Mazdutide: A Beginner's Guide to the First GLP-1/Glucagon Dual Agonist

🔥

What Is Mazdutide? I've been getting asked to cover it so here's everything you need to know.

Mazdutide is a next-generation peptide that targets two receptors instead of just one. While semaglutide (Ozempic/Wegovy) only hits the GLP-1 receptor, and tirzepatide (Mounjaro/Zepbound) hits

GLP-1 and GIP.

Mazdutide takes a different approach:

GLP-1 + Glucagon (GCG)

This makes it the world's first approved dual GLP-1/glucagon receptor agonist.

How Does It Work? (Simple Version)

Think of mazdutide as having two engines working together:

Engine 1: GLP-1 Activation

Reduces appetite and cravings
Slows gastric emptying (food stays in your stomach longer)
Promotes insulin secretion
This is the same mechanism as semaglutide

Engine 2: Glucagon Activation

Increases energy expenditure (you burn more calories)
Improves fat metabolism in the liver
Helps reduce liver fat content

The glucagon component is what makes mazdutide unique. While it might seem counterintuitive (glucagon raises blood sugar, right?), when combined with GLP-1, the insulin-promoting effects dominate while you still get the metabolic boost from glucagon activation.

The result: You eat less AND burn more. Plus significant improvements in liver fat, which most GLP-1s alone don't address as effectively.

Who Makes It? The Story

Eli Lilly originally developed mazdutide (also called LY3305677 or IBI362). It's actually an analog of oxyntomodulin—a natural hormone your gut produces after eating that activates both GLP-1 and glucagon receptors.

In 2019, Lilly licensed the China rights to Innovent Biologics, a Chinese biopharma company. Innovent ran all the major clinical trials and pushed it through approval.

June 2025: China's NMPA approved mazdutide for chronic weight management—making it the world's first approved GLP-1/glucagon dual agonist.

Lilly still holds the rights outside China and is running Phase 2 trials in the US, but Innovent has been the driving force behind its development.

The Clinical Trial Results

GLORY-1 Trial (Phase 3 - Weight Loss)

610 participants with overweight/obesity
48 weeks of treatment
Results at Week 48: 4mg dose: -11.0% body weight loss 6mg dose: -14.0% body weight loss Placebo: +0.3% (basically no change)
49.5% of people on 6mg lost ≥15% of their body weight

DREAMS Trials (Phase 3 - Type 2 Diabetes)

Mazdutide beat both placebo AND Lilly's own Trulicity (dulaglutide)
HbA1c reductions of 1.5-2.15% depending on dose
Also showed weight loss of ~9.6% in diabetes patients

Head-to-Head vs Semaglutide (October 2025)

Mazdutide 6mg vs Semaglutide 1mg
Mazdutide won on both blood sugar AND weight loss
First direct comparison of a GLP-1/GCG drug against semaglutide

High-Dose Phase 1 Trial (16mg - US)

20 weeks of treatment
-20% to -21% body weight loss
This shows higher doses may push results even further

Dosing From the Trials

Mazdutide uses a slow titration approach similar to other GLP-1s. Here's what the clinical trials used:

Standard Protocol (to 6mg maintenance):

→ Weeks 1-4: 2mg → Weeks 5-8: 4mg → Weeks 9+: 6mg (maintenance)

Alternative Protocol (to 4.5mg):

→ Weeks 1-4: 1.5mg → Weeks 5-8: 3mg → Weeks 9+: 4.5mg (maintenance)

Higher Dose Protocol (to 9mg):

→ Weeks 1-4: 3mg → Weeks 5-8: 6mg → Weeks 9+: 9mg (maintenance)

Dosing is once weekly via subcutaneous injection.

Side Effects (What to Expect)

The side effect profile is similar to other GLP-1s—mostly GI-related and typically mild to moderate:

Nausea
Diarrhea
Decreased appetite
Vomiting
Abdominal distension

Good news: In GLORY-1, discontinuation rates due to adverse events were actually very low:

4mg: 1.5%
6mg: 0.5%
Placebo: 1.0%

This suggests mazdutide may actually be better tolerated than some other GLP-1s.

How Does It Compare?

Semaglutide 2.4mg (GLP-1 only) → ~15% weight loss at 68 weeks

Tirzepatide 15mg (GLP-1 + GIP) → ~21% weight loss at 72 weeks

Mazdutide 6mg (GLP-1 + GCG) → ~14% weight loss at 48 weeks

Mazdutide 16mg (GLP-1 + GCG) → ~20-21% weight loss at 20 weeks

The glucagon component may offer unique advantages for liver fat reduction and metabolic health that aren't fully captured by weight loss numbers alone.

Key Takeaways