Tirzepatide (Mounjaro/Zepbound) Clinical Data Deep Dive

Tirzepatide is an evolution of GLP-1 agonists like semaglutide that adds the GIP receptor — improving insulin efficiency and engaging fat tissue directly in energy metabolism. In non-diabetic obesity trials, the 15 mg dose produced about 21% mean weight loss over 72 weeks.¹

At maximum tolerated doses, tirzepatide produced 20.2% loss versus 13.7% with semaglutide in the direct head-to-head.² Separate matched-population DXA anchors read at about 75:25 versus 62:38.³ That body-composition split explains "less hollowed out" reports better than any face-specific drug effect does.

The advantage narrows in type 2 diabetes. A three-arm body-composition study there found nearly identical fat-to-lean shares for both drugs, about 87:13 and 86:14, with tirzepatide still ahead on absolute fat loss and on HbA1c.⁴ Diabetes changes the ratio story; it does not change which drug removes more fat.

Every trial capped at 15 mg weekly, which leaves the range above it uncharacterized at any duration. Compounded vials sold at 30 or 60 mg hold multiple sub-15 mg weekly doses; the strength on the vial is a packaging decision.

The dose decision that matters after titration is where to stop. The 72-week curve flattens sharply above 10 mg: 5 mg retains about 72% of the maximum effect and 10 mg about 93%, at a meaningfully lower GI burden than 15 mg.¹

Across five recent cohorts totaling more than 40,000 users, 56–74% of persistent users were below 10 mg by their sixth prescription. Non-diabetic users lost 11–13% at six months.¹³ The 112-week maintenance trial adds the step-down instrument: 5 mg preserved substantial loss, but less than continued maximum-tolerated dosing.⁹

Comparing options? Try the GLP-1 Comparison tool, the Retatrutide vs Tirzepatide deep dive — or explore individual guides on Semaglutide (Ozempic/Wegovy), Retatrutide, and Oral GLP-1s (Rybelsus/Orforglipron).

What Tirzepatide Is

Tirzepatide is a single peptide that activates two hormone receptors: GLP-1 and GIP. Both normally respond to signals released after you eat.

The dual-signal effect: one limb quiets appetite and slows gastric emptying, while the other improves insulin efficiency and engages fat tissue in burning fuel. This combination lets people eat less while feeling functional, smooths glucose handling, and shifts weight loss toward fat rather than lean tissue.

Given as a once-weekly injection. Different brand names (Mounjaro, Zepbound) reflect regulatory approvals, not different molecules.

How Tirzepatide Works

The body uses incretin hormones to coordinate appetite, digestion, and insulin after meals. Tirzepatide amplifies both signals, but not equally.

Those figures come from receptor assays and describe relative potency, not how much of each receptor a weekly injection engages. The practical shape is the part that reaches the user: at lower doses the GIP arm leads, and as the dose climbs the GLP-1 arm brings more appetite pressure, more gastric slowing, more nausea and constipation, and a small rise in resting heart rate.

Tirzepatide spreads its signal across both receptors instead of pushing GLP-1 harder.⁸ Its GLP-1 arm is weaker than native GLP-1 and recruits less beta-arrestin, while its GIP arm reaches a receptor that fat tissue expresses and GLP-1 receptors do not. The weight and body-composition results follow from that architecture as a whole. No trial has split either result into a GIP share and a GLP-1 share, which is why the ratios above stay as pharmacology rather than as an explanation of the outcome.

GLP-1 receptor effects: Slows gastric emptying, strengthens satiety signals, boosts insulin when glucose is high while backing off when it is normal. Meals feel smaller but more satisfying.

GIP receptor effects: Improves insulin efficiency (less hormone needed for the same glucose) and engages fat cells to burn fuel rather than store it. The technical mechanism is a heat-producing calcium cycle inside white fat cells (SERCA-mediated futile calcium cycling⁷). Pure GLP-1 agonists cannot access this pathway because GLP-1 receptors are not expressed in adipose tissue.

Tirzepatide Weight Loss Results

The dose-response curve — and why it flattens

In non-diabetic obesity over 72 weeks, the three measured doses produced:¹

The curve flattens sharply between 10 and 15 mg. Each additional milligram adds about 0.9% weight loss across the 5 → 10 step but only about 0.28% across the 10 → 15 step — roughly a threefold collapse in per-mg return. The last 7-28% of effect costs a 50-200% dose increase.

5 mg already holds most of the effect. The 5 mg arm’s −15.0% is 72% of the 15 mg arm’s −20.9%, for a third of the drug and a meaningfully lower GI burden. These percentages are fractions of absolute mean weight loss at 15 mg, not placebo-adjusted drug effect; the placebo-subtracted comparison gives similar but slightly different figures, with 5 mg capturing about 67% of the drug-attributable effect and 10 mg about 92%. Both framings support the same conclusion.

About 57% of 15 mg participants reach 20%+ weight loss; 36% reach 25%+. Trial averages with structured support, not individual guarantees.

The trajectory at any maintenance dose: early months are titration and adaptation, months 3–6 accelerate as plasma exposure stabilizes (steady state lands around four weeks at any new dose), months 6+ continue trending down as visceral fat responds.⁷

Body composition and fat-to-lean ratio

In the 160-participant body-composition substudy, the pooled 5, 10, and 15 mg tirzepatide group lost 21.3% of body weight at 72 weeks. Fat mass fell 33.9% and lean mass 10.9%. About 75% of the measured fat-plus-lean loss came from fat and 25% from lean tissue.³

Read the placebo row before reading the drug row. Placebo landed at the same 75:25 split. The partition is what happens when a body loses weight, and the drug’s contribution is the size of the loss rather than a cleaner division of it. Semaglutide 2.4 mg produced about 62:38 in its own DXA substudy, which is a different trial in a different cohort.¹² Adipocyte GIP signaling remains the leading explanation for that gap, on two separate trials rather than one comparison.

The practical read for anyone who lifts: 25% of every kilogram lost comes off as lean tissue, which at 21% total loss is roughly 5.5 kg. Protein and resistance training are what move that fraction. The drug does not.

In type 2 diabetes, a separate 28-week three-arm study found similar fat-to-lean shares for tirzepatide and semaglutide, about 87:13 versus 86:14, with tirzepatide removing more total fat.⁴ The ratio advantage is a non-diabetic finding.

Head-to-head vs semaglutide

In the direct head-to-head trial in non-diabetic obesity over 72 weeks (max-tolerated doses, open-label):²

Tirzepatide produced 47% greater weight loss than semaglutide at maximum doses in that 72-week comparison.² Neither participants nor investigators were blinded, which probably inflates the gap somewhat. The direction holds independently in the blinded dose-response trials.

Diabetes trials

In type 2 diabetes on metformin over 40 weeks, tirzepatide at 15 mg produced about 13% weight loss⁵ versus about 6% on semaglutide 1 mg. HbA1c reductions reached 2.0–2.3% — among the largest reported for any incretin.

The population gap is large. The same 15 mg dose produces about 13% weight loss in diabetes against about 21% in non-diabetic obesity. Shorter trial duration accounts for part of it. Altered incretin biology is the leading candidate for the rest, and the diabetic body damps semaglutide the same way, which points at the population rather than at this molecule.

That gap is one reason a stronger GIP signal plus a glucagon arm is worth watching in retatrutide.

For triglyceride and LDL effects, see the GLP-1 cholesterol guide.

Tirzepatide Dosing

Injected once weekly, subcutaneous.

Titration is titration. 2.5 mg is now a lower-dose track, not only a tolerance step.

The label ladder (2.5, 5, 7.5, 10, 12.5, 15 mg, four weeks per step) follows the drug’s pharmacokinetics. With an approximately 5.4-day half-life and steady state at about four weeks,⁷ each step settles before the next loads on top of it. The 2.5 mg starter was originally designed as a tolerance-calibration step before the effective 5 mg dose.

The ramp itself changes tolerability. With little or no escalation, the tirzepatide dose associated with nausea in half the exposed population was 15.6 mg per week; with the full regimen it was 78.7 mg per week, a 5.04-fold shift. Vomiting moved 4.83-fold, and the phase-specific confidence intervals did not overlap. Across nine incretin drugs, tolerance tracked escalation duration and step count, while the starting dose as a fraction of maintenance did not.¹⁵

A 70-person non-diabetic obesity cohort recorded −4.7% body weight, −25% fasting insulin, and −30% on its insulin-resistance score during an initial 2.5 mg phase lasting 4.2 ± 0.7 weeks.¹⁴ The same participants then moved to 5 mg for 13.1 ± 5.4 weeks. This was a sequential lower-dose signal, not a dose-isolated comparison. Across larger real-world datasets, 2.5 mg is a common lower-dose track; 5 mg remains the modal maintenance dose.¹³

Starting below 2.5 mg (0.5-2 mg) for tolerance-sensitive users is a microdose decision, covered separately below, rather than a titration choice.

Stopping short: 5 mg and 10 mg are defensible maintenance doses

Per the dose-response table above, 10 mg weekly retains about 93% of the 15 mg maximum weight-loss effect, and 5 mg retains about 72%. The incremental gain from 10 → 15 mg is 1.4 percentage points over 72 weeks. GI side effects scale with dose throughout the range.

The effective dose is the lowest one that keeps weight trending and appetite controlled, which for most users sits in the 5-10 mg band rather than at the top of the ladder.

The 52-week withdrawal-vs-continuation trial established that continuing tirzepatide at an effective dose matters for maintaining loss. At one year, 89.5% of continuators held at least 80% of their loss, while the placebo-switch group regained about 14% body weight.⁹

The 112-week maintenance trial then measured step-down directly. Continued maximum-tolerated dosing was at −21.9% from baseline, step-down to 5 mg at −16.6%, and placebo switch at −9.9%. Rescue therapy was needed by 8%, 25%, and 67%, respectively.⁹ Five milligrams preserved substantial loss, but it did not reproduce continued top-dose treatment.

Real-world prescribing has already converged on this band. Across five cohorts totaling more than 40,000 users, 56–74% of persistent users were below 10 mg by their sixth prescription. Non-diabetic users lost 11–13% at six months, and 5 mg was the modal maintenance dose.¹³

One telehealth cohort using flexible titration and prolonged lower-dose intervals reported 21% reaching 15 mg and −23% mean weight at 52 weeks. That is an observational, protocol-selected cohort, not randomized proof that lower doses equal maximum-dose trial outcomes.

One divergence shows up before the pharmacokinetics predict it. Patient-generated reports describe regain after a dose reduction, short of full cessation, arriving faster than washout alone accounts for. Those reports carry no incidence rate and no comparison arm, and what they support is a slower step-down cadence when weight drifts early rather than a wait for the half-life math to catch up.

Microdose (0.5-2.5 mg): the measured boundary

A 26-week diabetes dose-range trial tested 1 mg weekly as a real dose arm, below the current 2.5 mg label floor.¹¹ HbA1c reduction was measurable and dose-dependent from 1 → 5 → 10 → 15 mg. Sub-label dosing produces pharmacologic activity on a glycemic endpoint. Weight loss at trial duration is a separate question the trial did not ask.

A separate 70-patient non-diabetic obesity cohort recorded −4.7% body weight, −25% fasting insulin, and −30% on its insulin-resistance score during an initial 2.5 mg phase lasting 4.2 ± 0.7 weeks.¹⁴ The same cohort then moved to 5 mg. Dose and time changed together in the same people, which makes this a direct short-phase measurement at 2.5 mg rather than a flat-dose trial.

No weight-loss trial has run below 5 mg for 72 weeks. The microdose expectation for weight therefore rests on three measured things: the 1 mg dose-response on metabolic markers, linear pharmacokinetics across 0.25-15 mg with no absorption or metabolic break point,⁷ and the GIP-forward bias that shows up at lower exposure before GLP-1 appetite suppression takes over.

One direction is load-bearing for a metabolically preserved user. The 1 mg anchor was measured in diabetes, where GIP signaling is impaired. At the same 15 mg dose, non-diabetic obesity produced about 21% against 12-15% in diabetes-with-obesity. Pathway responsiveness is the leading explanation for that gap.

A microdose user with a fully responsive axis sits on the favorable side of that translation. Expect more effect per mg than the diabetes anchor alone implies, not less. The dosing page’s microdose section develops the practical case, including split schedules, reconstitution math, and the evidence boundary for sub-2.5 mg dosing.

The 15 mg ceiling

The label maximum is 15 mg weekly, and there is zero prospective trial data above this dose. Compounded vials at 20, 30, or 60 mg are cost-efficient containers holding several sub-15 mg weekly doses.

The longest controlled exposure runs 72-88 weeks at doses up to 15 mg, with multi-year cardiovascular data covering the same range. Above that the safety record is empty, and the flattening curve offers no efficacy reason to go looking.

Dose bands and evidence grades

Evidence grade by band:

• Microdose (0.5–2 mg) — Directly measured at 1 mg (HbA1c)¹¹ · Mechanism-consistent for weight/body-comp at microdose
• Real-world lower-dose track (2.5 mg) — Directly measured during a short initial phase in a sequential cohort
• Effective stop-short (5 mg) — Directly measured¹
• Mid-range maintenance (7.5–10 mg) — Directly measured (10 mg) · Mechanism-consistent (7.5 mg interpolated)
• Full dose (12.5–15 mg) — Directly measured¹
• Above 15 mg — Uncharacterized at any endpoint

Compounded tirzepatide changes the arithmetic rather than the pharmacology. The tirzepatide dosing calculator handles reconstitution, per-injection volumes, microdose titration, and split-frequency schedules. The GLP-1 dosing optimizer splits weekly doses across 2-3 injections to flatten the peak-trough curve. GI effects cluster earlier after a dose; late-week hunger return tracks the trough.

Translating Trials to Practice

The registration trials enrolled specific populations: non-diabetic BMI ≥27 with comorbidity, or type 2 diabetes with BMI ≥25. Real-world use extends past them — post-loss maintainers, metabolically preserved microdose users, and recomp-focused users at 2–5 mg.

For anyone outside the enrollment criteria, the question is not "what does the trial say I will get." It is "how does the mechanism extrapolate to me."

The label answers a narrower question than most readers assume. It marks the band the manufacturer took to registration for the indications those trials enrolled, which is a commercial and regulatory scope decision as much as a pharmacologic one. Outside those populations the usable reasoning runs through the dose-response curve, the linear pharmacokinetics, and the sub-label evidence above.

Tirzepatide Side Effects (Mounjaro/Zepbound)

Side effects are primarily gastrointestinal and dose-dependent. The dual GLP-1/GIP mechanism produces a slightly different GI pattern than pure GLP-1 agonists, with reports skewing toward less nausea and more constipation.

The published percentages count events people volunteered, after mitigation. In the protocol sections checked for this update, a nonleading open question prompted the report, and dietary counseling, antiemetics, dose interruption, or dose reduction could all come first. The antiemetic-treated fraction is unpublished. Read the table below as post-mitigation rates in a supported trial setting, which is a lower bar than an unsupported user meets.¹⁶

Common Side Effects

Frequencies below reflect 15 mg over 72 weeks in the main non-diabetic obesity trial:¹

Tirzepatide may feel less energy-flattening than semaglutide for some users because the appetite signal is less GLP-1-heavy. Fatigue still occurs, especially with under-eating, dehydration, poor sleep, or rapid weight loss.

Less Common Side Effects (1–10% of Users)

• Fatigue. Usually tied to under-eating, dehydration, sleep disruption, or rapid loss; often less prominent than with semaglutide. The managing GLP-1 fatigue guide carries the full breakdown.
• Hair thinning. Tracks rapid weight loss rather than the drug, and it is temporary.
• Injection-site reactions. Redness, itching, or swelling, usually mild.
• Acid reflux. Slowed gastric emptying worsens existing GERD.
• Decreased appetite. The intended effect, and the reason adequate protein takes deliberate effort.

Serious Side Effects (Rare but Important)

Gallbladder problems (1–2%): Rapid weight loss increases gallstone and cholecystitis risk. Pain typically localizes to the right upper abdomen after eating.

Pancreatitis (<1%): Severe, persistent abdominal pain radiating to the back. Stop tirzepatide and seek immediate care if suspected.

Severe GI events (<1%): Rare cases of severe gastroparesis or intestinal obstruction have been reported with GLP-1 class drugs.

Thyroid concerns: Same thyroid tumour signal as semaglutide in rodent studies. Contraindicated with personal or family history of medullary thyroid carcinoma or MEN2.

Heart Rate: Small Dose-Dependent Increase

Tirzepatide produces a dose-linked rise in resting heart rate. At week 72, the mean change was +0.6 bpm at 5 mg, +2.3 bpm at 10 mg, and +2.6 bpm at 15 mg versus +0.1 bpm on placebo.¹

Those endpoint means hide the escalation window. The regulatory review recorded larger group means around weeks 16-20, and a rise above 20 bpm at some visit in about 10% of tirzepatide participants against 3.35% on placebo. Resting heart rate is a titration-phase measurement that the week-72 figure averages away.

Oral Medications and Contraception

Tirzepatide delays gastric emptying most strongly after starting and after each dose increase. That matters for oral medications with narrow timing windows. A single 5 mg dose cut ethinylestradiol peak concentration by 59% and norelgestromin by 55%. The label calls for a non-oral method or added barrier contraception through four weeks after initiation and four weeks after each escalation.

When To Seek Medical Attention

The presentations that warrant immediate medical assessment rather than a dose adjustment:

• Severe, persistent abdominal pain, especially radiating to the back
• Inability to keep fluids down for 24 hours or more
• Signs of severe dehydration: dark urine, dizziness, rapid heartbeat
• Severe right-sided abdominal pain after eating
• Allergic reaction symptoms: hives, facial swelling, difficulty breathing

Managing Side Effects

Most GI side effects resolve with time. The measures that reduce them, in rough order of effect:

1. Slower titration — four weeks minimum at each dose. Escalation duration and step count are the two regimen variables that track tolerance across the incretin class.¹⁵
2. Smaller meals — large portions overwhelm slowed gastric emptying
3. Protein first — before carbohydrate and fat in the same meal
4. Fewer trigger foods — fatty, fried, and spicy foods worsen symptoms
5. Hydration — dehydration amplifies nearly all of these, including heart-rate drift and constipation
6. Evening injection — some tolerate the dose better before sleep

Where symptoms persist through those, the two remaining levers are a longer hold at the current dose and a step back to the previous one. Layering a new dose onto an unresolved reaction is the common avoidable route into intolerance.

Monitoring

The measurements that separate a good response from a fast one:

• Weight, waist circumference, and body composition where a scan is available
• Fasting glucose, HbA1c, and fasting insulin
• Lipid panel and liver enzymes
• Blood pressure and resting heart rate

Weight alone cannot see the lean fraction. Waist and a body-composition measure are what distinguish fat loss from total loss, and resting heart rate is a titration-phase reading rather than an endpoint one.

Tirzepatide vs Semaglutide

In non-diabetic obesity, tirzepatide produced 47% more weight loss than semaglutide (20.2% vs 13.7% in the head-to-head)². Separate matched-population DXA anchors were about 75:25 for tirzepatide and 62:38 for semaglutide; that cross-trial comparison is useful context, not a randomized body-composition contrast. Tirzepatide’s measured safety surface is gastrointestinal and escalation-sensitive, with resting-heart-rate change, delayed gastric emptying, and oral-contraceptive timing relevant to selected users.

In type 2 diabetes, tirzepatide still delivers more absolute fat loss and stronger HbA1c reductions, while one three-arm body-composition study found nearly identical fat-to-lean shares with tirzepatide and semaglutide. Altered GIP responsiveness in diabetes is the leading explanation for that population difference.

Brand confusion clarified

"Ozempic vs Mounjaro" and "Wegovy vs Zepbound" are really asking about semaglutide vs tirzepatide.

See also: Semaglutide Guide (established GLP-1) and Retatrutide Guide (triple-agonist, Phase 3 topline: 28.7% weight loss).

Where Tirzepatide Is the Evidence-Led Choice

Tirzepatide’s load-bearing advantages versus alternatives in the class:

• Non-diabetic obesity with body-composition priority. The pooled DXA substudy landed near 75:25 fat-to-lean, holding across most subgroups.³ Semaglutide’s matched-population anchor is about 62:38. Among approved incretins that makes tirzepatide the stronger body-composition choice on the available measurements, with the caveat from the DXA section above: two separate trials, and placebo in the tirzepatide substudy split the same way.
• Aggressive weight-loss magnitude. About 21% at 15 mg in non-diabetic obesity over 72 weeks,¹ a 47% advantage over semaglutide in the direct head-to-head,² and substantial liver-fat reduction in diabetes with fatty liver⁶ are the measured anchors. For anyone whose metabolic risk rests on total weight-loss magnitude, tirzepatide is where the evidence concentrates.
• Post-semaglutide users whose response plateaued. Tirzepatide adds a GIP signal instead of pushing the GLP-1 arm harder, and the head-to-head shows the molecule produces more weight loss at maximum tolerated doses. A switch is a change of pharmacologic strategy rather than a dose increase.
• Type 2 diabetes with body-composition concern. Tirzepatide still delivers more absolute fat loss than semaglutide in diabetes, even where the incretin defect blunts the body-composition ratio advantage.

Where tirzepatide is not the evidence-led choice:

• Cardiovascular risk reduction as the primary goal. Tirzepatide’s cardiovascular trial ran against dulaglutide, an active comparator, in high-risk type 2 diabetes, and met noninferiority without superiority. Semaglutide’s ran against placebo in obesity with established cardiovascular disease. For a reader whose question is cardiovascular risk, the placebo-controlled instrument answers it and the active-comparator one does not.
• MASH histologic resolution. Semaglutide has the stronger late-stage anchor. Tirzepatide has positive histologic data too,¹⁰ so this is not a blank area for tirzepatide, but semaglutide currently has the stronger late-stage shelf.
• Oral delivery. Rybelsus (oral semaglutide) is the only oral GLP-1 currently available; tirzepatide has no approved oral form.

The decision turns on whether the mechanism matches the goal: GIP-driven fat-cell thermogenesis, dual-receptor engagement, and a mean weight-loss ceiling near 21%.

FAQ

Related Topics

• Tirzepatide Dosing Calculator — full reconstitution math, dose schedule, BAC water by vial size, microdosing
• Semaglutide vs. Tirzepatide — head-to-head decision framework
• Retatrutide vs. Tirzepatide — same receptors plus glucagon arm
• GLP-1 Hub — broader GLP-1 family coverage
• Complete GLP-1 Comparison — interactive cross-compound tool
• Semaglutide Guide — the established GLP-1 benchmark for comparison
• Retatrutide Guide — triple-agonist with 28.7% weight loss in Phase 3 topline and 86% liver-fat reduction in a MASLD subset
• Oral GLP-1 Guide — Wegovy pill vs orforglipron for needle-free options
• GLP-1 Muscle Preservation — protect lean mass during weight loss
• Ask FoxAI — research chat for tirzepatide titration and dual-agonist questions
• NAD+ Guide — cellular energy support that complements metabolic interventions

References

¹ Non-diabetic obesity anchor — SURMOUNT-1 randomized 2,539 adults to 5/10/15 mg for 72 weeks. The page uses the treatment-regimen estimates, -15.0/-19.5/-20.9%, because they include discontinuation and rescue. Week-72 pulse changes were +0.6/+2.3/+2.6 bpm versus +0.1 placebo, but the FDA Zepbound review shows larger means around weeks 16–20 and a rise above 20 bpm at any visit in 9.98% versus 3.35% placebo. That is why endpoint efficacy and escalation-phase heart rate are read through different time windows. Jastreboff NEJM 2022; FDA Zepbound NDA 217806 Medical Review.

² Tirzepatide versus semaglutide — the direct 72-week non-diabetic-obesity trial measured -20.2% versus -13.7% under the treatment-regimen estimand at maximum tolerated doses. This replaces a subtraction across separate registration trials for weight. It was open-label and carried no DXA endpoint, which leaves the body-composition claim to ref ³. Aronne NEJM 2025.

³ DXA body composition — pooled 5/10/15 mg tirzepatide: body weight -21.3%, fat mass -33.9%, lean mass -10.9%, yielding about a 75:25 fat-to-lean share. "Lean" includes water and organs, which is why the page does not relabel the 25% as muscle. Placebo also landed near 75:25; the trial measures the partition under tirzepatide but does not prove that GIP caused it. Look DOM 2025.

⁴ T2D body-composition instrument — in a 28-week three-arm study, tirzepatide and semaglutide produced similar fat-to-lean shares, about 87:13 and 86:14, while tirzepatide reduced more total fat mass. This is why the page does not export the 75:25 versus 62:38 non-diabetic cross-trial contrast into every phenotype or make the ratio itself a receptor proof. Heise Diabetes Care 2023.

⁵ T2D efficacy comparison — over 40 weeks on metformin, tirzepatide 15 mg produced about 13% weight loss versus about 6% on semaglutide 1 mg, with tirzepatide HbA1c changes of -2.01/-2.24/-2.30 points across 5/10/15 mg. The page uses this for the diabetes cohort and glycemic ceiling; the doses and duration differ from the obesity head-to-head in ref ². Frías NEJM 2021.

⁶ Liver-fat MRI — relative liver-fat reductions were -29.8/-39.6/-47.1% at 5/10/15 mg versus -11.2% on insulin degludec. This is a T2D fatty-liver substudy. It supports direction and dose response where baseline liver fat exists, and forecasts nothing for a metabolically healthy liver. Gastaldelli Lancet Diabetes & Endocrinology 2022.

⁷ Mechanism and PK — adipocyte GIPR activation produced SERCA-mediated futile calcium cycling in a mouse transgene model. That supplies a mechanism candidate, not human DXA causality. Yu Cell Metabolism 2025. Schneck’s 19-study popPK gives post-hoc CL/F 0.061 L/h, half-life 5.4 days, and about 1.7× accumulation; the four-week steady-state clock follows from that disposition. Its BW^0.8 clearance term was fixed rather than estimated, inherited from generic therapeutic-protein scaling across 39,644 samples the model never used to fit it. Subgroup exposure ratios are therefore model outputs, not per-weight measurements. Schneck 2024; Wang & Prueksaritanont 2010; Mounjaro FDA label §12.3.

⁸ Receptor architecture — tirzepatide is GIPR-forward and GLP-1R-biased: full cAMP signaling with reduced GLP-1R beta-arrestin recruitment. The common 1.0× GIPR/0.2× GLP-1R shorthand is a functional-potency comparison inside a specific assay, not a literal allocation of clinical effect. That is why the page carries the architecture while refusing to partition weight loss or tolerability into receptor percentages. Willard JCI Insight 2020.

⁹ Maintenance decision — the withdrawal trial held the lead-in constant, then continued tirzepatide or switched to placebo: continuers lost a further 5.5% while switchers regained about 14% over 52 weeks. Aronne JAMA 2024. The 112-week trial then isolated a real step-down: continued maximum tolerated dose, 5 mg, and placebo ended at -21.9/-16.6/-9.9% from baseline, with rescue therapy in 8/25/67%. Horn Lancet 2026. Together they support continued treatment and a measured 5 mg compromise; they do not prove the untested 2.5 mg or extended-interval bands.

¹⁰ MASH histology — after 52 weeks in biopsy-confirmed MASH with F2-F3 fibrosis, 15 mg produced 62% MASH resolution without worsening fibrosis versus 10% placebo. This is a disease-resolution instrument in an already diseased liver, not a general liver-health percentage. Loomba NEJM 2024.

¹¹ Lowest direct dose anchor — the 26-week T2D trial randomized 1/5/10/15 mg. The 1 mg arm had measurable HbA1c activity below the current 2.5 mg start. It supports "pharmacologically active below 2.5 mg"; it does not supply a 72-week obesity weight-loss estimate, and doses below 1 mg remain extrapolated. Frías Lancet 2018.

¹² Semaglutide DXA context — the roughly 62:38 fat-to-lean split is derived from reported STEP 1 DXA mass changes in non-diabetic obesity at 2.4 mg over 68 weeks. It is a separate study, not a randomized body-composition comparison, and "lean" is not equivalent to muscle. Wilding exploratory DXA analysis.

¹³ Real-world dosing — five datasets exceed 40,000 users, but their outcome spread is a denominator and achieved-dose story rather than conflicting potency: broad cohorts, persisters, and selected telehealth completers see different slices. Mody shows 5 mg as the modal maximum and 56–74% of persistent users below 10 mg by the sixth fill; Hankosky’s non-diabetic persisters lose about 11–13% by month six; Duncan’s selected flexible-titration completers approach 23% at one year with only 21% reaching 15 mg. These support a lived median below the label ceiling, not equivalence between low and high doses. Mody · Hankosky · Duncan.

¹⁴ Sequential lower-dose cohort — 70 non-diabetic participants recorded -4.7% body weight, -25% fasting insulin, and -30% on the insulin-resistance score during an initial 2.5 mg phase lasting 4.2 ± 0.7 weeks, then advanced to 5 mg for 13.1 ± 5.4 weeks. Because dose and time changed together in the same people, this is a direct short-phase 2.5 mg measurement, not a flat-dose long-term trial or a valid between-phase GI-rate comparison. Barrea 2026.

¹⁵ Titration decision — tirzepatide’s nausea ED50 moved 15.6→78.7 mg/week and vomiting ED50 43.3→209 mg/week under the full escalation regimen, about fivefold shifts with non-overlapping intervals. Across nine incretin mimetics, escalation duration (r²=0.834; p=0.0010) and step count (r²=0.764; p=0.0045) tracked tolerance while starting fraction did not (p=0.093). The result supports more time and more steps; it does not say a fast ramp is harmless below a chosen threshold. Nauck 2026.

¹⁶ Adverse-event ascertainment — the checked protocol sections use nonleading open enquiry and permit dietary counseling, antiemetics, dose interruption, and dose reduction before the published rate is counted; the antiemetic-treated fraction is unpublished. The page therefore calls these volunteered, post-mitigation trial measurements rather than symptom-checklist incidence. Verified in SURMOUNT-3 §§6.6.2/8.3.2.11, SURMOUNT-CN §7.4.2, and GPIF §8.3.1.1; not assumed across the entire program.

¹⁷ Cardiovascular outcomes — in 13,165 high-risk T2D participants over a median four years, tirzepatide was noninferior to dulaglutide on MACE-3, HR 0.92 (0.83–1.01), but did not meet primary superiority. The testing sequence stopped there, leaving MACE-4 HR 0.88 and all-cause-death HR 0.84 as nominal downstream intervals; the paper states they are not adjusted for multiplicity. Of 103 fewer deaths, 62 were non-cardiovascular. The page therefore carries noninferiority in the enrolled cohort without turning the downstream figures into demonstrated cardiovascular superiority. Nicholls NEJM 2025.