The Big Picture
To understand how retatrutide works, it helps to first understand why weight loss is so difficult. The human body is designed to resist weight loss — it evolved over millennia in environments where food was scarce. Hormones, brain signals, and metabolic adaptations all work together to defend body fat stores and restore lost weight.
Retatrutide works by simultaneously hijacking three separate hormonal systems involved in energy balance and appetite — the GLP-1, GIP, and glucagon pathways. By activating all three at once, it applies pressure on multiple fronts in a way that no existing approved drug can match.
Analogy: Think of obesity as a locked vault with three combination dials. Semaglutide turns one dial. Tirzepatide turns two. Retatrutide turns all three simultaneously — dramatically increasing the chance of opening the lock.
The Three Receptors Explained
GLP-1 (Glucagon-Like Peptide-1)
GLP-1 is a hormone naturally released by your gut after eating. It signals your pancreas to release insulin, tells your brain you're full, slows the emptying of food from your stomach, and reduces the release of glucagon (which would otherwise raise blood sugar). GLP-1 receptor agonism is the foundation of drugs like Ozempic and Wegovy. It's the primary driver of appetite suppression and the reason people on these drugs eat significantly less without feeling deprived.
GIP (Glucose-Dependent Insulinotropic Polypeptide)
GIP is another gut hormone released after meals. It amplifies the insulin response to food and is thought to improve the tolerability of GLP-1 agonism — meaning adding GIP activation reduces the nausea and gastrointestinal side effects that many people experience on GLP-1-only drugs. GIP also plays a role in fat tissue regulation. Tirzepatide (Mounjaro/Zepbound) was the first drug to combine GLP-1 and GIP, and its superior weight loss vs. semaglutide validated the dual-agonist concept.
Glucagon Receptor Agonism — The Key Differentiator
This is what sets retatrutide apart from everything else. Glucagon is a hormone that normally raises blood sugar by signaling the liver to release stored glucose. At first glance, activating glucagon receptors seems counterproductive — but at the doses used in retatrutide, glucagon receptor agonism produces two powerful metabolic effects: it dramatically increases energy expenditure (the body burns more calories at rest), and it directly stimulates fat breakdown in the liver, which is particularly relevant for people with fatty liver disease. The net effect is that the body is not just eating less — it is also burning more, potentially accelerating and sustaining weight loss beyond what appetite suppression alone can achieve.
What Happens After Each Injection
Here is a simplified step-by-step of what occurs after a weekly retatrutide injection:
Absorption (Days 1–2)
The drug is absorbed slowly from the subcutaneous injection site into the bloodstream, reaching peak concentration within 1–3 days of injection.
Brain Signalling — Appetite Suppression
GLP-1 receptor activation in the hypothalamus and brainstem reduces appetite signals. Food becomes less appealing, portions feel more satisfying, and cravings diminish — particularly for high-fat, high-calorie foods.
Gut Slowing — Extended Fullness
Gastric emptying is slowed, meaning food remains in the stomach longer. This extends the sensation of fullness after smaller meals and blunts post-meal blood sugar spikes.
Pancreas — Insulin Regulation
Both GLP-1 and GIP receptor activation enhance insulin secretion in a glucose-dependent manner (meaning only when blood sugar is elevated), reducing the risk of hypoglycemia compared to older diabetes drugs.
Liver & Fat Tissue — Increased Calorie Burning
Glucagon receptor activation signals the liver to increase fat oxidation and energy expenditure. This raises the body's metabolic rate and promotes breakdown of stored liver fat — the mechanism thought to drive retatrutide's advantage over dual agonists.
Why Triple Is Better Than Double
The addition of glucagon receptor agonism to a GLP-1/GIP backbone addresses a key limitation of existing drugs: metabolic adaptation. When people lose weight, the body compensates by reducing its resting metabolic rate — burning fewer calories even at rest. This is why weight loss tends to plateau and why weight regain is so common after stopping medication.
By simultaneously increasing energy expenditure through the glucagon pathway, retatrutide may partially counter this metabolic adaptation. This is supported by the Phase 2 data, where weight loss curves had not flattened at 48 weeks — suggesting the body had not fully adapted. Whether this holds true in Phase 3 over longer durations is one of the key questions the ongoing trials will answer.