Dulaglutide
(Trulicity)

The Discovery

The Convenience Problem

Why Good Drugs Weren't Good Enough

By the mid-2000s, GLP-1 drugs were proving their worth. Exenatide (Byetta) lowered blood sugar and helped patients lose weight. But there was a problem: patients had to inject it twice a day, every day, right before meals.

For many people, that was just too much. Studies showed that nearly half of diabetes patients stopped taking their medications within the first year. Missed doses meant uncontrolled blood sugar, which meant kidney damage, blindness, amputations, and heart attacks down the road.

The math was brutal: a drug that works perfectly but isn't taken is worse than a mediocre drug taken every day. Pharmaceutical companies raced to create longer-lasting GLP-1 drugs. The prize was a once-weekly injection — something so convenient that patients would actually stick with it.

The Breakthrough

The Fusion Strategy

Building a Better Molecule

At Eli Lilly's research labs in Indianapolis, scientists tried something nobody had done before with GLP-1. Instead of just tweaking the peptide like others were doing, they fused it to something much bigger: an Fc fragment — the tail end of a human antibody.

Antibodies are the immune system's guided missiles. They're large proteins that naturally circulate in the blood for weeks before being cleared. By attaching GLP-1 to an antibody fragment, Lilly's team created a molecule that was enormous compared to natural GLP-1 — about 59,000 daltons versus just 3,300. This giant size meant the kidneys couldn't filter it out, and enzymes couldn't easily reach the GLP-1 part to destroy it.

The team made critical tweaks along the way. They modified the GLP-1 sequence to resist the DPP-4 enzyme. They used a special linker to connect the peptide to the Fc fragment. And they chose the IgG4 subtype specifically because it wouldn't accidentally trigger an immune attack. After years of engineering, the molecule — codenamed LY2189265 — was ready for human testing.

The Trials

The AWARD Program

Proving It Works in the Real World

Lilly launched one of the largest clinical trial programs ever for a diabetes drug. They called it AWARD — Assessment of Weekly Administration of dulaglutide in Diabetes. Across eleven major trials, thousands of patients tested dulaglutide against the leading diabetes treatments.

The results were consistently impressive. Dulaglutide matched or beat the competition in lowering blood sugar, while also helping patients lose weight. The once-weekly injection improved adherence dramatically — patients actually took their medicine.

On September 18, 2014, the FDA approved Trulicity. It came in a simple, pre-filled pen that patients could use at home without mixing or measuring. The injection took seconds. For many patients, it was the first time managing diabetes didn't feel like a full-time job.

The Crisis

The Heart Question

A Tense Wait for the REWIND Results

After approval, a shadow hung over all GLP-1 drugs. The FDA required large cardiovascular safety trials — not to prove benefit, but to prove the drugs weren't secretly causing heart attacks. Several diabetes drugs had been pulled or restricted after unexpected heart risks surfaced years after approval.

The REWIND trial was massive: 9,901 patients across 24 countries, followed for over five years. Unlike other heart outcome trials that focused only on patients with existing heart disease, REWIND included many patients who simply had risk factors. This made the trial more challenging — it's harder to show benefit in healthier patients.

When the results dropped in June 2019, the room went silent, then erupted. Dulaglutide cut major cardiovascular events — heart attacks, strokes, and cardiovascular death — by 12%. And it worked even in patients who didn't already have heart disease. The drug designed for blood sugar was protecting hearts.

The Legacy

The Blockbuster Era

A $7 Billion Drug and Growing

Trulicity became a juggernaut. By 2022, it was generating $7.4 billion in annual sales, making it one of the best-selling drugs in the world. Millions of patients in over 60 countries used it weekly.

But the GLP-1 landscape was shifting beneath Lilly's feet. Novo Nordisk's semaglutide (Ozempic, Wegovy) showed even greater weight loss, and Lilly's own tirzepatide (Mounjaro) — a dual GLP-1/GIP drug — was producing jaw-dropping results. Trulicity suddenly faced fierce competition from the very revolution it helped create.

Yet dulaglutide's legacy is secure. It proved that protein engineering could transform a fragile gut hormone into a once-weekly medicine. It showed that GLP-1 drugs could protect the heart. And for millions of patients, it was the drug that made diabetes manageable for the first time. The antibody shield had done its job.