Retatrutide - better than semaglutide b/c WAY lower nausea/side effect profile

#194

8 v 9mg may be from a higher starting BMI in Phase 3.

Here’s what I ended up with after some discussion with Gemini about the 8mg vs 9mg disproportionate variation between Phase 2 and 3:

Assuming the knee pain relief was the same or close between 8mg (Phase 2) and 9mg (phase 3) doses, the 9 mg result appears disproportionately better than the 8 mg (Phase 2) result because:

  1. *The Patients were Different: The Phase 3 cohort had Class III obesity (BMI 40.4), a phenotype that biologically allows for more profound initial weight reduction via glucagon-mediated lipolysis than the Class II phenotype in Phase 2 (BMI 37.2)
  2. The Delivery was Better: The 6 mg bridge dose in the Phase 3 protocol prevented the “tolerability shock” of the Phase 2 protocol, ensuring higher quality adherence and consistent drug exposure. Phase 2 dosing was 4 mg → 8 mg, but Phase 3 has a bridge dose from 4 mg → 6 mg → 9 mg. This may have improved tolerability and reduced drop outs of strong responders.

Summary from Gemini:
Retatrutide 8mg vs. 9mg: Explaining the Efficacy Gap
The disproportionate efficacy observed in the Phase 3 (9mg) cohort compared to Phase 2 (8mg) is primarily driven by structural differences in patient phenotype and dosing mechanics, rather than the minor 1mg dose increment.

  1. Baseline Adiposity (The “Glucagon Reservoir”)
    The most significant variable is the baseline phenotype. Phase 2 participants averaged 107.5 kg (BMI ~37), while Phase 3 participants were significantly heavier at 112.7 kg (BMI 40.4, Class III Obesity). Retatrutide’s glucagon agonist component drives energy expenditure; £a higher baseline fat mass provides a larger substrate for this lipolysis.* The Phase 3 cohort effectively had “more fuel to burn,” allowing the drug to sustain a steeper negative slope for a longer duration before metabolic adaptation occurred.
  2. Titration Optimization (Dose Intensity)
    Phase 2 utilized an aggressive “doubling” protocol (4mg → 8mg), which triggered a “tolerability shock” and high rates of gastrointestinal distress. This likely led to inconsistent dosing or “aversion-driven” restriction. Phase 3 introduced a crucial bridge dose (4mg → 6mg → 9mg). This smoothed receptor desensitization, ensuring higher “dose intensity” and quality adherence.
  3. Selection Bias
    Unlike Phase 2, Phase 3 dropouts were uniquely correlated with “perceived excessive weight loss.” The final data (-26.4%) reflects a “survivor” cohort of hyper-responders, whereas Phase 2 retained a broader mix of responders.
    Conclusion
    The superior 9mg result is an artifact of treating a heavier, more responsive population with a pharmacokinetically optimized dosing schedule.
#195

People Are Already Taking This Unapproved New Weight-Loss Drug
via Wired

The article describes one individual’s experience and their involvement in setting up a peptide supplier.

Terry was so impressed that he moved into the grey-market pharmaceutical biz himself, ordering APIs from Chinese manufacturers, and selling them—clearly marked as “research chemicals”—through his website, Compound Sciences, based out of Utah.

Anyone have experience with tis supplier?

#196

This is an important aspect of being successful with GLP1’s

I have a few clients who want the weight gone NOW!

And that is a challenge to help them understand it’s a journey that requires thoughtful dosing to ensure success. I try to get people to understand the scale is their friend now and the data they get from the scale is what determines their dose ramp (up or down). Very few are non-compliant but there are the outliers who don’t seem to be able to follow a simple, rational protocol.

This is probably why clinics don’t do it this way, they ramp up as fast as they can to get a result as quickly as they can so they can justify that process and cost. I have a few people who went through that and had bad side effects and dropped out. They came to us through referrals and they are now successful on their journey.

1 Like
#197

No, because they are about 300% higher than everyone else in the gray market. Clearly, it says he sources the product from Chinese gray market, then why would I buy from them same exact product for 300% more expensive. Having said that I do buy once in a while from Nexaph which is exactly same scenario as this supplier, BUT I always wait until he does what’s called pre-order sales and they are usually 20%-30% higher than sourcing it from Chinese gray suppliers with USA warehouses, but that is justifiable IMO given the ease of transaction, Credit card pmt, simple online order process same as shopping anywhere else online, i.e. same process as ordering from amazon, as an example. So, if you want the USA based route for ease of transaction no need to go with anyone else other than NEXAPH. His prices are only about 100% higher even when he doesn’t have any presales going on.

Case in point here is his preorder sale for 10 vials of 24MG Reta only $300(tempted to buy if I didn’t already have a two-year supply):

Pre-order GLP-3RT 24mg (10 vials/kit) – NEXAPH

1 Like
#198

New video from Dr. Brad

5 Likes
#199

I don’t know if you’ve mentioned it before, but do you mind sharing your RETA journey with regards to dosing, what dose you started on, how fast you titrated, and what is your maintenance dose etc…? Thanks,

https://www.undergroundsupply.shop/ -Agreed, I’ve ordered couple times from him and it was very fast and easy.

2 Likes
Hazel Szeto, SS-31 and the World's First FDA-Approved Mitochondria-targeted Drug (Longevity Summit, 2025)
#200

What dose / frequency did you use? Have you phased off now that you’ve achieved your goal, or adjusted your dosing?

2 Likes
#201

Sure, although we are derailing this thread :laughing:

Pre-Reta starting stats:

160lb
5’7”
Age 40 Male

LDL — generally between 80-120 for years. 80 only when I’m extremely strict with my diet (low saturated fat, high fiber). Diet did work for me, it just wasn’t fun (or as effective) as Reta. Lowest ApoB ever pre-Reta was 73.

————

Started Reta: December 2024.

Doses: 1mg, scaled by an additional 1-2mg every 2 weeks until I hit 6mg.

Result: Cut 30 lbs by March, stopped early March.

Bloods April: LDL was to 100, but I had been off Reta for a month at that point.

Comments:

Appetite suppression hits hardest initially. So does weight loss. So can gastrointestinal side effects (loose stools). Staying hydrated can be a challenge, as you lose the desire to drink as well.

The weight loss is really effortless at first.

——

April - June 2025 (Reta break):

I took a break for 2 months as I wanted to see what happened when I went off.

My appetite came storming back, as I quit cold turkey. I gained back 20 lbs within 2 months.

Quite the yo-yo. I was also “bulking” so I mentally justified it.

I do not suggest cold turkey if you cycle off.

The main thing I noticed is my ability to consume food was insane. It was insane before Reta too, I was fat growing up and have a high appetite. Pre-Reta, I would compensate for this by eating extremely satiating foods (lentils, egg whites, etc).

——

Restarting: June 2025

I made the mistake of “jumping back in” with a 3-4mg dose. In my experience, tolerance reset fully in 8 weeks.

4mg hit me like a truck. I had no appetite, fatigue, some diarrhea, etc.

I lost weight quickly but it wasn’t fun.

Luckily, most of the side effects dissipate over time. I stuck with 4mg for a while before escalating quite gradually up to 8-10mg.

I lost so much weight I got down to 125 and my wife complained I was too skinny. Had an unflexed 6 pack though which was kinda sweet.

Bloods:

August 2025: LDL 45, Apo-B 53
November 2025: LDL 50, Apo-B 57

Those are the best numbers in my life and I no longer force down fiber. I still eat low fat as Reta seems to give my body to handle carbohydrates like they are water.

———

Present:

I’m maintaining on 8mg, but I’ll probably lower it to 4-6mg as I’d like to slowly bulk some muscle and I’ll need more appetite for that.

I did gain some weight back (for the relationship :grin:) on purpose by kind of eating whatever I want, up to 133 or so.

Oddly, if I overeat on carbohydrates I cannot seem to gain weight. I joke that the Reta “eats the carbs” for me. As an experiment I ate 2,800 calories for 3-4 weeks, keeping fat low, and the scale didn’t budge.

I ran a CGM for 2 months out of curiosity and the lack of spikes were remarkable. I also experience zero fatigue after a high carb meal.

My diet is actually much less “clean” than it was before Reta. But I don’t overeat as much.

——-

Side effects that went away:

— extreme appetite suppression (I can eat now)
— loose stools
— fatigue (perhaps due to very low consumption)

Side effects that remain:

— elevated RHR (from 55-60 to 70-75)
— skin sensitivity // cold sensitivity

3 Likes
#202

Thank you for your detailed explanation. Great stuff bookmarked the post.

1 Like
#203

Short answer: for pure GLP-1 receptor agonism per unit exposure, retatrutide is slightly stronger than tirzepatide, but they’re in basically the same ballpark, and both are already stupidly supra-physiologic even at “micro” doses. The bigger difference is that retatrutide is an experimental triple agonist with glucagon on board, and tirzepatide is a dual agonist that’s actually approved.

So:

GLP-1R potency per molecule: tiny edge to retatrutide

Real-world sanity / safety / regulation: giant edge to tirzepatide

Let me unpack without turning this into a whole NEJM supplement.

  1. Receptor potency: who hits GLP-1 harder?

Retatrutide (LY3437943)
In vitro EC50s (human receptors):

GIPR: 0.0643 nM

GLP-1R: 0.775 nM

Glucagon receptor: 5.79 nM

So it’s insanely potent at GIPR, then GLP-1R, then GCGR.

Tirzepatide (LY3298176)

At GLP-1R, tirzepatide is ~13× less potent than native GLP-1 (EC50 ≈ 934 pM for tirzepatide vs 70.5 pM for GLP-1).

Retatrutide’s GLP-1 EC50 (0.775 nM) vs tirzepatide’s (~0.934 nM) are basically identical. If you squint, retatrutide is slightly more potent at GLP-1R, but it’s like arguing whose Ferrari is 2% faster on paper.

So per molar exposure:

Retatrutide ≳ Tirzepatide at GLP-1R, but the difference is tiny compared to how much both dwarf endogenous GLP-1.

  1. PK: how much drug is hanging around at a “microdose”?

Both are albumin-bound, once-weekly peptides with similar half-lives:

Tirzepatide: t½ ≈ 5 days

Retatrutide: t½ ≈ ~6 days (dose-proportional PK, 0.1–6+ mg)

So for the same mg/week, their average plasma levels over the week are roughly comparable, and so GLP-1R engagement scales ≈ linearly with dose for both in the “microdose” regime.

If you imagine:

0.25 mg weekly retatrutide vs 0.25 mg weekly tirzepatide
→ same exposure order of magnitude, almost identical GLP-1 potency
→ retatrutide might give you a tiny edge in GLP-1R tone, but in practice you’re still in the “tens-fold above physiological” zone either way.

So in terms of “orders of magnitude above normal GLP-1” at microdose, it’s:

Both: ~1 OOM above normal GLP-1R tone at peak.
Retatrutide: maybe a fraction more, but not “one is 10× the other” territory.

  1. But their profiles are very different

This is where the choice actually starts to matter.

Tirzepatide

Dual GIP + GLP-1 agonist

More GIP-biased: higher effective engagement at GIPR than GLP-1R at clinical doses

GLP-1R signaling is cAMP-biased (less β-arrestin / internalization), which might sustain signaling differently from straight GLP-1 RAs.

Retatrutide

Triple agonist: GIP + GLP-1 + glucagon

Extremely potent at GIPR, high potency at GLP-1R, moderate at glucagon receptor

Glucagon agonism is intentional: it increases energy expenditure on top of GLP-1/GIP’s appetite suppression.

So if you microdose retatrutide, you’re not “just” micro-GLP-1’ing; you’re also tickling glucagon and GIP in a way that might:

help weight loss / metabolic rate more

but also possibly increase side-effect risk (HR, GI, etc) at a given GLP-1R tone.

From a “GLP-1 purity” perspective, neither is great. You’re always in some mixture of GLP-1 + GIP (+ glucagon for retatrutide). If you wanted “clean GLP-1 with microdose precision,” honestly you’d be talking sema / lira, not these multi-agonist chimera beasts.

  1. The very boring but important real-world part

Tirzepatide is approved, mass-produced, and dosed in a known, controlled way for diabetes and obesity (5–15 mg weekly).

Retatrutide is still in trials, not approved anywhere.

There are already counterfeit / illicit “retatrutide” pens being sold with unknown contents and multiple reported adverse events, which regulators are actively going after.

So from a “what’s better for GLP-1 microdosing” standpoint:

Pharmacology: retatrutide probably has a slight GLP-1R potency edge per nM, but it’s basically noise compared to the fact you’re massively supraphysiologic with either.

Reality check: using experimental triple-agonist from grey-market supply to squeeze out a maybe-10-20% GLP-1 edge is… let’s say not a locally optimal risk–reward ratio.

If you had to pick on GLP-1 grounds alone at equal mg and clean pharma-grade material:

Retatrutide wins by a hair on GLP-1R potency, Tirzepatide wins by a landslide on “not being a sketchy unapproved research drug.”

TL;DR in human words

Microdosing tirzepatide vs retatrutide: for GLP-1 specifically, they’re very similar, with retatrutide slightly more GLP-1-potent per molecule.

The difference is tiny compared to the fact that even “microdoses” send GLP-1R signaling way above natural physiology.

The real tradeoff is:

Tirzepatide: safer, approved, dual GIP/GLP-1.

Retatrutide: experimental triple agonist with glucagon on board, heavier-duty and less characterized, especially at weird low dosing.

So if the goal is “max GLP-1 for a given mg,” retatrutide edges it.
If the goal is “do something not totally insane in the current universe we live in,” tirzepatide is the less cursed option.

And as usual: all of this should be run past an actual endocrinologist, not a sarcastic transformer you’ve emotionally outsourced your pharmacology to.

3 Likes
#204

You conflate regulatory status with risk profile. If you’re using tirzepatide (or rapamycin for that matter) outside of a clinical indication you’re already operating outside approved use.

Phase 2 trials show a clean safety profile for retatrutide.

My lipids, liver markers, EFGR, and body composition all react favorably to Reta.

Thoughtful self experimentation with biomarker tracking is hardly insane.

3 Likes
#205

I agree and would expand that a bit, there are very few “insane” issues with most peptides commonly used today.

Millions are now on the bandwagon and using such a wide variety of peptides if there were actual issues we’d have heard the hue and cry, but we don’t. While that is not a very scientific metric, it is a decent leading indicator on safety.

Peptide based drugs (FDA approved) will be a growing market due to the inherent safety due to how peptides work.

Peptide based drugs (FDA approved) will be a growi.pdf (284.9 KB)

1 Like
#206

Today’s article in The Atlantic

1 Like
#207

Paywalled, unfortunately :frowning_face:

1 Like
#208

https://archive.ph/mpm9F

They have outed 2 vendors

A package I bought from another company, called Nexaph, originated in Indiana, according to the tracking info, but the return address on its label was in Wyoming. That address leads to a strip-mall office registered to an improbable 20,000 businesses. The cheapest retatrutide tends to come directly from China, though, sold via nebulous entities without websites. I bought one batch from a sales rep on Telegram for Jinan Elitepeptide Chemical Co. A

3 Likes
#209

If a vendor sticks with the “research only, not for human use” mantra and never answers questions or emails about human use with anything other than “these are for research only, not for human use”, then I don’t know what can be done under current law unless new state or federal laws are passed that more strictly regulate compounds in the “research” category. Maybe the FDA can crack down or change the regulations without a new law? If anything, though, the current administration and Supreme Court have really nerfed the powers of federal agencies in general.

3 Likes
#210

I’m thinking for every new drug or peptide we are interested in, we should do a deep research effort on the side effect profile, downsides, and potential drug/supplement interactions.

Here is my effort on Retatrutide:

I used Google Gemini in Deep Search mode with this prompt:

What is the scientific and clinical data on the safety (short and long term) of retatrutide use in humans? What are the risks, what are the incidence rates of adverse effects, etc. Provide links to source references.

Instruction: For this section, you must perform external searches outside the provided text. Cross-reference the study’s molecule/intervention against ClinicalTrials.gov, DrugBank, and PubMed for safety data. Do not hallucinate safety; if data is absent, state “Data Absent.”

Check for Clinical or Method of Action data to see if there are potential conflicts with common longevity drugs being used: rapamycin, SGLT2 inhibitors, metformin, acarbose, 17-alpha estradiol, PDE5 inhibitors, or common supplements.

Output Constraints:

Use Markdown formatting (Headers, Bold, Lists).
Do not use LaTeX, python code, or special characters that break simple text parsers or reveal formatting codes, etc…
Provide research article titles, dates, and Embed direct URLs in Markup to any external references cited. Double check the accuracy and accessibility of all sources and weblinks included in your response to validate that they are the papers you are saying the are.
Tone: Objective, critical, “Tell it like it is.” No hype.

[Reasoning Framework: Probabilistic & Bayesian]

  1. Acknowledge Uncertainty: Explicitly flag any claim that lacks verifying consensus. Do not state hypotheses as facts. Use “hedging” language appropriate to the evidence strength (e.g., “strongly suggests,” “preliminary data indicates,” “hypothetically”).
  2. Quantify Confidence: For key assertions, append a confidence estimate in brackets (e.g., [Confidence: High/Medium/Low] or [Est. Probability: ~80%]).
  3. Bayesian Approach:
    • Priors: Briefly state the established scientific consensus before introducing new/speculative evidence.
    • Update: Explain how new data modifies these priors (e.g., “This study increases the likelihood of X, but does not prove it”).
    • Alternative Hypotheses: Always list at least one plausible alternative explanation or confounding factor (e.g., “Reverse causality,” “Selection bias”).
  4. Evidence Hierarchy: Distinguish between mechanism (in vitro/murine) and outcome (human clinical data). Discount mechanistic speculation if human outcome data is absent.

Google Gemini response

Receptor-Specific Safety Implications

The safety profile is a composite of the downstream signaling of these three GPCRs:

  • GLP-1 Receptor (GLP-1R):
    • Mechanism: Activates adenylyl cyclase, increases cAMP, recruits beta-arrestin.
    • Safety Signal: Primarily drives the gastrointestinal (GI) adverse event profile (nausea, vomiting, delayed gastric emptying). It is also the primary driver of heart rate elevation via receptors in the sinoatrial (SA) node.
  • GIP Receptor (GIPR):
    • Mechanism: Potentiates glucose-dependent insulin secretion and modulates lipid storage in white adipose tissue.
    • Safety Signal: GIP agonism is hypothesized to reduce the emetic potential of GLP-1 agonism, potentially allowing for higher titration ceilings. However, its long-term effects on bone turnover and adipocyte health are critical unknowns in the context of massive weight loss.
  • Glucagon Receptor (GCGR):
    • Mechanism: Stimulates hepatic glycogenolysis and gluconeogenesis (raising blood sugar) and lipolysis (breaking down fat). It also exerts positive inotropic (contractility) and chronotropic (heart rate) effects on the myocardium.
    • Safety Signal: This is the source of the unique safety concerns regarding retatrutide: potential for hyperglycemia (if insulin secretion is compromised), cardiac arrhythmias, and muscle catabolism.
Adverse Event Retatrutide (12 mg) Incidence Mechanism Clinical Management
Nausea ~45-60% GLP-1R (CNS/Gastric) Slower titration, smaller meals
Vomiting ~15-20% GLP-1R (CNS) Antiemetics, hydration
Sinus Tachycardia Mean +5.6 to +6.7 bpm GLP-1R + GCGR (SA Node) Monitor; typically peaks at 24wks
Cutaneous Hyperesthesia ~7% Neural Sensitization (Unknown) Dose reduction, Gabapentin (rarely needed)
Arrhythmia (Any) 4-14% (Pooled) Sympathetic Tone (cAMP) ECG monitoring in high-risk patients
Discontinuation Rate 6-16% GI Intolerance Titration “Start Low, Go Slow”

Question 2: Does chronic Glucagon Receptor (GCGR) activation accelerate cardiac aging via sympathetic overdrive?

  • Bayesian Prior (Moderate Probability): Chronic tachycardia is an independent risk factor for all-cause mortality and heart failure. The mammalian “heart rate hypothesis” suggests an inverse correlation between heart rate and lifespan. Glucagon is a known inotrope/chronotrope.
  • New Evidence (Likelihood): Retatrutide increases HR by ~6 bpm, peaking at 24 weeks and then declining but remaining elevated above baseline.
  • Posterior Probability & Reasoning: Moderate Probability of Cardiac Wear. Even a modest 5 bpm increase equates to ~2.6 million extra beats per year. Over a decade, this mechanical stress could theoretically accelerate valvular wear or myocardial fibrosis. However, the net benefit on cardiac risk (via reduced afterload, resolved sleep apnea, and lipid normalization) likely outweighs this mechanical cost. The risk is specific to “rate-related” aging, while the benefit is “metabolic” rejuvenation.

Question 4: Does the robust insulinotropic effect (GIP/GLP-1) hyper-activate mTORC1, thereby antagonizing longevity?

  • Bayesian Prior (High Probability): Insulin is the primary activator of mTORC1. Chronic mTOR activation inhibits autophagy and accelerates aging. Longevity strategies (Rapamycin, Fasting) aim to lower insulin/mTOR.
  • New Evidence (Likelihood): Retatrutide stimulates insulin secretion acutely (post-prandial). However, systemically, it dramatically improves insulin sensitivity, lowering fastinginsulin and glucose levels significantly.
  • Posterior Probability & Reasoning: Low Probability of Antagonism. The drug creates a pulsatile insulin profile (high when eating, low when fasting) rather than the chronic hyperinsulinemia of obesity. By resolving insulin resistance, it likely lowers total integrated mTOR activation over 24 hours, effectively permitting autophagy during fasting windows.

Question 5: Does Retatrutide create a “Hidden” Sarcopenia masked by the massive fat loss?

  • Bayesian Prior (High Probability): Rapid weight loss induces catabolism. Without anabolic stimulus, muscle protein synthesis drops.
  • New Evidence (Likelihood): DEXA substudies show lean mass loss is proportional (25-30%).
  • Posterior Probability & Reasoning: High Probability (Context Dependent). The risk is not that the drug is “myotoxic,” but that the magnitude of weight loss strips meaningful muscle mass. A 60-year-old losing 20 lbs of muscle along with 60 lbs of fat improves their metabolic health but degrades their functional frailty index. Retatrutide must be paired with resistance training to be safe for longevity.

Question 7: Does the “Anhedonia” effect blunt the benefits of hormetic stressors (Exercise/Socializing)?

  • Bayesian Prior (Moderate Probability): Dopamine drives motivation. GLP-1 receptors in the Nucleus Accumbens regulate reward.
  • New Evidence (Likelihood): Anecdotal reporting of “flatness” and “loss of mojo” is persistent in user communities.
  • Posterior Probability & Reasoning: Moderate-High Probability. By clamping the dopamine reward system to treat food addiction, there is likely a “spillover” effect that blunts the endorphin rush of exercise or the dopaminergic reward of social interaction. This could reduce adherence to the lifestyle pillars of longevity (community, movement) even while solving the metabolic pillar.

Drug Interactions and Polypharmacy in the Longevity Protocol

Longevity specialists often utilize “stacks” of off-label medications. The interaction of retatrutide with these agents is a critical translational safety consideration.

6.1 Retatrutide + Rapamycin (Sirolimus)

  • Mechanism: Rapamycin is an mTORC1 inhibitor used to mimic caloric restriction and enhance autophagy. Retatrutide (via Insulin/GIP) stimulates pathways that can activate mTORC1, but systemically lowers insulin resistance.
  • Interaction Risk: Antagonistic (Muscle) / Synergistic (Metabolic). Rapamycin inhibits protein synthesis. Taking it during the rapid weight loss phase of retatrutide (where catabolism is already high) could severely exacerbate sarcopenia and muscle wasting.
  • Recommendation: Cycle Rapamycin. Avoid rapamycin during the active weight loss phase. Re-introduce it only during the weight maintenance phase, and consider timing it away from resistance training sessions.

6.2 Retatrutide + SGLT2 Inhibitors (e.g., Empagliflozin, Dapagliflozin)

  • Mechanism: SGLT2 inhibitors dump glucose in urine and raise endogenous glucagon. Retatrutide provides exogenous glucagon agonism.
  • Interaction Risk: Euglycemic DKA (High Risk). The dual elevation of glucagon tone (endogenous + exogenous) combined with the glucose-lowering effect could prime the liver for runaway ketogenesis, particularly if the patient is dehydrated or fasting. The insulinotropic effect of retatrutide mitigates this, but the risk is non-zero.
  • Recommendation: Extreme Caution. If combined, monitor blood ketones (beta-hydroxybutyrate). Discontinue SGLT2i 3-4 days before any surgery or high-intensity endurance event.

6.3 Retatrutide + Metformin

  • Mechanism: Metformin activates AMPK and modulates the gut microbiome.
  • Interaction Risk: Gastrointestinal Toxicity (Additive). Both drugs frequently cause diarrhea, nausea, and cramping. Combining them often leads to intolerable GI side effects. Furthermore, the robust glycemic control of retatrutide often makes metformin redundant.
  • Recommendation: Deprescribing. In many patients, retatrutide monotherapy is superior to the combination. Consider tapering metformin to improve GI tolerability.

6.7 Retatrutide + Common Supplements

  • Berberine: Acts similarly to mild metformin (AMPK activator). Risk: GI distress (diarrhea) is additive. Avoid combining with retatrutide during the titration phase.
  • Psyllium Husk / Fiber: Risk: Reduced efficacy/Severe constipation. Because retatrutide slows gastric emptying, adding bulk-forming fiber without massive water intake can lead to bezoar formation or impaction. Recommendation: Use caution; ensure hyper-hydration.
  • Creatine Monohydrate: Benefit: Highly recommended. Helps preserve intracellular water and muscle mass during the rapid weight loss phase.

Full Gemini Analysis here: https://gemini.google.com/share/249943f31891

4 Likes
#211

And of course, we should compare any new drug to other drugs in the same category:

Table 3: Comparative Efficacy and Safety Profile (Retatrutide vs. Tirzepatide vs. Semaglutide)

Feature Semaglutide 2.4 mg (Wegovy) Tirzepatide 15 mg (Zepbound) Retatrutide 12 mg (Investigational)
Mechanism Mono-agonist (GLP-1) Dual-agonist (GLP-1 / GIP) Triple-agonist (GLP-1 / GIP / Glucagon)
Primary Trial Reference STEP 1 (68 Weeks) SURMOUNT-1 (72 Weeks) TRIUMPH-4 (68 Weeks) / Phase 2 (48 Weeks)
Weight Loss (Non-Diabetic) ~15% - 17% ~21% - 22.9% ~24% (Phase 2) / 28.7% (TRIUMPH-4)1
% Achieving >20% Loss ~30% ~57% - 63% ~64% - 82% (est. from Phase 2/3)
HbA1c Reduction (T2D) ~1.6% - 1.8% ~2.0% - 2.3% ~2.0% - 2.2% (Phase 2)
Resting Heart Rate Impact +1 to 4 bpm +2 to 6 bpm +5.6 to 6.7 bpm (Phase 2)3
Cardiac Arrhythmia Risk Low / Neutral Low / Neutral Signal observed (4-14% in Ph2 supplement)2
Cutaneous Hyperesthesia Rare (<1%) Rare (<1%) ~7% (Specific to Reta)[6]
Discontinuation Rate (AEs) ~4.5% - 7% ~4% - 7% 6% - 16% (Phase 2)2 / 18.2%(TRIUMPH-4 12mg)
Primary Adverse Events Nausea, Diarrhea Nausea, Diarrhea Nausea, Diarrhea, Skin Sensitivity, Palpitations
Liver Fat Reduction Significant Robust Near-total resolution (>80-85%)5
4 Likes
#212

This is actually a really good point I hadn’t thought of, specific to psyllium since it’s really the only bulk-forming fiber that is minimally fermented by colon microflora.

Definitely would not want to fast or get dehydrated on this combo, but ketoacidosis should otherwise be extremely rare in anyone with a well-functioning pancreas. On the plus side, it should prove to be a remarkable combination for metabolic health and weight loss (especially when combined with adequate protein intake and some resistance training).

2 Likes
#213

I don’t know what can be done either to stop them from selling. I’ve mostly been following how compounding is surviving legal challenges from Lilly and Co, with the FDA largely on the sidelines, by choice it seems.

The most impactful legislation will come from the states. Florida in particular is looking at a bill that would eventually choke out compounding. This is notable because a lot of the big pharmacies are in FL.

On the research only side, I’m more worried about more intense scrutiny. But that is also part of the game