Semaglutide and tirzepatide are the two GLP-1 medications worth knowing about. Both are weekly injections. Both produce clinically meaningful weight loss far beyond what diet and training alone can sustain. Tirzepatide produces more weight loss on average (≈20.9% body weight at 72 weeks in SURMOUNT-1); semaglutide has the longer track record and a lower price point (≈14.9% body weight in STEP-1 at 68 weeks).
The hard parts: nausea in the first 2-4 weeks, the risk of losing significant muscle mass alongside fat, the need to actually keep eating protein and training, and the question of what happens when you stop. None of these are reasons to avoid the medications. They are reasons to use them with a real protocol around them.
What this guide covers
How GLP-1 medications work
GLP-1 (glucagon-like peptide-1) is a hormone your gut releases after you eat. It does three useful things: it signals satiety to your brain, it slows gastric emptying so food sits in your stomach longer, and it improves insulin sensitivity. GLP-1 receptor agonist medications are synthetic analogs of this hormone, dosed weekly, that hold those signals at therapeutic levels around the clock.
Semaglutide activates one receptor (GLP-1). Tirzepatide activates two (GLP-1 and GIP, glucose-dependent insulinotropic polypeptide). That second receptor is why tirzepatide produces meaningfully more weight loss on average — GIP signaling amplifies appetite suppression and improves how your body uses fat for fuel.
If you want the deeper mechanism, see GLP-1 and dopamine for how appetite is actually rewired, and food noise, explained for the subjective experience most patients describe within the first month.
Semaglutide vs tirzepatide, head to head
The simplest version of the choice: tirzepatide is the stronger weight-loss molecule; semaglutide has the longer track record and is cheaper. Both are weekly subcutaneous injections.
| Marker | Semaglutide | Tirzepatide |
|---|---|---|
| Mechanism | GLP-1 agonist | Dual GIP / GLP-1 agonist |
| Pivotal trial | STEP-1 (NEJM 2021) | SURMOUNT-1 (NEJM 2022) |
| Average weight loss | 14.9% at 68 weeks (2.4 mg) | 20.9% at 72 weeks (15 mg) |
| ≥5% loss | ~86% of participants | ~96% of participants |
| Cardiovascular outcomes | SELECT: 20% reduction in MACE in patients with obesity + prior CV disease, no diabetes (NEJM 2023) | Outcomes trial (SURPASS-CVOT) ongoing |
| OPTML price (compounded) | $249/mo | $349/mo |
FDA disclosure: STEP-1 and SURMOUNT-1 were conducted with FDA-approved branded products. OPTML dispenses compounded preparations via licensed 503A pharmacies under U.S. physician prescription. Compounded preparations are not FDA-approved. Individual results vary.
For a deeper head-to-head, see. For "which one should I pick if I'm new to GLP-1s," see.
Who GLP-1 medications are for
The FDA-approved branded products (Wegovy®, Zepbound®) are indicated for adults with a BMI of 30+ (obesity), or BMI 27+ (overweight) with at least one weight-related comorbidity (high blood pressure, type 2 diabetes, dyslipidemia, sleep apnea, etc.). Most prescribers extend that framework to compounded preparations as well.
That said, the "right candidate" question is rarely about BMI alone. It's about whether weight loss is a leverage point on your specific health trajectory. Some realistic profiles where GLP-1s tend to be the right tool:
- The 30+ lb weight-to-lose adult who has lost and regained weight repeatedly. GLP-1s solve for the satiety setpoint that diet alone can't.
- The metabolically dysfunctional but lean-ish adult. Visceral fat, insulin resistance, fatty liver — GLP-1s improve all three independent of total weight loss.
- The already-fit optimizer who's stalled. Microdosing (lower doses, see microdose GLP-1) gets some of the metabolic upside without the dramatic appetite suppression.
Articles on candidacy: GLP-1 and fertility · GLP-1 and menopause weight · GLP-1 and sleep apnea.
What to expect, month by month
The trajectory is reasonably predictable. Numbers below are averages from the Phase 3 trials and our clinical experience; individual variation is wide.
Month 1
You'll start at a low dose (semaglutide 0.25 mg; tirzepatide 2.5 mg) for a reason: tolerance. Expect mild nausea in the first 24-72 hours after each dose, particularly weeks 1-3. Hunger signal noticeably dampens by week 2. Weight loss is small (1-3% body weight). The point of month 1 is not weight loss — it's confirming tolerance and titrating up.
Months 2-3
Doses titrate up monthly. Appetite suppression is now substantial — most patients describe being "uninterested" in food rather than feeling forced to restrict. Weight loss accelerates to roughly 1-1.5% body weight per week on tirzepatide, slightly less on semaglutide. This is the easiest stretch.
Months 4-9
Steady progression. By month 6, semaglutide patients average ~10% body weight loss; tirzepatide patients average ~15%. Plateaus are common around month 4-5 and again around month 7-8 — usually resolved by another titration step or a protocol tweak.
Months 10-18
Weight loss continues at a slower rate. Trial endpoints (68-72 weeks) generally fall in this window. By month 12-15, most patients are approaching their personal ceiling on the medication. This is when the muscle-preservation conversation becomes critical (see next section).
Deep dives on the trajectory: · ·.
Side effects, what's real and what's overblown
GLP-1 side effects fall into three categories: the predictable ones (manageable), the rare-but-real ones (worth knowing about), and the manufactured ones (overblown in media).
Predictable: GI tolerance
Nausea, constipation, occasional reflux. Almost always worst in the first 1-3 weeks of any new dose. Resolved by slower titration, smaller meals, and hydration. See the full side effects guide for tactical management.
Real but rare: pancreatitis, gallbladder, gastroparesis
These exist but are uncommon and signal-flagged. Pancreatitis: ~0.2% incidence in trials, less than the background rate in patients with obesity. Gallbladder disease: increased risk modestly, mostly during rapid weight loss (true of any rapid weight loss). Gastroparesis: very rare; nearly always reverses on discontinuation.
Overblown: "Ozempic face," hair thinning, alcohol metabolism
"Ozempic face" is just rapid fat loss showing up in facial volume. Not a unique pharmacologic effect. Full breakdown here. Hair thinning during significant weight loss happens whether you're on a GLP-1 or not — it's a telogen-effluvium response to caloric deficit. Alcohol changes are real but mild — see GLP-1 and alcohol.
Muscle preservation, the biggest miss
Roughly 25-40% of the weight you lose on a GLP-1 is lean mass — muscle, organ tissue, water (per body composition analyses from STEP-1 and SURMOUNT-1). That's the number that almost nobody talks about and that quietly determines whether your GLP-1 outcome is a win or a setback in five years.
Muscle mass drives resting metabolic rate, insulin sensitivity, glucose disposal, fall risk, and all-cause mortality. Losing 30 lb of which 12 lb was muscle leaves you with a lower metabolic floor and lower long-term healthspan than losing 30 lb of which 5 lb was muscle. Both look identical on the scale.
The protective protocol is unambiguous:
- Protein: 1.0-1.2 g per pound of goal body weight, daily. Most patients fall to ~50-60 g/day on a GLP-1 unless they actively track. Plan it.
- Resistance training: 3-4 sessions weekly, progressive overload on compound lifts. Cardio is fine but does not preserve muscle.
- Adequate calories: Don't compound an aggressive deficit on top of GLP-1-induced appetite suppression. A 500 kcal/day deficit is plenty.
Articles: the muscle preservation playbook · GLP-1 + lifting · protein on GLP-1.
Microdosing GLP-1s
Microdose GLP-1 protocols use 25-50% of the standard maintenance dose. The use case isn't weight loss — it's metabolic and anti-inflammatory optimization for people who are already lean or near-lean and want the cardiometabolic upside without dramatic appetite suppression.
Microdosing maps to a different patient: the already-fit optimizer, the post-significant-weight-loss maintainer, the metabolically dysfunctional but BMI-normal adult. See our microdose page for the protocol detail, and for the conceptual frame.
What happens when you stop
The STEP-4 trial answered this. Patients who hit a strong response on semaglutide and then switched to placebo regained about two-thirds of the lost weight within 68 weeks. Weight regain on GLP-1 discontinuation is not a moral failure — it's the predictable consequence of removing a satiety signal you've been holding artificially.
The maintenance answer is one of three:
- Stay on a maintenance dose indefinitely. Most realistic for patients with significant weight to lose. Semaglutide and tirzepatide are safe long-term per current evidence.
- Step down to microdose. A lower dose holds enough satiety signal to prevent the rebound without full appetite suppression.
- Off-cycle with a serious lifestyle backbone. Possible if the lean mass was preserved, the training pattern is established, and the patient is comfortable with some weight regain.
See maintenance after weight loss, what happens when you stop, and our post-GLP-1 protocol The Bridge.
Compounded vs branded GLP-1s
Branded GLP-1s (Wegovy, Ozempic, Zepbound, Mounjaro) are FDA-approved finished products manufactured by Novo Nordisk and Eli Lilly. They are expensive and frequently unavailable through insurance. Compounded GLP-1s are preparations of the same active pharmaceutical ingredient (semaglutide or tirzepatide) prepared by licensed 503A compounding pharmacies under U.S. physician prescription.
Compounded preparations are not FDA-approved. The FDA permits compounding when patient-specific clinical needs (e.g., dosage form, ingredient sensitivity) justify it, and during periods of branded drug shortage. OPTML works with three named 503A partners — Strive, Boothwyn, and Absolute — all U.S.-licensed and operating under USP <797> sterility standards.
Compounded preparations cost roughly 80% less than branded equivalents at retail. They are the form most telehealth GLP-1 prescribing currently uses. See brand vs compounded.
FDA disclosure: All efficacy data on this page (STEP-1, SURMOUNT-1) was generated with FDA-approved branded products. OPTML dispenses compounded preparations. Compounded preparations are not FDA-approved.
Frequently asked questions
Will I have to stay on a GLP-1 forever?
Not necessarily, but probably for longer than you initially think. Most patients who maintain results either stay on maintenance dosing indefinitely, step down to a microdose, or off-cycle with a strong lifestyle backbone. The "weeks-of-treatment" mental model from antibiotics doesn't apply.
Is one safer than the other?
Both have well-characterized safety profiles. Tirzepatide produces slightly more nausea on average; semaglutide has the longer safety record. Both have cardiovascular outcomes data being collected in real time. SELECT (semaglutide, 2023) was strongly positive.
Can I drink alcohol?
Yes, in moderation. Most patients find their tolerance is reduced and they want less. See GLP-1 and alcohol.
Will I lose muscle?
Some, yes, unless you train and eat protein. See the muscle preservation section.
Can I exercise normally?
Yes. Lifting is encouraged; cardio is fine. Some patients feel mildly fatigued in week 1 of a new dose, which resolves.