Generic Name

Orladeyo

Mechanism

• Dual GLP‑1/GIP receptor activation:
• *GLP‑1 receptor agonism* → ↑ insulin secretion, ↓ glucagon release, delayed gastric emptying, appetite suppression.
• *GIP receptor agonism* → enhances insulinotropic action, improves β‑cell function, and provides an additive signal that augments GLP‑1 effects.
• The combined agonism yields synergistic effects on glycaemic control and greater weight loss than GLP‑1 alone.

Pharmacokinetics

• Route of administration: Subcutaneous injection (weekly).
• Bioavailability: ~60 % at the first dose, increases with titration; no oral bioavailability.
• Distribution: Large volume (∼4 L), high protein binding (~70 %).
• Metabolism: Primarily proteolytic cleavage into peptides; no major cytochrome‑P450 involvement.
• Elimination: Renal clearance is minimal; half‑life ≈ 5–6 days, allowing weekly dosing.
• Food interactions: No clinically relevant interaction; meals can be taken at any time.

Indications

• Type 2 diabetes mellitus (T2DM): Adults with inadequate glycaemic control on metformin or other oral agents.
• Obesity/overweight with T2DM: Significant weight‑loss benefit (≥5 % of baseline body weight).
• Potential future indication: Clinical trials are evaluating Orladeyo for chronic weight management in non‑diabetic individuals (currently investigational).

Contraindications

• Contraindications:
• Personal or family history of medullary thyroid carcinoma (MTC).
• Multiple endocrine neoplasia type 2 (MEN 2).
• Warnings:
• Pancreatitis: Rare but serious; monitor for abdominal pain, nausea.
• Gallbladder disease: May precipitate cholelithiasis or cholecystitis.
• Hypoglycaemia risk: Low‑risk when used alone; significant risk if combined with insulin or sulfonylureas – adjust concomitant agents and educate patients.
• Pregnancy/Lactation: Not studied; avoid if possible.
• Renal Impairment: Not required for dose adjustment; caution if severe.

Dosing

• Start at 2.5 mg or 5 mg weekly, depending on baseline HbA1c.
• Titrate every 4 weeks up to a maximum of 15 mg (standard) or 30 mg (high‑dose studies).
• Administration: SC injection in thigh, abdomen, or upper arm; rotate sites.
• Food: No special instruction – can be given on an empty stomach or with food.

Adverse Effects

• Common (≥10 %)
• Nausea, vomiting, diarrhea, constipation.
• Reduced appetite, dyspepsia.
• Injection‑site reactions (erythema, pruritus).
• Serious (≤1 %)
• Acute pancreatitis.
• Thyroid C‑cell tumors (preclinical; not yet reported in humans).
• Allergic reactions (anaphylaxis rare).
• Other notable events
• Palpitations, dizziness, mild weight‑gain rebound post‑treatment.
• Rare reports of gallstones.

Monitoring

• Glycaemia
• HbA1c every 3 months; fasting glucose at baseline and 12–16 weeks.
• Weight
• Baseline and monthly for first 3 months; then quarterly.
• Pancreatic enzymes
• Amylase/lipase if symptoms of pancreatitis develop.
• Thyroid function
• TSH and free T4 if symptoms of thyroid dysfunction arise.
• Renal/hepatic
• Routine labs; not required for dose adjustment unless severe impairment.
• Adverse event reporting
• Document GI intolerance; adjust dose or add anti‑emetics if needed.

Clinical Pearls

1. Dual‑Receptor Advantage – Orladeyo’s GIP component synergistically enhances insulin secretion especially in patients with a blunted GLP‑1 response, giving superior HbA1c reductions (~2% lower than GLP‑1 monotherapies).

2. Weight‑Loss Out‑performance – In pivotal studies, Orladeyo led to an average weight loss of 9–11 % versus 5–7 % with GLP‑1 agonists; useful for addressing the obesity‑diabetes intersection.

3. Titration Cushion – The 4‑week stepwise titration mitigates GI side effects; patients often tolerate higher doses after the first 8 weeks when tolerability improves.

4. Pancreatitis Vigilance – While baseline risk is low, patients with a history of pancreatitis or gallstones should be disclosed to the prescriber and monitored closely.

5. Use in Insulin Combo – A drop in hypoglycaemia risk is seen when Orladeyo replaces a sulfonylurea; however, when combined with basal insulin, dose adjustment of insulin (≈25 % reduction) is prudent.

6. No Food Restrictions – Unlike some other GLP‑1 agents, Orladeyo does not require specific timing relative to meals, improving adherence.

7. Adherence Aid – Weekly dosing (vs daily for many analogues) increases patient satisfaction and reduces overall injection burden.

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• Reference‑Friendly Summary
• FDA approval: 2022 (Tirzepatide, brand Orladeyo), diabetes & weight‑control.
• Key clinical trials: SURPASS‑1, SURPASS‑2, SURPASS‑3 (HbA1c ↓ 2.6–3.0 %, weight loss 9–11 %).
• Published guidelines (ADA 2025, EASD 2024) recommend Tirzepatide for T2DM with obesity when other GLP‑1 ARAs fail or are insufficient.

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