is a severe condition that affects a 1/3 of the American population. Obesity can lead to weight-related conditions such as diabetes, PCOS, heart disease, and more. Tirzepatide is a powerful tool for weight control & Retatrutide and Pemvidutide promises to match, if not exceed, these benefits.
- Type 2 diabetes: both drugs are highly efficient for the treatment of type 2 diabetes mellitus. Individuals with diabetes are prompt to have high blood sugar levels, which present a threat to their health. Tirzepatide & Retatrutide help patients to achieve & maintain healthy blood glucose levels. Pemvidutide appears to have these hormones cancel each other out.
- Anti-inflammatory properties: Retatrutide & Pemvidutide exert potent anti-inflammatory effects through multiple mechanisms. They inhibit the activation of nuclear factor-kappa B (NF-κB), which is a master regulator of inflammation. These anti-inflammatory properties contribute to its efficacy in mitigating inflammatory conditions such as rheumatoid arthritis & inflammatory bowel disease.
- Cardiometabolic conditions: at the highest dose, Tirzepatide has shown to improve cholesterol. Some studies also suggest this drug can help with blood pressure. In the latest studies, both Retatrutide & Pemvidutide proved to have the potential to aid with cardiometabolic improvements, such as blood pressure, cholesterol, fasting glucose, glycated hemoglobin, & triglycerides.
- These cardioprotective properties make both of these new medications a promising therapeutic agent for preventing & managing cardiovascular disease such as heart attack, heart failure, & atherosclerosis-associated events such as stroke.
- All of these drugs are the same but very different so please do not try to compare doses. There is no 1:1 comparison because they’re all different drugs. Yes, Retatrutide & Tirzepatide are incredibly similar but that glucagon agonism makes a literal whole world of difference.
- PCOS: polycystic ovary syndrome (PCOS) is a health condition deeply connected to obesity. This condition affects women during their childbearing years; the body produces too much of the androgen hormone. This hormonal disbalance can lead to insulin sensitivity, type 2 diabetes, subfertility, & obesity. Recently, experts started studying Mounjaro (brand name Tirzepatide) and Ozempic (brand name Semaglutide) for PCOS treatment. Retatrutide will likely also be suitable for PCOS improvement.
- Neuroprotective effects: Retatrutide exhibits neuroprotective effects through its ability to modulate neuronal survival & synaptic plasticity. It promotes the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), supporting neuronal growth & function. Additionally, neuroprotective effects offered by Retatrutide make it a potent treatment option for neurodegenerative disorders such as Alzheimer’s Disease & Multiple Sclerosis.
Other added Benefits:
- Wound healing: Retatrutide & Pemvidutide accelerates wound healing by promoting angiogenesis, collagen synthesis, & epithelialization. It stimulates the proliferation & migration of endothelial cells, leading to the formation of new blood vessels & improved tissue perfusion. It also enhances the deposition of extracellular matrix proteins such as collagen & fibronectin, which are essential for wound closure & tissue remodeling. It also accelerates the healing of acute & chronic wounds, including diabetic ulcers, & pressure sores.
- Immunomodulatory effects: Retatrutide modulates immune responses by regulating the activity of immune cells & cytokine production. It enhances innate immune surveillance by promoting phagocytosis & antigen presentation, leading to improved pathogen clearance. The immunomodulatory effects make this medication a promising treatment agent for autoimmune diseases, infectious diseases, & immune-mediated conditions such as allergies & asthma.
- Muscle growth & repair: Retatrutide stimulates muscle growth & repair by activating satellite cells, which are responsible for muscle regeneration. It promotes the proliferation & differentiation of satellite cells into mature myofibers, leading to increased muscle mass & strength. Additionally, Retatrutide enhances protein synthesis & inhibits protein degradation, thereby promoting muscle hypertrophy & reducing muscle wasting. These are valuable tools for athletes seeking to enhance muscle recovery, performance, & adaptation to training. Pemvidutide also minimized the loss of muscle mass, which other rival medications didn’t seem to do so well.
- Anti-aging properties: Retatrutide counteracts cellular aging processes by mitigating oxidative stress, DNA damage, & cellular senescence. Additionally, Retatrutide promotes DNA repair mechanisms & inhibits the accumulation of senescent cells, thereby delaying age-related functional decline. These anti-aging properties contribute to its potential to extend a healthy lifespan & improve the overall quality of life in our ever-aging populations.
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- Pemvidutide also helps with MASH, a liver condition known as MASLD. Pemvidutide’s GLP-1/glucagon dual agonism could have additive effects on MASH resolution & fibrosis improvement compared with GLP-1 alone. Pemvidutide not only has meaningful weight loss in addition to the liver effects.
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Side effects of Retatrutide & Pemvidutide:
In clinical trials, the most common side effects were nausea, low blood sugar, diarrhea, constipation, vomiting, headache, decreased appetite, upset stomach, fatigue, dizziness, & abdominal pain. With the right medical guidance & nutrition, many of these can be reduced or eliminated. With All U Health’s extensive experience with these peptides, we are available to discuss all the options available for your weight loss journey. Our goal is to develop a plan that works with your lifestyle & offers affordable options for you to choose from. We only partner with FDA registered pharmacies that maintain the highest level of quality control & that only use raw materials that are tested. Don’t fall for the cheaper, no prescription needed ads/clinics as this means the medication is for “research purposes only”. If you have any questions, you may call or text us at 480.939.4669 and we will respond promptly. We can only ship medications within the United States.
To read our other blog on both Tirzepatide & Semaglutide, click here:
https://www.alluhealth.com/optimal-weight-loss-peptide/
How the process works at All U Health:
- Start your weight loss journey today by calling All U Health and scheduling your consultation with one of the medical providers. Since these are prescription drugs, you will be unable to purchase them on-line, they must be in a script form written from a medical provider. (call/text 480.939.4669)
- Appointments can be conducted in person or virtual via phone call.
- No blood testing is needed for peptide prescriptions.
- Medications are shipped directly to you from the pharmacy.
- Call or text when refills are needed.
- All U Health does NOT take insurance or coupons but you may use your HSA or FSA cards.
- Utilizing machines that measure both weight & body fat will be a great tool for you to use. If you don’t have something at home, most fitness centers offer them free of charge.
- Most scales don’t differentiate between weight/fat loss & muscle loss, for that reason, tracking only your weight isn’t a reliable way to determine whether you’re losing weight, fat, or muscle & in what amounts
- Conversely, a body fat scale can provide a more accurate picture of your body composition by measuring the percentage of all components
- Be sure to measure yourself on a weekly or bi-weekly schedule to understand the changes that are happening. Know that every time you fluctuate. Do not get discouraged, the medication is still working.
- We suggest that you take monthly progress photos of you in the same outfit, front, side, side, back. This will be a great physical indicator of your progression.
Common Questions:
- Are there check-ins?
- No check-ins are necessary
- Do I need to come to the clinic to receive medications?
- All medications are made to order from our compound pharmacy & shipped directly to you
- Does the medication need to be refrigerated after it is received?
- Yes
- If the cold pack is not cold upon receiving the medication it is still good to use as it shipped this way to maintain an even temperature during shipping
- Do I take the medication on an empty stomach?
- They may be taken 30 minutes before the first food, drink, or other oral medications
- Listen to your body, you may need to take the medication before bed, everyone is going to be slightly different
- How often do I take the medication?
- Once weekly injection
- Where are the injections done?
- Administered SubQ (subcutaneously)
- How long will it take to lose weight?
- You may start to feel the effects the same day of medication and body composition changes start to happen within 1-2 weeks on average
- Weight loss refers to a decrease in your overall body weight from muscle to water, whereas fat loss refers to weight loss from fat, and it is a more specific & healthful goal than weight loss
- Can I do a combination of Retatrutide, Semaglutide, & Tirzepatide?
- There is no reason to combine these medications as they target the same receptor so you would just be engaging in overkill with no additional benefits
- However, there are times when you can add additional or stack peptides such as CJC 1295/Ipamorelin, AOD 9604, or MOTS-C, although these would need pre-approval from one of our medical providers
- How do I avoid GI (gastrointestinal) upset?
- Increase medications gradually over time to minimize any GI side effects
- GI upset usually occurs days 3-5 after dosing & is common with overeating or not eating the correct food
- What if I miss a dose?
- Simply take the medication & change your dosing day
- Will I gain weight back if I stop taking the medication?
- Yes, if there have been no modifications to your diet, exercise, & lifestyle
Sources: LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept – ScienceDirect
https://www.sciencedirect.com/science/article/pii/S1550413122003126?via%3Dihub#sec1
Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2301972
https://www.nejm.org/doi/full/10.1056/NEJMoa2301972
Pemvidutide graph:
https://altimmune.com/pemvidutide/
The novel GIP, GLP‐1 and glucagon receptor agonist Retatrutide delays gastric emptying – Urva – 2023 – Diabetes, Obesity and Metabolism https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15167
Hemodynamic Effects of Glucagon: A Literature Review | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic https://academic.oup.com/jcem/article/103/5/1804/4931669
Day 1 – Video 4: GLUCAGON ACTION THE KNOWN UNKNOWNS by Daniel Drucker https://www.youtube.com/watch?v=4U0OorK9Gb4