Retatrutide
(LY3437943)

2010s

The Third Hormone

Glucagon's Redemption

While GLP-1 drugs dominated obesity research, some scientists were looking at glucagon — the hormone that raises blood sugar by releasing stored energy. In diabetics, glucagon is the enemy. But in obesity research, it offered something valuable: the ability to increase energy expenditure.

Studies showed that glucagon made the body burn more calories, especially from fat. The problem was the blood sugar spike that came with it. How could you get the fat-burning benefit without the dangerous glucose surge?

The answer emerged from dual and triple agonist research. By combining glucagon with GLP-1 (which lowers blood sugar) and GIP (which enhances insulin), scientists could balance the equation — getting glucagon's benefits while neutralizing its risks.

2018-2020

The Lilly Program

Building on Tirzepatide

Eli Lilly had already proven that dual GIP/GLP-1 agonism worked spectacularly well with tirzepatide. Their scientists began asking: what if we added glucagon to the mix?

The chemistry was even more complex than before. The molecule had to activate three different receptors, each in the right proportion. Too much glucagon and blood sugar would spike. Too little and you'd lose the fat-burning benefit. Too much GLP-1 and side effects would become intolerable.

By 2020, Lilly had created LY3437943 — later named retatrutide. The 39-amino-acid peptide hit all three targets. Early animal studies showed dramatic results: more weight loss than any dual agonist, with manageable effects on blood sugar.

2021-2022

Phase 2 Trials

Numbers That Stunned

The Phase 2 trial enrolled patients with obesity but without diabetes. For 48 weeks, participants received weekly injections of retatrutide at various doses, while researchers measured weight loss and side effects.

The results, presented at scientific conferences in 2023, were extraordinary. At the highest dose, patients lost an average of 24.2% of their body weight. Some lost nearly a third of their starting weight. These were numbers previously seen only after gastric bypass surgery.

The medical community was stunned. Tirzepatide's 22% weight loss had seemed like a ceiling. Retatrutide had broken through it. The triple agonist approach was working even better than anyone had hoped.

2023-2024

The Phase 3 Push

Racing Toward Approval

The stunning Phase 2 results accelerated Lilly's development program. Phase 3 trials expanded to thousands of patients across multiple conditions: obesity, type 2 diabetes, fatty liver disease, and sleep apnea.

But questions remained. Could the results hold up in larger, more diverse populations? Would the side effects — mainly gastrointestinal, like tirzepatide — prove tolerable long-term? And how would regulators view a drug that activates glucagon, traditionally seen as the diabetic's enemy?

Competitors watched nervously. If retatrutide succeeded, it could make even tirzepatide seem like last year's model. The race for the ultimate weight loss drug was entering its final lap.

2025-Future

The New Standard?

Rewriting the Possible

As Phase 3 data emerges, the medical community is grappling with what these results mean. If 25% or more weight loss becomes routinely achievable with a weekly injection, what happens to bariatric surgery? To the diet industry? To how we think about obesity itself?

FDA approval, expected within the next few years, will likely trigger the same explosive demand seen with semaglutide and tirzepatide. Manufacturing capacity, insurance coverage, and access will become critical issues.

But retatrutide represents more than just another weight loss drug. It's proof that the multi-agonist approach works — that combining hormone signals can produce effects greater than any single target. The triple threat may be just the beginning.