GLP-1 and GLP-2 receptor agonist

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1. Semaglutide:

• Class: GLP-1 receptor agonist

• Mechanism: Mimics the action of glucagon-like peptide-1 (GLP-1), a hormone released after meals that enhances insulin secretion, slows gastric emptying, reduces glucagon release, and increases satiety.

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Uses: 

• Originally developed for type 2 diabetes (brands: Ozempic, Rybelsus for oral version).

• Widely used for weight management (brand: Wegovy).

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Administration:

• Injectable (once-weekly subcutaneous) or oral (daily tablets, though less bioavailable).

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Benefits:

• Significant weight reduction, often greater than older GLP-1 agonists.

• Strong glucose-lowering effect, improves HbA1c.

• May reduce cardiovascular risk in type 2 diabetes.

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Limitations/Side Effects:

• Nausea, vomiting, constipation, or diarrhea are common.

• Risk of pancreatitis and gallbladder disease is debated.

• Contraindicated in individuals with a history of medullary thyroid carcinoma or MEN2 (in animals, thyroid C-cell tumors were observed).

 

2. Liraglutide:

• Class: GLP-1 receptor agonist (earlier generation than semaglutide).

• Mechanism: Same as semaglutide, but shorter half-life. Requires daily dosing.

• Uses:

• Type 2 diabetes (brand: Victoza).

• Weight management (brand: Saxenda).

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Administration:

• Once-daily subcutaneous injection.

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• Benefits:

• Improves blood sugar control.

• Promotes weight loss, though typically less than semaglutide.

• Proven cardiovascular benefits in type 2 diabetes (reduced risk of heart attack, stroke, and death).

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Limitations/Side Effects:

• Gastrointestinal issues similar to semaglutide.

• Daily injection is less convenient.

• Same thyroid and pancreatitis precautions.

 

3. Tirzepatide:

• Class: Dual GLP-1 and GIP receptor agonist (called a "twincretin").

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• Mechanism:

• Activates GLP-1 receptors like semaglutide and liraglutide.

• Also activates GIP (glucose-dependent insulinotropic polypeptide) receptors, which may further enhance insulin secretion and fat metabolism.

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Uses:

• Approved for type 2 diabetes (brand: Mounjaro).

• Recently approved for weight loss (brand: Zepbound).

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Administration:

• Once-weekly subcutaneous injection.

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Benefits:

• ​Typically produces even greater weight loss than semaglutide, with some patients losing 20% or more of body weight.

• Very effective at lowering blood glucose and HbA1c.

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Limitations/Side Effects:

• Same gastrointestinal issues as GLP-1 drugs, sometimes stronger.

• Long-term data on cardiovascular protection is still being gathered, though early signs are positive.

• Same thyroid/pancreatitis cautions.

 

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In simple terms:

• Liraglutide works well but needs daily shots and is less powerful.

• Semaglutide is stronger, more convenient (weekly), and widely used for weight loss and diabetes.

• Tirzepatide is the newest and seems to outperform both, but long-term safety and outcomes are still being studied.

 

 

1. Liraglutide (Saxenda, Victoza):

• Starting dose: 0.6 mg once daily (subcutaneous).

• Titration: Increase by 0.6 mg each week until the target is reached.

• Weight management target dose: 3.0 mg daily (Saxenda).

• Diabetes target dose: 1.2–1.8 mg daily (Victoza).

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Notes:

• Daily injection is required due to its shorter half-life.

• Some patients can’t tolerate 3.0 mg and stay on lower doses.

 

2. Semaglutide (Ozempic, Wegovy, Rybelsus):

• Injectable (Ozempic/Wegovy)

• Start: 0.25 mg once weekly.

• Increase: 0.25 mg every 4 weeks

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Usual doses:

-Diabetes (Ozempic): 0.5–1.0 mg weekly (up to 2 mg).

-Weight loss (Wegovy): 2.4 mg weekly is the target dose.

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Oral (Rybelsus):

-Start: 3 mg daily for 30 days.

-Increase: 7 mg daily, then up to 14 mg if needed.

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Notes:

-Longer half-life allows once-weekly dosing.

-Wegovy dosing escalates more slowly to help with tolerability.

 

3. Tirzepatide (Mounjaro, Zepbound)

Starting dose: 2.5 mg once weekly.

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Titration: Increase by 2.5 mg every 4 weeks.

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Usual target doses:

-5 mg, 10 mg, or 15 mg weekly, depending on tolerance and goals.

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Notes:

-Even at the lowest doses, patients often see significant effects.

-Higher doses (10–15 mg) drive the most weight loss but also more GI side effects.

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How doctors typically approach it:

• Start low and slow to avoid nausea and vomiting.

• Stay on a tolerable dose if side effects appear, then try increasing later.

• If someone cannot tolerate a GLP-1 at all, they may stay at the lowest effective dose rather than hitting the “maximum” target.

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Best for Fat Loss:

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• Tirzepatide (Mounjaro/Zepbound)

• Head-to-head trials show it outperforms semaglutide for weight loss.

• Average reductions: ~15–20% body weight at higher doses, some patients exceeding that.

• Works by combining GLP-1 + GIP agonism, which seems to boost both appetite suppression and fat metabolism.

• Semaglutide is also excellent, producing ~10–15% average weight loss, but usually less than tirzepatide.

• Liraglutide lags behind, with average weight loss of ~5–8%, and requires daily injections.

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Ranking for fat loss:

1. Tirzepatide

2. Semaglutide

3. Liraglutide

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Best for Blood Sugar Control (Type 2 Diabetes):

• Tirzepatide shows the largest reductions in HbA1c, often 2% or more, which is very strong.

• Semaglutide comes next, usually lowering HbA1c by 1–1.5%.

• Liraglutide is effective but tends to be the least potent of the three, around 0.8–1.2% HbA1c reduction.

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Ranking for glucose control:

1. Tirzepatide

2. Semaglutide

3. Liraglutide

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Best for Cardiovascular Protection:

• Liraglutide and semaglutide both have long-term trial data showing reduced risk of heart attack, stroke, and cardiovascular death in high-risk type 2 diabetics.

• Tirzepatide looks promising, but large cardiovascular outcome trials are still ongoing, so it doesn’t yet have the same level of proof.

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Ranking for heart protection (so far):

1. Liraglutide / Semaglutide (tie, proven)

2. Tirzepatide (likely good, but still under study)

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Overall Takeaway:

• If fat loss is the primary goal: Tirzepatide is the strongest option.

• If diabetes control is the primary goal: Tirzepatide still leads, but semaglutide is a close second and already well-established.

• If cardiovascular risk reduction is the top concern: Semaglutide or liraglutide are safer bets until more tirzepatide data comes in.

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1. Liraglutide (Saxenda for weight, Victoza for diabetes):

• Starting dose: 0.6 mg subcutaneous daily

• Titration: Increase by 0.6 mg each week

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Target dose:

-Weight loss (Saxenda): 3.0 mg daily

-Diabetes (Victoza): 1.2–1.8 mg daily

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Notes:

-Daily injection required due to short half-life

-If side effects are severe, remain on the current dose until tolerated

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2. Semaglutide (Ozempic/Wegovy injectable, Rybelsus oral)

Injectable (weekly) – Ozempic/Wegovy

• Start: 0.25 mg weekly

• Titration: Increase every 4 weeks

• Target dose:

-Diabetes (Ozempic): 0.5–1 mg weekly, can increase to 2 mg if needed

-Weight loss (Wegovy): 2.4 mg weekly

• Notes: Once-weekly injection improves convenience and compliance

Oral (Rybelsus)

• Start: 3 mg daily for 30 days

• Titration: Increase to 7 mg daily, then 14 mg if needed

• Notes: Absorption is lower than injectable; must take on empty stomach

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3. Tirzepatide (Mounjaro, Zepbound)

• Start dose: 2.5 mg weekly

• Titration: Increase by 2.5 mg every 4 weeks

• Target dose: 10–15 mg weekly depending on goals and tolerance

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Notes:

• Weekly injection

• Higher doses give stronger weight loss but also higher risk of GI side effects

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Practical Tips for Dosing

1. Start low, go slow – all three drugs can cause nausea, vomiting, and diarrhea if titrated too quickly.

2. Monitor tolerance – stay at a dose until side effects are manageable before increasing.

3. Consistency matters – weekly injections should be given on the same day each week; daily injections at roughly the same time each day.

4. Adjustments for renal/hepatic issues – dosing may need modification; always follow a physician’s guidance.

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Key Notes

• Liraglutide: daily injection; titrate weekly by 0.6 mg until 3.0 mg. Stop at lower dose if side effects persist.

• Semaglutide: weekly injection; start low to prevent nausea, gradually increase to target (2.4 mg for weight loss). Oral form is slower to titrate.

• Tirzepatide: weekly injection; increase by 2.5 mg every 4 weeks until goal dose (usually 10–15 mg). GI side effects often peak during titration.