Semaglutide

What it is

Semaglutide is a long-acting synthetic analog of GLP-1 (glucagon-like peptide-1), one of the gut hormones your body releases after you eat. It’s the molecule behind Ozempic (the diabetes brand), Wegovy (the obesity brand), and Rybelsus (the daily pill) — all the same active compound at different doses and routes.

It matters historically because it’s the drug that broke the ceiling. For years, weight-loss medicine topped out around 5–9% (the liraglutide era). Semaglutide roughly doubled that to ~15% in its pivotal obesity trial, and then did something no weight-loss drug had ever done: in a 17,604-person trial it cut major cardiovascular events by 20%. That turned “weight-loss drug” into “cardiometabolic medicine” overnight.

On raw weight loss it has since been passed — Tirzepatide (dual agonist, ~21%) and Retatrutide (triple agonist, ~24%+) hit more receptors and lose more weight. But semaglutide still owns the deepest evidence base in the class. If you want the molecule with the most human-outcome data behind it — not just scale numbers, but heart, kidney, and liver endpoints — this is it.

How it works

Semaglutide is a single-receptor drug: it agonizes the GLP-1 receptor, and that one lever does three useful things.

In the brain — GLP-1 receptors in the hypothalamus and hindbrain lower appetite and quiet “food noise.” You feel full sooner and think about food less.

In the gut — it slows gastric emptying, so food sits in the stomach longer. Satiety hits earlier in a meal and lasts longer, so intake drops without willpower doing the heavy lifting.

In the pancreas — it amplifies glucose-dependent insulin secretion. The “glucose-dependent” part is the safety feature: it only pushes insulin when blood glucose is actually elevated, so on its own it carries a low risk of driving you hypoglycemic (unlike old-school insulin or sulfonylureas).

What it does not have is a second or third receptor. Tirzepatide adds GIP (better fat handling and insulin synergy); retatrutide adds glucagon on top of that (raised energy expenditure — burning more, not just eating less). Semaglutide works almost entirely through the “eat less” side of the ledger. That’s why its weight-loss number lands below the dual and triple agonists — and why some people plateau on it and step up to those. See The 2026 GLP-1 pipeline — Dulaglutide, Liraglutide, Semaglutide, Tirzepatide, CagriSema, Mazdutide, MariTide, Pemvidutide, Petrelintide, VK2735, Orforglipron, Survodutide, Eloralintide, Retatrutide for the full Sema → Tirz → Reta mechanism progression.

What the research shows

Semaglutide has the strongest, broadest human evidence in this entire cluster — large phase-3 RCTs with hard clinical endpoints, not just surrogate markers.

Obesity:

• STEP-1 (Wilding 2021, NEJM, n=1,961, 68 wks) — semaglutide 2.4 mg/wk + lifestyle produced −14.9% body weight vs −2.4% placebo; 86% lost ≥5%. The benchmark every newer agent is measured against. [PMID 33567185]
• STEP-1 extension (Wilding 2022) — after stopping, participants regained about two-thirds of their lost weight (from −17.3% at week 68 to net −5.6% at week 120). This is the honest durability fact: it’s a tool that works while you use it, not a one-time cure. [PMC9542252]
• STEP-4 (Rubino 2021, JAMA) — a withdrawal-design trial: continuing semaglutide kept weight coming off, while switching to placebo reversed the loss. Confirms continued treatment maintains the result. [PMID 33755728]

Type 2 diabetes:

• STEP-2 (Davies 2021, Lancet, n=1,210, 68 wks) — −9.6% vs −3.4% placebo in overweight/obese adults with T2D. Note the smaller number: weight loss is consistently blunted in diabetic vs non-diabetic populations across this whole drug class. [PMID 33667417]
• SUSTAIN-6 (Marso 2016, NEJM, n=3,297) — reduced cardiovascular death/MI/stroke vs placebo in high-CV-risk T2D. [PMID 27633186]
• SOUL (McGuire 2025, NEJM, n=9,650) — oral semaglutide reduced major cardiovascular events vs placebo in high-risk T2D with established vascular or kidney disease. [PMID 40162642]

Cardiovascular — the landmark:

• SELECT (Lincoff 2023, NEJM, n=17,604, ~40 months) — in overweight/obese adults with established cardiovascular disease but without diabetes, semaglutide cut major adverse cardiovascular events to 6.5% vs 8.0% placebo — a 20% relative risk reduction (HR 0.80, 95% CI 0.72–0.90, p<0.001). The first weight-management drug ever proven in a rigorous RCT to reduce cardiovascular events. This is the trial that reframed obesity as a modifiable cardiovascular risk factor. [PMID 37952131]

Kidney:

• FLOW (Perkovic 2024, NEJM, n=3,533, ~3.4 yr) — slowed kidney-disease progression and reduced cardiovascular death risk in T2D with chronic kidney disease. [PMID 38785209]

Liver / MASH:

• ESSENCE part 1 (Sanyal et al. 2025, NEJM) — phase 3, biopsy-confirmed MASH (metabolic-dysfunction-associated steatohepatitis) with stage 2–3 fibrosis, 72 weeks. Steatohepatitis resolution without worsening fibrosis: 62.9% vs 34.3% placebo (difference +28.7%, p<0.001); fibrosis improvement without worsening MASH: 36.8% vs 22.4% (p<0.001); mean weight −10.5% vs −2.0%. A strong, biopsy-confirmed liver signal that parallels the liver-fat findings for Tesamorelin and Retatrutide. [PMC11784563]

Head-to-head — where it sits in the class:

• Frías 2021 (NEJM) — head-to-head in T2D, Tirzepatide beat semaglutide on both HbA1c and weight loss. [PMID 34170647]
• REDEFINE / Garvey 2025 (NEJM) — CagriSema (cagrilintide + semaglutide) beat semaglutide alone (−20.4% vs placebo; ~12.9% vs 9.2% head-to-head) but, in REDEFINE-4, missed non-inferiority against tirzepatide 15 mg. [PMID 40544433] See The 2026 GLP-1 pipeline — Dulaglutide, Liraglutide, Semaglutide, Tirzepatide, CagriSema, Mazdutide, MariTide, Pemvidutide, Petrelintide, VK2735, Orforglipron, Survodutide, Eloralintide, Retatrutide.

The honest read: semaglutide is a Tier-A, FDA-approved drug with more proven hard outcomes (heart, kidney, liver) than any newer agent in the class — and a lower peak weight-loss number than the dual/triple agonists that came after it. Its biggest practical limitation is durability: stop, and most of the weight comes back, because it doesn’t change the underlying biology, it manages it. There is no meaningful preclinical-vs-human disagreement here; the dataset is human and large. The real expert disagreement is operational (titration speed, split dosing, compounded supply) — covered below.

Real-world protocol

The doses and information here are educational only. Semaglutide is a prescription drug; compounded versions are dispensed under a prescription. This is not medical advice. Loop in a qualified physician — especially if you have any of the contraindications below.

FDA-label titration (Wegovy/Ozempic), the conservative spine:

Weeks	Dose	Increment from previous
1–4	0.25 mg/wk (starting dose — not a treatment dose)	—
5–8	0.5 mg/wk	+0.25 mg
9–12	1.0 mg/wk	+0.5 mg
13–16	1.7 mg/wk	+0.7 mg
17+	2.4 mg/wk (full obesity dose)	+0.7 mg

— the 2.4 mg/wk obesity maintenance dose is the STEP-1 dose and is firm. The increment pattern is “a little funny — you increase by either a quarter of a milligram or 0.7 milligram” — small at the bottom, larger as you climb, so it’s worth tracking your last dose to know your next step.

Concrete syringe anchor (NEW 2026-06-13, via Sassin): 0.25 mg/wk = 10 units on a U-100 insulin syringe = 0.1 mL volume. That implies a vial concentration of 2.5 mg/mL — which is what you get reconstituting a typical compounded 15 mg vial with ~6 mL of bacteriostatic water (matching Emer’s reconstitution reference and closing the prior on vial concentration). The full ladder on a U-100 syringe: 10 → 20 → 40 → 68 → 96 units for 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg respectively (rounded to the nearest unit).

What practitioners actually do differently (Dr. Stirrett): start at 0.25 mg/wk for 2 weeks, then reassess — in his clinical experience roughly half of patients don’t need to escalate at all. If you do escalate, the smoother first move is split dosing: 0.25 mg twice a week (same weekly total as 0.5 mg once weekly, but steadier blood levels instead of a once-weekly spike) — widely reported to cut injection-day nausea. Then step up to 0.5 mg once weekly only if needed. The single biggest avoidable mistake on semaglutide is escalating too fast — the “telemedicine pill-mill” pattern of starting at 0.5–1 mg to show fast results, which just front-loads side effects.

What practitioners actually do differently (Dr. Sassin, NEW 2026-06-13): Sassin’s framing complements Stirrett’s with one operational nuance worth knowing — escalation timing is more flexible than the FDA label suggests, mechanistically. The label says “step up every 4 weeks,” but with a ~7-day half-life what matters is cumulative blood level, not the calendar. Two practical consequences:

• You can escalate “anytime” if your current dose isn’t working and side effects are tolerable. If you take the 0.25 mg starter dose and feel it’s not enough at day 2, a second 0.25 mg dose at day 2 just totals 0.5 mg in your system — “a fifth of the maximum dose.” Not a spike; just an earlier arrival at the next step.
• Dose timing within the week is irrelevant. “Does it matter what time of day you take it? Nope. Does it matter if you take it a day early or a day late? No. But what matters is how much medication you have in you.” Useful for removing false-precision anxiety many users have around weekly injection timing.
• Subjective appetite-suppression onset: ~0.5–1 day after injection. Useful for setting realistic first-shot expectations — “didn’t feel anything 2 hours in” isn’t a reason to think the dose is wrong.
• If you’ve been on GLPs before, restart can begin at a higher dose than the 0.25 mg true-naive starter — depending on how much you took previously and how you tolerated it. The full re-titration from scratch is for true-GLP-1-naive patients.

The convergent point across all three sources (FDA label + Stirrett + Sassin): minimum-effective dose, conservative on the ramp, escalate only when current dose underperforms AND side effects are tolerable. Different operational tactics; same underlying philosophy.

Sassin’s escalation decision rule, captured cleanly: three variables at each follow-up — current dose × current weight-loss rate × side-effect tolerability → escalate or hold. Side effects tolerable + weight loss stalling → bump it up. Side effects rough → stay. Weight loss going well at current dose → stay.

The full 6-variable dose-decision algorithm (NEW 2026-06-13, via Dr. Spencer Nadolsky — applies to BOTH semaglutide AND Tirzepatide). Sassin’s three-variable rule is the lean version of what experienced obesity-medicine practitioners actually use. Nadolsky (triple-board-certified MD: family medicine + obesity medicine + lipidology; founder of Vineyard) lays out the full algorithm in clean decision-rule form. The trials (STEP for semaglutide, SURMOUNT for tirzepatide) titrated dose on a fixed schedule regardless of how patients were doing — and Nadolsky is explicit that “there has not been a randomized trial looking at how we do it in clinical practice versus the trials that have just increased their dose no matter what”. The clinical-practice algorithm is what follows, sequential, with each variable able to halt or reverse escalation:

#	Variable	Decision rule
1	Side effects (0–5 scale: 0 none, 5 severe)	3-5 → HOLD or DECREASE. Always comes first. Write the insurance letter if a payer is forcing escalation on a poorly-tolerating patient.
2	Rate of weight loss (% TBW/week)	> 1%/wk → HOLD or DECREASE. 0.5–1%/wk = the Goldilocks zone. < 0.5%/wk and no side-effect veto → escalate.
3	BMI floor	At or near BMI 21 → DECREASE the dose, even if other variables would allow more. Don’t drop below this floor.
4	Hunger / appetite (forward indicator)	In-zone weight loss BUT hungry and unlikely to sustain → ESCALATE proactively. Prevents plateaus before they happen.
5	Patient preference (tiebreaker)	When other variables are neutral, defer to the patient. Push back when preference conflicts with safety.
6	Cost (modifier)	Self-pay / Lilly Direct → bias slightly aggressive to maximize bang-for-buck. Insurance-covered → neutral. Current Lilly Direct Zepbound (tirzepatide) pricing as of Feb 2026 (verified 2026-06-13): 2.5 mg = $299/mo, 5 mg = $399/mo, 7.5/10/12.5/15 mg = $449/mo with the 45-day refill-compliance window (without compliance: $599/$699/$849/$1049 respectively). Nadolsky’s quoted “$499/mo” figure (transcript ~[06:21–06:25]) was outdated — Eli Lilly significantly lowered self-pay Zepbound pricing effective Feb 23, 2026. Useful pricing-environment context for OHM content: the Lilly Direct cash-pay tier is now substantially cheaper than wellness-spa retail markup ($500-$1000/mo per Dr. John yesterday’s digest) and approaches compounded-503A pricing.

Why the 1%/wk ceiling. Faster weight loss raises gallstone-formation risk (the existing wiki Side-Effects section already flags this generically — Nadolsky pins the threshold at 1%/wk) AND raises muscle-loss risk regardless of method (drug or diet alone). Both reinforce the existing wiki recommendations for resistance training + ~1 g/lb protein during the loss phase.

The first-month water-weight caveat (overrides variable 2 in weeks 1-4): TBW loss may run 1.5-2%/wk in the first few weeks and that’s largely water weight, not fat. Don’t penalize a patient for “going too fast” in month 1. After month 1, normalize the target back to 0.5-1%/wk.

Trial protocol vs clinical practice — the load-bearing honest framing. The STEP and SURMOUNT trials cranked dose on a fixed protocol regardless of weight-loss rate or tolerance. Real clinical practice individualizes. No RCT compares the two approaches head-to-head for long-term outcomes — meaning the “right” titration aggressiveness is genuinely open, and an algorithm built on side effects, weight-loss rate, BMI, hunger, preference, and cost is a reasonable evidence-asymmetric extension of the trial data. Source:.

The split-dose path in detail (NEW 2026-06-13, via Dr. G — lifestyle-medicine practitioner; applies to BOTH semaglutide AND Tirzepatide). Stirrett (above) introduced the split-dose alternative as a smoother first move; Dr. G provides the full operational framework for when split-dose helps, when it doesn’t, and how to use it safely. Captures the patient-experience phenomenology the prior sub-sections don’t articulate:

The peak-and-trough roller-coaster (why patients say “it stopped working”). ~[01:43–02:21] Many users on once-weekly GLP-1s describe a predictable pattern: shot day → 20–48 hours of nausea / reflux / fatigue / zero appetite (“the medication is actually working”) → midweek “just okay” → end-of-week hunger and cravings creep back. Patients then say “it just stopped working.” The mechanism is the natural peak-trough waveform of any once-weekly drug — “what you’re feeling is a peak and trough pattern, meaning the highest level of the medication in your bloodstream and the lowest level of the medication in your bloodstream.” Split-dosing flattens that waveform by spreading the same total weekly amount into smaller portions on a structured schedule.

Who split-dose actually helps — three candidate patterns:

Pattern	Symptom	What it tells you
1	Strong side effects right after injection even with reasonable hydration/meals; you dread shot day	High peak is too high → split flattens it
2	Feel great for 3–4 days, then hunger and cravings return hard near end of week	Low trough is too low → split keeps levels above hunger threshold longer
3	Every dose increase makes you miserable, so you get stuck below your goal dose	Step-ups are too steep → smaller increments smooth the transition

Who it is NOT for: if results are stalled because of low protein / missing strength training / dropped daily steps / wrecked sleep / high-fat-meal-triggered nausea — “split-dosing won’t fix the real problem.” And severe abdominal pain, persistent vomiting, significant dehydration, or unclear evolving symptoms are “not a schedule tweak situation. That’s a medical evaluation situation.” Respect that boundary.

The five safety rules:

1. Never change dose or schedule without prescriber guidance.
2. 🔑 Split-dosing does NOT mean increasing the total weekly dose. This is the load-bearing anti-mislabeling guardrail — if a clinic is selling you “split-dose protocol” at a higher weekly total than your previous dose, that’s not split-dosing, that’s dose-escalation under a marketing label.
3. Consistency matters — set days, not random timing.
4. Side-effect basics still apply — hydration, smaller meals, lower-fat choices.
5. Follow pen, device, and pharmacy instructions exactly. No improvising.

Fix-the-basics-first self-audit (before talking to your prescriber):

Audit	What it catches	Fix
Meals	Large/fast/high-fat eating creates nausea that feels like the dose is too strong	Smaller, leaner, slower meals
Hydration + constipation	Constipation alone causes nausea + bloating + stalls	Fluids + daily walking
Protein	Low protein → fatigue + muscle loss + plateaus people blame on the medication	Consistent ~1 g/lb of goal weight

“If those are clean and the roller coaster remains, then the split-dose conversation becomes more reasonable.”

What to actually say to your prescriber:

Describe your specific pattern. “For one or two days after injection, side effects typically interfere with my eating and my function, and by day five, the hunger returns.” Or: “Each titration step-up causes side effects I can’t tolerate.”

Then ask the question. “Is there a safer titration approach or smaller increment strategy or split schedule that could smooth my peaks and troughs while keeping the same total weekly plan?”

Accept the answer — yes, no, or not yet. If they say “not yet,” it usually means basics first.

Why this matters editorially: tolerability + consistency → durable results. “Split-dosing is not a shortcut to faster weight loss. The real benefit is often tolerability and consistency. And consistency is what produces the long-term results. If you can tolerate the plan, you can stay on it. If you can stay on it, you can protect muscle, avoid plateaus, and prevent regain.” Direct-quote candidate; OHM editorial voice match.

Source:.

🚨 Terminology note (NEW 2026-06-13) — “microdose” means two different things in the GLP-1 space. Dr. G’s video (above) and many clinical YouTube sources use “microdose” as a loose synonym for either (a) smaller titration increments or (b) split-dosing the same total weekly amount across two days. This collides directly with the strict definition the rest of this KB uses for the word, sourced from the a popular practitioner GLP-1 masterclass and documented in Tirzepatide → Real-world Protocol:

Definition	What it means	Source
Strict (Williams/Campbell, the KB’s house definition)	A literal fraction of the starting dose (e.g., 0.5–1.5 mg tirzepatide vs 2.5 mg starting). A hormone-balance + metabolic-optimization strategy, not aggressive weight loss.	Tirzepatide Real-world Protocol
Loose (Dr. G + several other lifestyle-medicine sources)	Smaller titration increments OR split-dosing the same total weekly dose. A tolerability-smoothing strategy, not a dose reduction.

These are not the same thing. The strict definition is what telemedicine pill-mills are mislabeling when they sell standard 2.5 mg starting doses as “microdose protocols” (the existing tirzepatide.md wiki flags this pattern explicitly, citing Tyna’s documentation of patients miserable from vomiting at standard starting doses being told it’s a microdose). The loose definition is what Dr. G uses honestly above — but using the same word for both creates exactly the confusion the pill-mill marketing exploits.

OHM editorial standard going forward (this article’s house position): use “microdose” ONLY for the strict Williams/Campbell definition (literal fraction of starting dose for hormone-balance / metabolic-optimization). Use “split-dose” or “split-dosing” for the same-total-weekly-dose-spread-across-two-days approach. Preserves both concepts cleanly and gives readers an unambiguous vocabulary to push back against pill-mill mislabeling. Per OHM doctrine on contradictions: both definitions captured; conditions mapped; OHM’s house position stated transparently with the counter visible.

Reconstitution & technique (research/compounded vials, Dr. Emer): reconstitute with bacteriostatic water — Emer used ~6 mL per vial; on the typical 15 mg compounded vial that gives 2.5 mg/mL (confirmed via Sassin’s 10-units = 0.25 mg syringe anchor, 2026-06-13). Draw a working volume of ~0.1–1 mL on a U-100 insulin syringe (the dosing-table column above), inject subcutaneously once weekly. Powder is room-temp stable; once reconstituted, refrigerate. Swirl gently, never shake. Rotate injection sites every time — same-spot injecting causes lumps and scar tissue.

Brand-name pen note: only the lower-strength “starter” pen dials down to 0.25 mg; the higher fixed-dose pens don’t. If you’re on brand-name and starting therapy, that’s the pen to be on.

🚨 Hard rule — never stack with another GLP-1 receptor agonist. Do NOT combine semaglutide with Tirzepatide (Mounjaro / Zepbound), Retatrutide, Liraglutide, or any other GLP-1 receptor agonist. All of these molecules bind the same GLP-1 receptor (tirzepatide and retatrutide additionally hit GIP; retatrutide adds glucagon). Stacking them double-binds the receptor and compounds the entire side-effect tail — GI severity, hypoglycemia risk, gallstone and pancreatic stress, dehydration, electrolyte loss, and heart-rate effects all stack — without a corresponding compounding of the weight-loss benefit. Pick one drug in this class and titrate it slowly. The protocol builder on this site enforces this rule and will warn you if you try to combine them. This applies across the whole class: semaglutide ⨯ tirzepatide, semaglutide ⨯ retatrutide, tirzepatide ⨯ retatrutide — none of these combinations are safe or productive.

Stacking. Resistance training (2–3×/wk) plus adequate protein (~1 g per pound of goal body weight) is the non-negotiable to keep the weight you lose fat rather than muscle — true for every drug in this class. The most-cited lean-mass-preservation adjuvant is CJC-1295 / Ipamorelin (GH-axis support); Tesamorelin is the visceral-fat / GH-axis pairing; for skin laxity after rapid loss, GHK-Cu / GLOW. For loose skin (“Ozempic face”), slower titration + protein + topical collagen support are the levers.

Cycling / stopping. Obesity is a chronic, relapsing condition; semaglutide is generally continuous, not cycled. If you stop, expect to regain roughly two-thirds of the loss unless the lifestyle foundation (training, protein, sleep, real food) is fully in place — taper rather than quit cold, and have a maintenance plan.

Side effects & management

Standard GLP-1 profile, well characterized across tens of thousands of trial participants:

• GI dominant — nausea, diarrhea, constipation, occasional vomiting. Worst during titration (especially the first 1–2 weeks of each step), mostly mild-to-moderate, and they ease over 4–8 weeks. Fixes: slow titration (or split dosing), smaller and lower-fat meals during the ramp, and hydration (GLP-1s blunt thirst, so people dehydrate without noticing).
• “Ozempic face” / loose skin — a function of rapid weight loss in general, not a semaglutide-specific effect. Slower loss + adequate protein + topical GHK-Cu mitigate it.
• Gallstones — any rapid weight loss raises the risk; sudden right-upper-quadrant pain after a fatty meal warrants evaluation.
• Pancreatitis — a low-rate class concern; severe upper-abdominal pain radiating to the back means stop and get seen. These two are the “don’t push through” red flags.
• Thyroid C-cell tumors — a class-wide boxed warning based on rodent studies. Contraindicated if you (or a first-degree relative) have medullary thyroid carcinoma or MEN-2 syndrome.
• Muscle loss — covered above; protein + resistance training is the only real prevention.
• Diabetic retinopathy — in SUSTAIN-6, a rapid drop in blood glucose was associated with early worsening of pre-existing retinopathy. If you have diabetic eye disease, this is a reason to titrate slowly and have it monitored — the effect is tied to the speed of glucose improvement, not the drug itself.
• Oral-medication absorption — because semaglutide slows gastric emptying, it can change how quickly oral drugs are absorbed. Usually minor, but worth spacing or flagging time-sensitive oral medications (and discussing with your prescriber if you take narrow-margin drugs).

Anyone with a personal/family history of MTC or MEN-2, prior pancreatitis, or active gallbladder disease should clear it with a physician before starting.

Regulatory status

Semaglutide is FDA-approved: Ozempic (type-2 diabetes, 2017), Rybelsus (oral, type-2 diabetes, 2019), and Wegovy (obesity, 2021), with Wegovy later cleared to reduce cardiovascular events in adults with established cardiovascular disease plus overweight/obesity (on the strength of SELECT).

How you actually get it — clinicians and compounding pharmacies only. Unlike the verified-vendor research-use-only peptides covered elsewhere on this site, semaglutide reaches you one of two ways: a prescription for brand-name Ozempic/Wegovy/Rybelsus, or a prescription-dispensed compounded version from a 503A/telehealth pharmacy (the cash-pay lane). There is no legitimate over-the-counter or “research-use-only catalog” path for it the way there is for, say, retatrutide or tesamorelin. After the FDA declared the semaglutide shortage resolved in 2025 and tightened the compounding rules, the compounded supply became more constrained — which is worth knowing if cost or access is your reason for considering it. If supply quality is a concern, the same principle that applies across this space applies here: a third-party certificate of analysis (COA) is the proof; unverified compounded supply is the real risk, not the molecule.

Not a named WADA-prohibited substance the way some growth-hormone secretagogues are.

Sources

• STEP-1 (Wilding 2021, NEJM): 33567185 · DOI 10.1056/NEJMoa2032183 · NCT03548935
• STEP-1 extension / weight regain (Wilding 2022, Diabetes Obes Metab): PMC9542252
• STEP-4 (Rubino 2021, JAMA): 33755728
• STEP-2 (Davies 2021, Lancet): 33667417 · DOI 10.1016/S0140-6736(21)00213-0
• SUSTAIN-6 (Marso 2016, NEJM): 27633186 · DOI 10.1056/NEJMoa1607141
• SELECT (Lincoff 2023, NEJM): 37952131 · DOI 10.1056/NEJMoa2307563
• SOUL (McGuire 2025, NEJM, oral sema CV): 40162642
• FLOW (Perkovic 2024, NEJM, CKD): 38785209
• ESSENCE part 1 (Sanyal 2025, NEJM, MASH): PMC11784563
• Frías 2021 (NEJM, tirzepatide vs semaglutide head-to-head): 34170647
• REDEFINE / Garvey 2025 (NEJM, CagriSema): 40544433
• KB: (this build’s sourced notes), (titration + split-dose), (reconstitution/technique), (class positioning), (added 2026-06-13) — Dr. G (Lifestyle Medicine Network YouTube channel; no full name disclosed on-camera). 10:02 single-topic video on split-dosing GLP-1s. Moderate practitioner-supervision overlay offset by fix-the-basics-first gating + patient-empowerment prescriber script. Net contribution: the peak-trough roller-coaster phenomenology (patient-experience reframe of “it stopped working”); the 3 candidate patient patterns for split-dose triage; the 5 safety rules with Rule 2 (total weekly dose unchanged) as the load-bearing anti-mislabeling guardrail; the fix-the-basics-first self-audit (meals, hydration+constipation, protein); the prescriber-conversation script as patient-empowerment tool; AND the microdose-vs-split-dose terminology disambiguation that resolves a contradiction with the existing tirzepatide.md Williams/Campbell strict definition. House editorial position now stated: “microdose” reserved for the strict Williams/Campbell definition (literal fraction of starting dose for hormone-balance / metabolic-optimization); “split-dose” for spreading the same total weekly dose across two days for tolerability. Per OHM doctrine on contradictions: both definitions captured side-by-side with conditions mapped; OHM’s house position stated transparently with the counter visible. Author-attribution rule for OHM content using this digest: “a lifestyle-medicine practitioner (‘Dr. G’ on YouTube)” — establishes the clinical role without making credential claims that can’t be verified. — (added 2026-06-13) — Dr. Spencer Nadolsky (triple-board: family medicine + obesity medicine + lipidology; CEO/founder of Vineyard online metabolic-obesity care). 6:41 single-topic video on the dose-decision algorithm for GLP-1s (applies equally to semaglutide and tirzepatide). Unusually light practitioner-supervision overlay — explicit evidence-gap acknowledgment, decision-rule teaching, insurance-advocacy voice, no upsell tactics. Net contribution: the full 6-variable decision algorithm (side effects + rate of weight loss + BMI floor + hunger forward-indicator + patient preference + cost) inserted into “Real-world Protocol” after the existing Stirrett + Sassin clinician blocks; the 1%/wk gallstone+muscle-loss threshold (with mechanism justifications); the BMI 21 floor (clinician practice convention, new operational rule to KB); the first-month water-weight caveat (1.5-2%/wk in weeks 1-4 is mostly water); the STEP/SURMOUNT-vs-clinical-practice contrast explicitly named with the honest “no RCT compares the two” acknowledgment; the Lilly Direct $499/mo pricing anchor as a useful direct-to-consumer pricing data point for OHM content. Algorithm applies equally to Tirzepatide — cross-link sentence added in that article’s Real-world Protocol section pointing to this algorithm here as the canonical insertion. Complements rather than duplicates Stirrett (starting-dose) and Sassin (early-titration mechanics) — three-clinician convergence on the same minimum-effective-dose philosophy at increasing operational layers. Author-attribution rule for OHM content using this digest: “Dr. Spencer Nadolsky, triple-board-certified physician (family medicine, obesity medicine, lipidology)” — establishes clinical credibility on prescription-drug dosing decisions; the credentials attach as transparency, not gatekeeping. — (added 2026-06-13) — Dr. Andre Sassin (Lighthouse Weight Loss, GLP-1 telemedicine clinic, “GLP University” YouTube series). 5:12 single-topic dosing-mechanics explainer. Unusually light practitioner-supervision overlay for the source class — free initial + follow-up consults, anti-escalation philosophy, no upsell tactics. Net contribution: the U-100 syringe anchor (0.25 mg = 10 units → 2.5 mg/mL vial concentration, which closes Emer’s prior on vial mg strength and unlocks the builder dosing-preset encoding); the increment-pattern explanation (0.25 → 0.25 → 0.5 → 0.7 → 0.7 mg steps); the “anytime escalation” rule with PK reasoning (cumulative blood level matters, not the calendar); the “timing doesn’t matter, cumulative levels do” PK frame; the 0.5–1 day subjective-onset anchor; the GLP-1-experienced-restarter rule (don’t re-titrate from scratch if you’ve cycled GLPs before). Complements rather than duplicates the existing Stirrett digest. All operational additions to the Real-world Protocol section; no changes to the evidence backbone (STEP-1 / SELECT / ESSENCE / FLOW / SOUL).

Builder integration note (2026-06-13): semaglutide is currently missing from src/_data/lib/dosing-presets.js despite being a builderEligible: true peptide in meta.js. The Sassin syringe anchor (this digest) provides the data needed to encode the preset cleanly. Recommended encoding (parallel to the existing tirzepatide entry): 'Semaglutide': {vial:15, bac:6, dose:250, unit:'mg', freq:1, range:[250, 2400], note:'Start 0.25 mg/wk (10 units). Step up every 4 wks: 0.5 → 1.0 → 1.7 → 2.4 mg. Steady at 2.4 mg/wk = full obesity dose. Some clinicians reassess at 2 wks (Stirrett) or use split-dosing 0.25 mg twice/wk.'} — plus the 'semaglutide': 'Semaglutide' entry in PRESET_BY_SLUG. ~2-line addition; closes the #1 missing builder preset per the same-session dosing-coverage audit.

Cross-links: Tirzepatide · Retatrutide · The 2026 GLP-1 pipeline — Dulaglutide, Liraglutide, Semaglutide, Tirzepatide, CagriSema, Mazdutide, MariTide, Pemvidutide, Petrelintide, VK2735, Orforglipron, Survodutide, Eloralintide, Retatrutide · Tesamorelin · CJC-1295 / Ipamorelin · GHK-Cu.