Weight Loss
SEMAGLUTIDE VS TIRZEPATIDE
Two medications. Different mechanisms. Both produce significant weight loss. Here's how they compare and how to decide.
HEAD-TO-HEAD
| Semaglutide | Tirzepatide | |
|---|---|---|
| Brand Names | Ozempic, Wegovy, Rybelsus | Mounjaro, Zepbound |
| Mechanism | GLP-1 receptor agonist | GLP-1 + GIP dual agonist |
| Avg Weight Loss | 15–20% | 20–25% |
| FDA Approved For | Diabetes (Ozempic), Weight loss (Wegovy) | Diabetes (Mounjaro), Weight loss (Zepbound) |
| Injection Frequency | Once weekly | Once weekly |
| Manufacturer | Novo Nordisk | Eli Lilly |
| Available Since | 2017 (Ozempic) | 2022 (Mounjaro) |
HOW THEY WORK (AND WHY IT MATTERS)
Both medications mimic gut hormones that your body produces naturally after eating. The difference is which hormones they mimic.
Semaglutide
GLP-1 Agonist
Mimics GLP-1 (glucagon-like peptide-1), a hormone released by your gut after eating. GLP-1 does three things:
- 1. Signals fullness to the brain — reduces appetite and food noise
- 2. Slows gastric emptying — food stays in your stomach longer, so you feel full longer
- 3. Improves insulin sensitivity — better blood sugar regulation
Semaglutide is a modified version of natural GLP-1 that lasts much longer in the body (natural GLP-1 breaks down in minutes; semaglutide lasts about a week).
Tirzepatide
GLP-1 + GIP Dual Agonist
Does everything semaglutide does, plus mimics a second hormone: GIP (glucose-dependent insulinotropic polypeptide).
- + GIP enhances insulin secretion — additional blood sugar control
- + GIP affects fat metabolism — may promote fat burning and reduce fat storage
- + Potentially more satiety signaling — two pathways instead of one
Think of it as a two-key approach. Semaglutide turns one lock. Tirzepatide turns two. Both open the door, but the dual mechanism may produce a stronger overall effect.
What this means practically: Tirzepatide tends to produce more weight loss in clinical trials. But biology is individual—some people respond better to one mechanism than the other. "Better on average" doesn't mean "better for you."
WHAT THE CLINICAL TRIALS SHOW
Semaglutide — STEP Trials
The STEP (Semaglutide Treatment Effect in People with Obesity) program enrolled over 4,500 participants across multiple trials.
-14.9%
Avg body weight loss (STEP 1)
83%
Lost at least 5% body weight
68 weeks
Trial duration
Tirzepatide — SURMOUNT Trials
The SURMOUNT program studied tirzepatide for weight management in over 5,000 participants.
-22.5%
Avg body weight loss at highest dose (SURMOUNT-1)
96%
Lost at least 5% body weight
72 weeks
Trial duration
Context: Clinical trial participants also received lifestyle intervention (diet and exercise counseling). Real-world results may differ. These numbers represent averages—some people lose more, some lose less. The data shows tirzepatide has an edge at the highest doses, but both produce clinically meaningful weight loss far beyond what lifestyle alone typically achieves.
WHAT TO EXPECT: MONTH BY MONTH
Both medications follow a similar timeline. You start at a low dose and titrate up over several months to reach your target dose. Here's the general trajectory.
Month
1–2
Starting Dose — Adjustment Phase
You'll start at the lowest dose. Appetite reduction begins—many people notice less "food noise" (constant thinking about food) within the first week or two. GI side effects are most common during this phase: nausea, mild stomach discomfort, sometimes constipation. These typically improve as your body adjusts. Weight loss: 2–5 lbs.
Month
3–4
Dose Titration — Momentum Builds
Dose increases to the next level. Appetite suppression is more consistent and pronounced. Most people find portion sizes drop naturally—you just don't want as much food. Side effects typically improve or become manageable. Weight loss accelerates: 8–15 lbs total. This is when most people start noticing visible changes.
Month
5–8
Target Dose — Steady State
You've reached (or are approaching) your target dose. Weight loss is steady—typically 1–2 lbs per week. Energy levels often improve as weight decreases. Metabolic markers start improving: blood sugar, triglycerides, blood pressure. This is the productive middle phase. Total loss: 20–40 lbs depending on starting weight.
Month
9–12+
Approaching Maximum — Plateau Management
Weight loss rate slows as your body approaches a new equilibrium. This is normal—it's not the medication "stopping working." Your body adapts to its new weight. Focus shifts to maintenance, habit consolidation, and body composition optimization. Total loss typically reaches 15–25% of starting body weight.
Individual variation is real. Some people respond rapidly at lower doses. Others need the full titration to see significant results. Some respond well to semaglutide but not tirzepatide, or vice versa. This is why medical oversight matters—adjusting dose, timing, and even switching medications when needed.
SIDE EFFECTS COMPARED
Both medications share similar side effect profiles because they work on the same pathways. The most common side effects are gastrointestinal.
Common (Both Medications)
Nausea
Most common side effect. Usually worst during dose increases. Typically improves within 2-4 weeks at each dose level.
Constipation or Diarrhea
GI motility changes affect bowel habits. Often manageable with hydration and fiber.
Reduced Appetite
This is the intended effect, but some people experience it more intensely—feeling no desire to eat at all. You still need to eat adequate protein.
Injection Site Reactions
Mild redness or discomfort at injection site. Usually minor.
Less Common but Notable
Fatigue
Some people experience tiredness, especially early on. Often related to reduced caloric intake rather than the medication itself.
Headache
May occur during dose titration. Usually temporary.
Gallbladder Issues
Rapid weight loss (from any cause) increases gallstone risk. Uncommon but worth monitoring.
Pancreatitis
Rare but serious. Symptoms include severe abdominal pain radiating to the back. Seek medical attention immediately.
Key difference: Side effect rates are roughly comparable between semaglutide and tirzepatide in clinical trials. Some patients tolerate one better than the other—this is individual. If side effects are intolerable on one, switching to the other is a reasonable option.
THE MUSCLE LOSS QUESTION
This is the biggest concern people have about GLP-1 medications, and it deserves a straight answer.
Yes, you will lose some muscle mass on GLP-1 medications. But context matters: you lose muscle mass with any method of rapid weight loss. Calorie restriction, bariatric surgery, GLP-1s—all of them result in some lean mass loss alongside fat loss. This isn't unique to GLP-1 medications.
The Numbers
In clinical trials, approximately 25-40% of total weight lost on GLP-1 medications was lean mass (muscle + other non-fat tissue). The rest was fat.
For comparison:
- • Calorie-restricted dieting: ~25-30% lean mass loss
- • Bariatric surgery: ~25-35% lean mass loss
- • GLP-1 medications: ~25-40% lean mass loss
The ranges overlap significantly. GLP-1s may be slightly higher because the weight loss is more rapid and dramatic.
How to Minimize Muscle Loss
Strength Training
This is the single most important factor. Resistance training 2-4x per week sends a "keep this muscle" signal to your body even while losing weight. The stimulus tells your body to preferentially burn fat instead.
High Protein Intake
Aim for 0.7–1.0 grams of protein per pound of body weight daily. This is harder on GLP-1s because your appetite is suppressed—you need to prioritize protein even when you don't feel like eating. Protein is the building material your muscles need to survive a calorie deficit.
Track Body Composition
The scale doesn't tell you what you're losing. A DEXA scan shows exactly how much is fat vs lean mass. If lean mass is dropping too fast, your protocol needs adjusting—more protein, more training, or a slower rate of loss.
Don't Undershoot Calories
GLP-1s can suppress appetite so aggressively that some people barely eat. Extreme caloric restriction accelerates muscle loss. You should still eat—aim for a moderate deficit with adequate protein, not starvation-level intake.
Our approach: Every weight loss patient at Moonshot gets baseline DEXA scanning to track body composition over time. We're not just watching the number on the scale go down—we're monitoring what kind of weight you're losing. If muscle loss is excessive, we adjust the plan.
WHAT HAPPENS WHEN YOU STOP?
This is the question everyone should ask before starting. The honest answer: most people regain a significant portion of the weight after stopping GLP-1 medications.
The STEP 1 trial extension showed that participants who stopped semaglutide regained about two-thirds of the weight they lost within one year. Tirzepatide data shows a similar pattern.
This isn't a failure of willpower. It's biology. These medications work by overriding your body's weight defense mechanisms—hunger hormones, metabolic adaptation, appetite signaling. When you stop the medication, those mechanisms return to their baseline settings.
What This Means for Your Plan
Option 1: Long-term use. Some patients stay on GLP-1 medications long-term at maintenance doses. This is increasingly recognized as a valid approach for obesity management, similar to how blood pressure or cholesterol medications are used long-term.
Option 2: Use as a bridge. Use the medication to lose weight while building exercise and nutrition habits. Taper off gradually and rely on lifestyle changes. Some weight regain is likely but not all—especially if you've maintained muscle and built real habits.
Option 3: Cycle on and off. Use the medication in defined periods, maintain with lifestyle between cycles. Less studied but commonly practiced.
HOW TO CHOOSE
Semaglutide might be a better fit if:
- • You want the medication with the longest track record (available since 2017)
- • Your insurance covers it (semaglutide has broader insurance coverage currently)
- • You've tried tirzepatide and experienced intolerable side effects
- • You prefer an oral option (Rybelsus is available as a daily pill, though the injectable form is more effective for weight loss)
Tirzepatide might be a better fit if:
- • You want the highest average weight loss based on clinical data
- • You have significant insulin resistance or type 2 diabetes (the dual mechanism may provide better blood sugar control)
- • Semaglutide wasn't effective enough at maximum dose
- • You want to maximize results and the cost difference isn't a barrier
The truth:
Both work well. For most people, the deciding factors end up being availability, cost/insurance coverage, and individual side effect tolerance. If one doesn't work optimally, you can switch to the other. This isn't a permanent decision.
COMMON QUESTIONS
Can I take a GLP-1 if I'm not obese?
FDA approval is for BMI 30+ (or 27+ with weight-related conditions). However, off-label use for lower BMIs is possible when there's a clinical rationale. This is a conversation for your provider based on your specific health picture.
Will I need to inject myself?
Yes. Both are weekly subcutaneous injections using a pre-filled pen—similar to insulin pens. The needle is very small and the injection is just under the skin (not into muscle). Most patients are comfortable with self-injection after the first time.
Can I drink alcohol on GLP-1 medications?
There's no strict prohibition, but many patients report lower alcohol tolerance and increased nausea with alcohol. GLP-1s slow gastric emptying, so alcohol absorption patterns may change. Many patients naturally drink less because they just don't want it. Excessive alcohol should be avoided as it adds empty calories and can worsen GI side effects.
How much does it cost at Moonshot?
Our full Weight Loss program is $405/month (includes medication, medical oversight, labs, DEXA tracking, and dose management). If your insurance covers the GLP-1 medication, we offer a Prescription Program at $105/month for oversight and monitoring.
References
- 1. Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." N Engl J Med. 2021;384(11):989-1002. (STEP 1)
- 2. Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." N Engl J Med. 2022;387(3):205-216. (SURMOUNT-1)
- 3. Wilding JPH, et al. "Weight regain and cardiometabolic effects after withdrawal of semaglutide." Diabetes Obes Metab. 2022;24(8):1553-1564. (STEP 1 Extension)
- 4. Aronne LJ, et al. "Continued treatment with tirzepatide for maintenance of weight reduction." JAMA. 2024;331(1):38-48. (SURMOUNT-4)
- 5. Heymsfield SB, et al. "Mechanisms, Pathophysiology, and Management of Obesity." N Engl J Med. 2017;376(3):254-266.
- 6. Mechanick JI, et al. "Clinical Practice Guidelines for the Perioperative Nutrition, Metabolic, and Nonsurgical Support of Patients Undergoing Bariatric Procedures." Obesity. 2020;28(4):O1-O58.
READY TO START?
We'll evaluate your health history, discuss which medication makes sense for you, and build a plan that protects muscle while you lose fat.
Book Consultation