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Semaglutide

Semaglutide is a long-acting GLP-1 receptor agonist used for Type 2 Diabetes, obesity, and cardiovascular risk reduction.

Brand names: • Ozempic (Type 2 Diabetes) • Wegovy (Obesity) • Rybelsus (Oral formulation)

→ GLP-1 Receptor Agonists Overview

Mechanism of Action

Semaglutide activates the GLP-1 receptor.

Effects:

• ↑ Glucose-dependent insulin secretion • ↓ Glucagon secretion • Slows gastric emptying • ↑ Satiety • Promotes significant weight loss

Net effects:

• ↓ HbA1c • ↓ Body weight • ↓ Major adverse cardiovascular events

Low hypoglycemia risk unless combined with insulin or sulfonylureas.

Indications

Type 2 Diabetes Mellitus

• Glycemic control • Cardiovascular risk reduction

Obesity ★

• Significant weight loss • Reduction in visceral adiposity • Improves cardiometabolic profile

Atherosclerotic Cardiovascular Disease (ASCVD) ★

Semaglutide reduces:

• Myocardial infarction • Stroke • Cardiovascular death

Particularly beneficial in patients with established ASCVD.

→ Cardiovascular Modules

Major Trials

SUSTAIN-6:

• Reduced major adverse cardiovascular events

STEP trials:

• Significant weight reduction

SELECT trial:

• Cardiovascular event reduction in overweight/obese patients without diabetes

Dosing Forms

Injectable (weekly): • Ozempic • Wegovy (higher obesity dose)

Oral (daily): • Rybelsus

Oral formulation requires: • Empty stomach • Limited water • No food for 30 minutes

Adverse Effects

Common:

• Nausea • Vomiting • Diarrhea • Early satiety

Serious (rare):

• Pancreatitis • Gallbladder disease • Theoretical risk of medullary thyroid carcinoma

Weight loss may increase gallstone risk.

Contraindications

• Personal or family history of medullary thyroid carcinoma • MEN2 syndrome • Severe GI disease

Use caution in:

• History of pancreatitis

Semaglutide vs Other GLP-1 Agents

Exenatide: • Shorter acting • Less weight loss

Liraglutide: • Daily injection • Proven ASCVD benefit

Dulaglutide: • Weekly injection • Strong ASCVD benefit

Semaglutide: • Strongest weight loss among GLP-1 RAs • Strong ASCVD reduction • Available oral formulation

GLP-1 vs SGLT2 in Cardiovascular Disease

Semaglutide:

• Strong ASCVD reduction • Weight loss dominant

SGLT2 Inhibitors:

• Strong heart failure benefit • Strong renal protection

These classes are often combined in cardiometabolic patients.

Clinical Pearls

✔ Weekly or oral option ✔ Powerful weight loss ✔ Reduces ASCVD events ✔ Low hypoglycemia risk ✔ Not a core heart failure therapy ✔ Monitor for GI intolerance