Honestly IMO you looked better/healthier in the 1st photo, but I guess if you’re a competitive bodybuilder (or aspiring to be one) then the 2nd photo is more what they’re looking for. Are you losing hair from exogenous androgens, or just a shorter haircut?
What do you mean? You had worse side effects on 2mg than 4mg??
Two milligrams was fine the worst dose for me -really relative- was 6mg. The higher you go in my personal experience the more glucagon is activated and counteracts the sides of the GLP1/GIP agonism.
Really not to be honest, what you can think was fat was at least 25% water retention, I was heavy and was breathing heavily. I can do cardio without issue and I can walk breathing with my nose again.
Absolutely no hair loss I just shaved my hair!
When body fat drops too much your face take a hit and you can look older/less healthy but it’s normal, fat face/water goes away.
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Max dose of tirz in trials was 15mg. What does this say about reta?
Corrected above. Good catch @Kelman
The Docs Who Life podcast had a nurse practitioner (some of you may know him) who was in the initial Reta trial discussing this, very informed discussion about relative doses and more.
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Extreme high doses of Semaglutide have been tested. As have other GLP1’s. That’s part of determining the safety profile.
Since all GLP1’s are dose dependent in performance with respect to weight loss, the max dose is determined by prevalence and severity of the common side effects of nausea, constipation and diarrhea, these parameters are part of how the max dose of GLP1’s are determined.
Example
For weight loss with Semaglutide the dose range is
0.24mg to 2.4mg per weekly dose.
Studies have been done that showed progressively greater weight loss up to 7.2mg per weekly dose but the sides were more common and more severe for some people but not all.
These common sides are what determines the max tolerable dose.
Semaglutide is approved in some places for use up to that tested 7.2mg per weekly dose.
One thing about GLP1’s and hypoglycemia, they do not cause hypoglycemia as they are “responsive” to glucose and do not over compensate. They are not like taking too much insulin.
I know a guy who accidentally did a double max dose (12mg x 2 = 24mg) of Reta. He had zero side effects other than losing 5lb that week.
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My guess is once you have agonized all the receptors you can increase the dose and it won’t do much.
12 to 15mg and I don’t really feel much of a difference. Same when I was on tirzepatide, I used to go up to 20mg (probably 22mg even, that was the level of the vial tested) and it was not really different.
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What about the sympathetic tone response? My heart rate is up and HRV tanked at 2 mg. Feeling pretty 
on it but trying to persevere. It’s my understanding that those side effects are dose dependent so in a sensitive person like I clearly am, taking a 24 mg dose might give me a cardiac event.
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My body has gotten used to the medicine. and I’ve been able to scale to a higher mg on reta.
First many months, just took out my appetite, but now my appetite feels close to normal and I am getting my calories/sustenance in at a high dose with no problems… and gain back some of the muscle I lose with my intense initial weight loss
Yes, it has in combination with the rest of my stack taken me to near hypotension, but the near hypotension hasn’t resulted in worse blood work for me so I’m just winging the theory that without symptoms near low blood pressure aint all that bad (like waking up with 90/60 reads - 100/70 daytime), and actually, fingers crossed, might be healthy
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Hello
How much reta week? I’m currently at 15mg!
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8mg… wow… 15, what prompted you to go so high?
I feel as if we need to bring up dosing and its benefits into the discussion more (that I have seen so far personally I should say)… there are a lot of theories on it…
It seems that at 15mg you get almost 100% of the glucagon activity from the retatrutide, so I wanted to try. Definitely stronger on the appetite suppression but sides effect are inexistant for me. I feel great.
I’m starting to be very lean 7-8% BF maybe so I might become less sensitive to the effect.
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I do agree retatrutide is a potent blood pressure reducing drug and in my case, I’m just on 2mg and not losing weight since I don’t have much to lose so it’s a direct drug effect.
Is there a reason you like Reta over Tirzepatide? I’ve done both, and prefer Tirzepatide more. Both increase my RHR, but Reta is noticeably higher. Tirzepatide helps with appetite suppression and food noise beta than Reta for me. There are other compounds that can combat that though.
On the flip side, Gastric emptying is a little bit less of an issue with Reta. And weight certainly drops off faster.
Just to share an n=1 on glp1s and heart rate.
This morning I did a deep dive with Fable (Claude).
He fetched my Oura history from when they created the website in 2021. My heart rate went up 3 bpm when I started semaglutide. It quickly stabilized.
I found it interesting to learn it never went any higher after switching to TZ or RT.
I’ve never been on a high dose on any of the 3, but I was pleasantly surprised to learn RT had zero additional effect.
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Retatrutide vs Semiglutide & Tirzepatide: Should YOU Actually Take It? (via Quinn Stillson MD)
I. Executive Summary
The analyzed discourse evaluates the therapeutic profile of retatrutide—a novel, synthetic 39-amino-acid triple agonist peptide developed by Eli Lilly—against established incretin therapies, specifically semaglutide (a selective GLP-1 receptor agonist) and tirzepatide (a dual GLP-1/GIP receptor agonist). Emerging data from phase III trials demonstrate that retatrutide achieves unprecedented weight reduction, averaging 28.7% total body weight loss at 68 weeks with the highest dose. Mechanistically built upon a gastric inhibitory polypeptide (GIP) structural backbone, retatrutide simultaneously co-activates three distinct receptors at asymmetric potencies: it acts as a hyper-potent agonist at the GIP receptor (8.9 times endogenous potency) while functioning as a lower-potency biased agonist at the glucagon receptor (30% potency) and the GLP-1 receptor (40% potency). Its biased GLP-1 receptor agonism selectively activates the intracellular G-protein/cAMP cascade while minimizing beta-arrestin recruitment, theoretically mitigating receptor desensitization.
Despite its exceptional efficacy in inducing mass reduction and profound clearing of hepatic steatosis (an 82% reduction in liver fat within 24 weeks), a critical translational and safety gap emerges when evaluating retatrutide for broader healthspan and longevity optimization in non-obese cohorts. The continuous pharmacological activation of the glucagon receptor introduces complex metabolic tradeoffs. While it drives hepatic fatty acid oxidation, decreases lipid synthesis, and downregulates the PCSK9 enzyme to achieve dramatic reductions in circulating LDL-C and triglycerides, it simultaneously accelerates hepatic amino acid catabolism. This catabolic pathway raises concerns regarding potential inhibition of muscle protein synthesis and acceleration of lean mass loss, which currently mirrors semaglutide’s profile (~36% of total weight lost derived from lean mass in diabetic cohorts).
Furthermore, retatrutide exhibits a unique and potentially concerning cardiovascular and immunological fingerprint: it does not significantly elevate cardioprotective HDL-C, suppresses diastolic blood pressure reduction, induces a transient but substantial increase in resting heart rate (+6.7 beats per minute), and significantly elevates the risk of cardiac arrhythmias (11% to 14% incidence) and dysesthesia (20.9% incidence at peak doses). From a direct geroscience perspective, independent of weight loss, selective GLP-1 activation mirrors rapamycin-like longevity signatures by downregulating mTOR and upregulating autophagy. Conversely, retatrutide’s hyper-potent GIP activation suppresses sirtuin 1 (SIRT1), potentially undermining key longevity pathways in leaner individuals. Because its cardiovascular outcomes trial will not conclude until 2029–2030, and its published literature base is 30 to 60 times smaller than tirzepatide and semaglutide respectively, retatrutide remains an experimental compound whose organ-level risks outweigh its benefits in non-obese or cardiomechanically vulnerable populations.
II. Insight Bullets
- Triple Receptor Agonism Architecture: Retatrutide is a synthetic 39-amino-acid peptide engineered to simultaneously stimulate GLP-1, GIP, and glucagon receptor signaling cascades.
- Structural GIP Dominance: Despite being grouped into the general GLP-1 class, retatrutide is structurally derived from an endogenous GIP backbone, making it chemically distinct from native GLP-1 molecules.
- Asymmetric Activation Potencies: Retatrutide exhibits highly asymmetrical receptor kinetics, firing GIP at 8.9 times native potency, while hitting GLP-1 at 40% and glucagon at 30% native potency.
- Biased Agonism Mechanics: At the GLP-1 receptor, retatrutide acts as a biased agonist, preferentially activating the therapeutic G-protein/cAMP pathway while minimizing the desensitizing beta-arrestin pathway.
- Enzymatic Stabilization and Extension: Retatrutide combines a position-2 amino acid substitution to block dipeptidyl peptidase-4 (DPP4) degradation with a position-17 fatty acid chain to facilitate reversible albumin binding, extending its half-life to 6 days.
- Continuous vs. Pulsatile Signaling: Unlike endogenous incretins that discharge in brief physiological pulses, retatrutide imposes chronic, unremitting receptor activation across all three target networks.
- Biphasic Central Appetite Regulation: GLP-1 signaling drives weight loss by concurrently blunting homeostatic metabolic hunger in the hypothalamus and suppressing hedonic reward signaling in the mesolimbic pathway.
- Independent End-Organ Protection: Selective GLP-1 receptor activation yields potent cardiovascular and renal protection via receptors on endothelial, immune, and renal cells, independent of aggregate weight loss.
- GIP-Driven Nausea Suppression: GIP receptor activation within brainstem neurons directly counteracts the emetic, nausea-inducing signals triggered by GLP-1 agonism, optimizing gastrointestinal tolerability.
- Mixed Extra-Metabolic GIP Signals: GIP receptors are absent in the kidney and demonstrate highly conflicting, context-dependent inflammatory effects in the cardiovascular system, contrasting with uniformly beneficial GLP-1 signaling.
- GIP-Mediated Alveolar Preservation: The clearest non-metabolic benefit of sustained GIP activation is the robust inhibition of osteoclast-mediated bone resorption, preserving mineral density.
- Hepatic Glucagon Counterbalance: Co-activating the glucagon receptor alongside GLP-1 and GIP allows the downstream insulinogenic responses to completely neutralize glucagon’s baseline glycogenolytic, blood-sugar-elevating effects.
- Unverified Energy Expenditure Claims: The widely repeated claim that glucagon co-activation elevates resting metabolic rate lacks robust human backing; clinical trials show weight loss is driven almost entirely by voluntary caloric restriction rather than increased thermogenesis.
- Unprecedented Weight Loss Magnitude: Phase III data demonstrate that retatrutide drives a peerless 28.7% mean reduction in total body weight at 68 weeks at maximum dosing.
- Targeted Hepatic Delipidation: Glucagon receptor stimulation in hepatocytes accelerates fatty acid beta-oxidation and halts lipid synthesis, inducing a massive 82% reduction in liver fat within 24 weeks.
- PCSK9 Degradation Mechanism: Retatrutide achieves a dramatic 21.7% reduction in circulating LDL-C by stimulating liver-level glucagon receptors to degrade the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme.
- HDL-C Clearing Side Effect: The same hepatic glucagon pathways that clear atherogenic lipids also inadvertently degrade beneficial high-density lipoprotein particles, preventing the HDL-C increases typically seen with tirzepatide.
- The Lean Mass Catabolism Risk: Chronic glucagon receptor activation forces the upregulation of hepatic amino acid catabolism, threatening skeletal muscle preservation by shifting amino acids toward energy substrate production.
- Relative Sarcopenic Proportions: Dual-energy X-ray absorptiometry (DEXA) sub-studies indicate that lean mass comprises 36% of the total weight lost under retatrutide, roughly matching semaglutide (~35%) but tracking higher than tirzepatide (~25%).
- Sympathetic Cardiovascular Fingerprint: Retatrutide increases resting pulse rate by up to 6.7 beats per minute and limits diastolic blood pressure reduction due to glucagon-mediated sympathetic nervous system stimulation.
- Pro-Arrhythmic Signal Emergence: Phase II data show that retatrutide induces a 11% to 14% incidence rate of cardiac arrhythmias, a signal significantly elevated relative to mono- or dual-incretin therapies.
- The Postmarket Surveillance Deficit: While semaglutide possesses over 40,000 patient-years of published clinical trial data and millions of real-world user tracking years, retatrutide’s published database is restricted to fewer than 700 patients.
- High-Dose Attrition Rates: Retatrutide’s maximum-dosage cohorts display an 18.2% treatment discontinuation rate, more than double the attrition seen in comparable semaglutide or tirzepatide arms, indicating a higher severity of adverse events.
- Neurological Dysesthesia Signal: Phase III data reveal a novel neurological side effect: 20.9% of patients on high-dose retatrutide develop cutaneous dysesthesia (burning or tingling skin sensations) compared to 0.7% on placebo.
- SIRT1 Longevity Pathway Suppression: Preclinical data show that hyper-potent GIP signaling suppresses sirtuin 1 (SIRT1)—a critical cellular survival pathway activated by caloric restriction—presenting a distinct molecular hazard for lean longevity seekers.
IV. Actionable Protocol
High Confidence Tier (Level A/B Evidence)
- Severe Class III Obesity Elimination: Deploy retatrutide preferentially in individuals presenting with an initial BMI greater than 35, where a ~28% body mass reduction drastically shifts all-cause mortality vectors and safely outweighs any unquantified organ-level risks.
- Advanced Non-Alcoholic Fatty Liver Disease (NAFLD/NASH) Reversal: Utilize retatrutide as a targeted therapeutic tool for rapid hepatic delipidation in cases of severe metabolic fatty liver disease, leveraging its glucagon-mediated mechanism to achieve a rapid ~82% reduction in intrahepatic triglyceride storage.
Experimental Tier (Level C/D Evidence)
- Hyper-Triglyceridemic and Low-LDL Refractory Management: Consider retatrutide for patients with severe metabolic syndrome displaying refractory hypertriglyceridemia and elevated LDL-C who fail to reach lipid targets on maximum dual-incretin therapy, exploiting its native PCSK9-degradation pathway.
- Skeletal Muscle Sarcopenia Mitigation: If utilizing retatrutide, mandatorily execute serial body composition monitoring (via DEXA, Bioelectrical Impedance Analysis, or equivalent multi-sensor metrics) to actively audit the lean mass-to-fat loss ratio, aggressively adjusting dietary protein intake and mechanical resistance training loads to counteract accelerated amino acid catabolism.
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Very good summary overall. Notes :
- energy expenditure form glucagon is pretty much a myth that people keep repeating, like the author said. It’s notable in mice studies (surprise, surprise ) but a rounding error in humans
- I’m more and more skeptical of muscle loss (not lean mass loss ) measured by dexa. Sadly, the companies conducting these studies don’t do themselves any favors by using dexa most of the time. But the studies that bothered to use mri show that muscle loss is way less than 30%. Recent study that showed that muscle loss for a GLP1/GCGR agonist is only 10%: Survodutide Once Weekly for the Treatment of Adults with Obesity (body composition results). We have similar mri data from semaglutide where muscle mass was around 15%. Funnily enough, liver mass reduction can account for 20% of lean mass loss, which surprised me.
- author mentioned retatrutide not raising hdl, as if raising hdl has proven to have any beneficial effect on cvd. Not relevant, in my view.
- I don’t really get the reasoning behind the obese vs non obese case for not using retatrutide. That’s probably because the author thinks most of the metabolic improvements are only weight dependent. My own labs show that’s not the case, so for my n=1 case, I think the author is wrong.
- worries about overactivation of glucagon receptor doesn’t make sense to me. In those studies, the activation is not only chronic, but it doesn’t come with GLP1 activation, which secretes insulin, counterbalancing glucagon. We have extensive human data showing that glucagon by itself is a no go (including trials) , so this is not some new issue discovered in mice studies cited by the author.
Fun fact about GIP : you get metabolic benefits from it (pretty much the same ones ) whether you agonise it, or suppress it. No one is sure why. Bone density concerns when it comes to suppression are so far mechanistically sound, but not proven in humans.
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Semaglutide slows epigenetic aging in a randomized trial of HIV-associated lipohypertrophy
“Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial’s primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( − 4.9 years/year, p = 0.004), PCGrimAge ( − 3.1, p = 0.007), GrimAge V2 ( − 2.3, p = 0.009), OMICmAge ( − 2.2, p = 0.009), RetroAge ( − 2.2, p = 0.030), and DunedinPACE ( − 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.”
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metformin will work in this context as well