Semaglutide vs Liraglutide

## Overview

Semaglutide and liraglutide are both GLP-1 receptor agonists (GLP-1 RAs) that stimulate insulin secretion, suppress glucagon, and promote weight loss. Semaglutide achieves substantially greater weight loss than liraglutide and has once-weekly dosing, driving its rapid adoption.

## Mechanism of Action

Both bind GLP-1 receptors in the pancreas (insulin secretion, glucagon suppression), hypothalamus (satiety, appetite suppression), and GI tract (delayed gastric emptying). Both are albumin-bound fatty acid analogs resistant to DPP-4 degradation.

## Pharmacokinetics

Liraglutide: once-daily SC injection, half-life ~13 h, albumin-bound. Semaglutide SC (Ozempic): once-weekly SC, half-life ~7 days (extended by C18 fatty diacid linkage with two mini-PEG spacers). Semaglutide oral (Rybelsus): first oral GLP-1 RA, ~1% bioavailability without absorption enhancer, taken on empty stomach with small amount of water.

## Glycemic Efficacy

Semaglutide produces superior HbA1c reduction vs. liraglutide head-to-head. SUSTAIN-4 trial: semaglutide 1 mg once weekly reduced HbA1c by ~1.5% vs. liraglutide 1.2 mg once daily ~1.0% reduction. Semaglutide 2.4 mg (Wegovy, obesity dose) produces ~15% body weight loss in SURMOUNT/STEP trials.

## Cardiovascular Outcomes

LEADER (liraglutide): 13% reduction in MACE. SUSTAIN-6 (semaglutide SC): 26% MACE reduction. SELECT trial (semaglutide 2.4 mg): 20% MACE reduction in overweight/obese without DM. Both have cardiovascular indications beyond glycemic control.

## Key Takeaways

- Semaglutide: weekly dosing, superior weight loss (~15% vs ~7%), superior CV data
- Liraglutide: once daily, longer clinical experience, also FDA-approved for obesity (3 mg)
- Both GLP-1 RAs with CV outcome data; semaglutide now preferred in most guidelines