GLP-1 Agonists (Incretin Mimetics)

Generic and Brand Names

• Exenatide — Byetta (twice-daily), Bydureon BCise (once-weekly)

• Lixisenatide — Adlyxin

• Liraglutide — Victoza (T2DM), Saxenda (obesity)

• Dulaglutide — Trulicity

• Semaglutide — Ozempic (T2DM), Wegovy (obesity), Rybelsus (oral)

• Tirzepatide — Mounjaro (T2DM), Zepbound (obesity) note dual GIP/GLP-1 agonist included for practical comparison

• Fixed insulin combinations — Insulin degludec plus liraglutide (Xultophy), insulin glargine plus lixisenatide (Soliqua 100/33)

Class

• Glucagon-like peptide-1 receptor agonists that mimic endogenous incretin signaling

• Enhance glucose-dependent insulin secretion, suppress inappropriate glucagon, slow gastric emptying, reduce appetite and energy intake

• Most agents are peptide injectables; one oral formulation exists for semaglutide

Mechanism of Action

• GLP-1 receptor activation on pancreatic beta cells increases cAMP leading to glucose-contingent insulin release

• Alpha-cell GLP-1 receptor signaling suppresses post-prandial glucagon

• Gastric and central nervous system actions delay gastric emptying and promote satiety

• Low intrinsic hypoglycemia risk unless combined with insulin or insulin secretagogues

Indications

• Type 2 diabetes mellitus to improve glycemic control and reduce body weight

• Chronic weight management in adults (and selected adolescents) with obesity or overweight with weight-related comorbidities specific products only

• Cardiovascular risk reduction in adults with T2DM and established ASCVD for selected agents class evidence varies by product

• Fixed insulin combinations for patients needing basal insulin plus incretin therapy in a single daily injection

Dosage and Administration

• Exenatide Byetta 5 micrograms subcutaneously twice daily for at least 1 month then 10 micrograms twice daily administer within 60 minutes before morning and evening meals

• Exenatide extended release Bydureon BCise 2 milligrams subcutaneously once weekly

• Lixisenatide 10 micrograms subcutaneously once daily for 14 days then 20 micrograms once daily give within 60 minutes before the same meal each day

• Liraglutide Victoza start 0.6 milligrams subcutaneously daily for 1 week then 1.2 milligrams daily may increase to 1.8 milligrams daily

• Liraglutide Saxenda titrate weekly 0.6 to 3.0 milligrams daily maintenance 3.0 milligrams

• Dulaglutide 0.75 milligrams subcutaneously once weekly may increase to 1.5 3.0 or 4.5 milligrams once weekly

• Semaglutide Ozempic start 0.25 milligrams once weekly for 4 weeks then 0.5 milligrams weekly may increase to 1.0 or 2.0 milligrams weekly

• Semaglutide Wegovy titrate 0.25 0.5 1.0 1.7 to 2.4 milligrams once weekly maintenance 2.4 milligrams

• Semaglutide oral Rybelsus 3 milligrams once daily for 30 days then 7 milligrams; may increase to 14 milligrams take on empty stomach with up to 120 mL water only wait at least 30 minutes before eating drinking or other oral drugs

• Tirzepatide 2.5 milligrams once weekly increase by 2.5 milligrams every 4 weeks to 5 7.5 10 12.5 or 15 milligrams once weekly

• Xultophy insulin degludec liraglutide single daily injection dose individualized

• Soliqua 100 33 insulin glargine lixisenatide single daily injection dose individualized

• Missed weekly dose administer within 5 to 7 days per label then resume schedule do not double doses

Monitoring

• A1C every three months until stable then at individualized intervals

• Weight blood pressure heart rate

• Renal function at baseline and periodically especially with exenatide and lixisenatide and during dehydration illness

• Signs of pancreatitis persistent severe abdominal pain with or without vomiting

• Diabetic retinopathy progression in patients with rapidly improving glycemia particularly with semaglutide

• For oral semaglutide adherence to fasting administration rule to ensure absorption

Contraindications

• Personal or family history of medullary thyroid carcinoma

• Multiple endocrine neoplasia syndrome type 2

• Prior serious hypersensitivity to the product

• Pregnancy for weight-management indications avoid use generally during pregnancy for diabetes unless benefits clearly outweigh risks

• Severe gastrointestinal disease such as gastroparesis use is generally not recommended

Precautions

• Pancreatitis risk discontinue if suspected avoid re-challenge if confirmed

• Gallbladder disease acute cholecystitis and cholelithiasis reported monitor for biliary symptoms

• Acute kidney injury risk increased with dehydration from GI adverse effects ensure hydration hold during acute illness causing volume depletion

• Hypoglycemia when combined with insulin or sulfonylurea reduce doses of those agents accordingly

• Diabetic retinopathy may transiently worsen with rapid glucose improvement plan close ophthalmic follow-up in high-risk patients

• Heart rate modest increases observed monitor if tachycardia or arrhythmia history

• Injection technique rotate sites abdomen thigh upper arm storage per label

Adverse Effects

• Very common gastrointestinal nausea vomiting diarrhea abdominal pain decreased appetite dyspepsia constipation

• Common injection site reactions headache fatigue dizziness reflux

• Less common gallbladder events mild tachycardia acute kidney injury secondary to dehydration hypersensitivity reactions

• Rare pancreatitis anaphylaxis angioedema medullary thyroid carcinoma signal in rodents class boxed warning

Drug Interactions

• Insulin and sulfonylureas increased hypoglycemia risk adjust background dose

• Oral medications with narrow therapeutic index affected by delayed gastric emptying monitor clinical effect spacing may be needed oral semaglutide requires strict dosing separation

• Warfarin no direct interaction but consider more frequent INR checks during initiation due to dietary changes weight loss and absorption variability

• Combination products with basal insulin follow specific titration and hypoglycemia precautions

Overdose

• Exaggerated GI symptoms dehydration hypoglycemia if used with insulin or secretagogues supportive care with fluid replacement antiemetics and temporary adjustment of concomitant antidiabetic therapy

Patient Counselling

• Explain glucose-dependent action low intrinsic hypoglycemia risk unless used with insulin or a sulfonylurea

• Review titration schedule slow increases improve tolerance

• Expect early nausea that usually diminishes eat smaller low-fat meals and maintain hydration

• Teach injection device priming and site rotation weekly products can be taken any time of day with or without food on the same weekday

• For oral semaglutide take immediately after waking with a small amount of water only and wait at least 30 minutes before anything else

• Report severe or persistent abdominal pain vision changes symptoms of gallbladder disease signs of dehydration or allergic reactions

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Comparison Table — GLP-1 and Related Incretin Therapies

Attribute	Exenatide BID	Exenatide ER	Lixisenatide	Liraglutide Victoza	Dulaglutide	Semaglutide Ozempic	Semaglutide Wegovy	Semaglutide oral	Tirzepatide dual
Route and frequency	SC twice daily pre-meal	SC weekly	SC daily pre-meal	SC daily	SC weekly	SC weekly	SC weekly	Oral daily fasting	SC weekly
Typical A1C reduction	0.7–1.0 percent	1.0 percent	0.7–1.0 percent	1.0–1.5 percent	1.0–1.5 percent	1.2–1.8 percent	n a diabetes dose not applicable	1.0–1.3 percent	1.5–2.0 percent
Mean weight effect	Loss 2–3 kg	Loss 2–3 kg	Loss 2–3 kg	Loss 2–4 kg	Loss 2–4 kg	Loss 4–6 kg at diabetes doses	Loss 10 percent or more at 2.4 mg chronic weight mgmt	Loss 3–4 kg	Loss often 12–20 percent at upper doses weight mgmt product dependent
Cardiovascular outcomes	Noninferior not superior	Noninferior	Noninferior	Reduced MACE	Reduced MACE	Reduced MACE injection data strongest	Approved for chronic weight mgmt and CV risk reduction in selected patients labels vary	Noninferior small trial	Reduced MACE data emerging product label dependent
Renal considerations	Avoid if CrCl <30 mL min caution 30–50	Avoid if CrCl <30	Caution if CrCl <30	No adjustment but monitor in severe impairment	No adjustment	No adjustment limited ESRD data	Same as Ozempic class	No adjustment; absorption variability in severe impairment	No adjustment
GI tolerability	Higher with BID start low	Moderate	Moderate	Moderate	Moderate	Moderate	Moderate during up-titration	Nausea early strict fasting intake improves absorption	Similar to GLP-1 with dose dependence
Unique notes	Short-acting prandial effect prominent	Autoinjector weekly	Co-formulated with insulin glargine as Soliqua	Also marketed as Saxenda for obesity at 3 mg	Broad dose range up to 4.5 mg	Broad dose range up to 2 mg for T2DM	Obesity-focused 2.4 mg maintenance	First oral GLP-1; strict administration rules	Dual GIP GLP-1 agonism greater weight loss and A1C lowering than GLP-1 alone