Tirzepatide: History & Discovery

The Discovery of GIP: Foundation for Dual Agonism

The story of tirzepatide begins with the discovery of glucose-dependent insulinotropic polypeptide (GIP) in 1973, making it the first incretin hormone identified. Initially called gastric inhibitory polypeptide due to its effects on gastric acid secretion, researchers soon recognized its more important role in stimulating insulin secretion. GIP is produced by intestinal K-cells in response to nutrient intake and accounts for 50-70% of the incretin effect in people with normal glucose tolerance.

For decades, GIP received less attention than GLP-1 in drug development. This was partly because GIP's insulinotropic effects are impaired in people with type 2 diabetes (a phenomenon called "GIP resistance"), leading researchers to question whether GIP receptor agonism would be therapeutically useful. Additionally, early studies suggested that GIP might promote fat storage, raising concerns that GIP agonists could cause weight gain—the opposite of what's desired for diabetes and obesity treatment.

However, research in the 2000s and 2010s began to challenge these assumptions. Studies showed that sustained GIP receptor activation could overcome GIP resistance in diabetes. Additionally, GIP's effects on adipose tissue appeared more nuanced than initially thought, potentially promoting beneficial fat distribution rather than simply increasing fat mass. These insights set the stage for exploring dual GIP/GLP-1 agonism as a therapeutic strategy.

Eli Lilly's Development Program

Eli Lilly and Company, an American pharmaceutical company with a century-long history in diabetes care (they produced the first commercial insulin in 1923), began developing tirzepatide in the early 2010s. The company had been researching incretin-based therapies and saw an opportunity to create a next-generation agent that might surpass the efficacy of pure GLP-1 agonists.

The Dual Agonist Concept

The key innovation was creating a single molecule that could activate both GIP and GLP-1 receptors. This required sophisticated molecular engineering because GIP and GLP-1 have different amino acid sequences and bind to structurally distinct receptors. The challenge was to design a peptide that could bind and activate both receptors with sufficient potency while maintaining favorable pharmacokinetic properties.

Eli Lilly's approach was to start with the GIP peptide sequence and modify it to gain GLP-1 receptor activity. Through structure-activity relationship studies, researchers identified specific amino acid substitutions that enabled GLP-1 receptor binding while maintaining GIP receptor activity. The resulting molecule binds GIP receptors with similar affinity to native GIP and GLP-1 receptors with approximately 5-fold lower affinity than native GLP-1—still sufficient for robust activation.

To enable once-weekly dosing, tirzepatide incorporates a C-20 fatty acid modification (longer than semaglutide's C-18) attached via a spacer to enable albumin binding. This extends the half-life to approximately 5 days. The molecule also includes amino acid substitutions to protect against enzymatic degradation. The final design represents a careful balance of dual receptor activation, extended half-life, and pharmaceutical properties.

Preclinical Development

Preclinical studies in the mid-2010s demonstrated that tirzepatide activated both GIP and GLP-1 receptors and produced robust glucose lowering and weight loss in animal models. Importantly, the dual agonism appeared to produce synergistic effects—greater efficacy than would be expected from either receptor activation alone. Toxicology studies identified the thyroid C-cell tumor finding (similar to GLP-1 agonists) that would later lead to a boxed warning.

Clinical Development: The SURPASS Program

Tirzepatide entered clinical development in the mid-2010s with a comprehensive program designed to establish efficacy and safety for type 2 diabetes. The SURPASS (Tirzepatide Once Weekly for the Treatment of Obesity and Type 2 Diabetes) program would eventually include 8 major phase 3 trials enrolling over 10,000 participants.

Phase 1 and 2 Studies (2015-2018)

Early phase studies established tirzepatide's pharmacokinetics, safety, and preliminary efficacy. Phase 1 studies confirmed the approximately 5-day half-life and demonstrated steady-state concentrations after 4-5 weeks of weekly dosing. Phase 2 dose-ranging studies tested doses from 1 mg to 15 mg weekly, establishing that 5 mg, 10 mg, and 15 mg were optimal doses balancing efficacy and tolerability.

These early studies revealed tirzepatide's exceptional glucose-lowering effects (HbA1c reductions of 2.0-2.5%) and substantial weight loss (10-15 kg). The results exceeded those typically seen with GLP-1 agonists, validating the dual agonist concept. The side effect profile was similar to GLP-1 agonists, with gastrointestinal effects being most common.

SURPASS-1: Establishing Efficacy (2021)

SURPASS-1, published in The Lancet in 2021, compared tirzepatide monotherapy to placebo in 478 participants with type 2 diabetes inadequately controlled with diet and exercise. Results were impressive: HbA1c reductions of 1.9% with 5 mg, 2.1% with 10 mg, and 2.4% with 15 mg, compared to 0.1% with placebo. Weight loss was 7.0 kg, 7.8 kg, and 9.5 kg respectively, compared to 0.7 kg with placebo. Remarkably, 42-52% of participants achieved HbA1c below 5.7% (normal range) without diabetes medications.

SURPASS-2: Head-to-Head with Semaglutide (2021)

SURPASS-2, published in The New England Journal of Medicine in 2021, was the pivotal trial that established tirzepatide's superiority over semaglutide. This trial enrolled 1,879 participants with type 2 diabetes inadequately controlled on metformin and compared tirzepatide (5 mg, 10 mg, or 15 mg weekly) to semaglutide 1 mg weekly.

Results showed tirzepatide's superiority for both glucose control and weight loss. HbA1c reductions were 2.0%, 2.2%, and 2.5% with tirzepatide vs 1.9% with semaglutide. Weight loss was 7.6 kg, 9.3 kg, and 12.4 kg with tirzepatide vs 6.2 kg with semaglutide. The 15 mg dose produced double the weight loss of semaglutide—a dramatic difference that generated enormous excitement in the diabetes and obesity communities.

SURPASS-3, 4, and 5: Comparisons to Other Agents (2021-2022)

SURPASS-3 compared tirzepatide to insulin degludec (a long-acting basal insulin) in 1,444 participants with inadequately controlled diabetes on metformin with or without SGLT2 inhibitors. Despite insulin being titrated to target, tirzepatide produced superior glucose control (HbA1c reductions of 1.9-2.4% vs 1.4%) and dramatic differences in weight (tirzepatide caused 7.5-12.9 kg loss vs 2.3 kg gain with insulin).

SURPASS-4 examined tirzepatide vs insulin glargine in 2,002 participants with type 2 diabetes at high cardiovascular risk. Again, tirzepatide showed superiority for glucose control and weight loss. Importantly, this trial included a cardiovascular safety assessment showing that tirzepatide was non-inferior to insulin for cardiovascular outcomes, establishing cardiovascular safety.

SURPASS-5 compared tirzepatide to placebo when added to insulin glargine, showing that tirzepatide could be safely and effectively combined with basal insulin, producing substantial additional glucose lowering and weight loss.

SURPASS-6 and Beyond

Additional SURPASS trials examined tirzepatide in various populations and treatment contexts, consistently demonstrating superior efficacy. SURPASS-J examined tirzepatide in Japanese participants, SURPASS-AP-Combo in Asian populations, and SURPASS-China in Chinese participants, establishing efficacy across diverse ethnic groups.

FDA Approval for Diabetes (2022)

On May 13, 2022, the FDA approved tirzepatide (brand name Mounjaro) for treatment of type 2 diabetes in adults. The approval was based on the SURPASS clinical trial program demonstrating superior glucose lowering compared to placebo and multiple active comparators including semaglutide. Approved doses were 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg once weekly, with a starting dose of 2.5 mg weekly for 4 weeks.

The approval included a boxed warning regarding thyroid C-cell tumors, contraindications for personal or family history of medullary thyroid carcinoma or MEN2, and warnings about pancreatitis, hypoglycemia when combined with insulin or sulfonylureas, and other risks. Despite these warnings, the approval was seen as a major advance, offering superior efficacy to existing treatments.

Mounjaro launched in the United States in June 2022 and immediately faced overwhelming demand. Within months, supply shortages developed as prescriptions far exceeded manufacturing capacity. The medication's exceptional efficacy, particularly for weight loss, drove demand not just from people with diabetes but also from those seeking weight loss, leading to widespread off-label use.

The SURMOUNT Program: Pivoting to Obesity (2019-2023)

While tirzepatide was being developed for diabetes, the dramatic weight loss observed in SURPASS trials led Eli Lilly to initiate the SURMOUNT (Study of Tirzepatide Once Weekly for the Treatment of Obesity) program, testing tirzepatide specifically for chronic weight management in people without diabetes.

SURMOUNT-1: Unprecedented Weight Loss (2022)

SURMOUNT-1, published in The New England Journal of Medicine in June 2022, was a game-changer. This trial enrolled 2,539 adults with obesity or overweight with weight-related comorbidities, but without diabetes. Participants received tirzepatide (5 mg, 10 mg, or 15 mg weekly) or placebo, both combined with lifestyle intervention.

Results were unprecedented: average weight loss of 15.0% with 5 mg, 19.5% with 10 mg, and 20.9% with 15 mg, compared to 3.1% with placebo. With the highest dose, 50% of participants lost at least 20% of body weight, and 30% lost 25% or more. These results approached or matched those typically seen with bariatric surgery, establishing tirzepatide as the most effective obesity medication available.

SURMOUNT-2, 3, and 4: Confirming Efficacy (2023)

SURMOUNT-2 examined tirzepatide in people with obesity and type 2 diabetes, showing 12.8-15.7% weight loss depending on dose. SURMOUNT-3 combined tirzepatide with intensive lifestyle intervention, producing 18.4% weight loss. SURMOUNT-4 examined weight loss maintenance, showing that continuing tirzepatide maintained weight loss while switching to placebo led to substantial regain.

FDA Approval for Weight Management (2023)

On November 8, 2023, the FDA approved tirzepatide for chronic weight management (brand name Zepbound) in adults with obesity or overweight with at least one weight-related comorbidity. This approval, coming just 18 months after the diabetes approval, reflected the exceptional efficacy demonstrated in the SURMOUNT program.

Zepbound launched in December 2023 and immediately faced supply constraints similar to Mounjaro. Eli Lilly invested billions in manufacturing expansion, but demand continued to exceed supply through 2024. The medication's superior efficacy compared to semaglutide positioned it as the new standard for pharmaceutical obesity treatment.

Cultural Phenomenon and Market Impact (2022-2024)

Tirzepatide's launch coincided with the cultural phenomenon around GLP-1 agonists sparked by semaglutide. Media coverage was extensive, with tirzepatide often positioned as "even better than Ozempic." The medication entered popular culture alongside semaglutide, with widespread discussion of its dramatic weight loss effects.

The economic impact was staggering. Tirzepatide generated over $5 billion in sales in 2023 (its first full year on market) and was projected to exceed $10 billion in 2024. Eli Lilly's market capitalization soared, making it one of the most valuable pharmaceutical companies globally. The success sparked intense competition, with multiple companies developing next-generation incretin-based therapies.

The supply shortages created a market for compounded tirzepatide, raising similar quality and safety concerns as with compounded semaglutide. The FDA issued warnings about compounded products, but demand continued to exceed supply of brand-name formulations.

Ongoing Research and Future Directions

Cardiovascular Outcomes

The SURPASS-CVOT trial, initiated in 2020, is examining whether tirzepatide reduces cardiovascular events in people with type 2 diabetes and established cardiovascular disease or high cardiovascular risk. Results are expected in 2024-2025 and will determine whether tirzepatide provides cardiovascular benefits similar to semaglutide.

Obstructive Sleep Apnea

The SURMOUNT-OSA trial is examining whether tirzepatide improves sleep apnea severity and potentially allows discontinuation of CPAP therapy. Preliminary results suggest substantial improvements in apnea-hypopnea index.

Heart Failure

Trials are examining tirzepatide for heart failure with preserved ejection fraction (HFpEF), a condition strongly associated with obesity for which few effective treatments exist.

NASH

Phase 2 trials are examining tirzepatide for non-alcoholic steatohepatitis, with early results showing substantial reductions in liver fat and improvements in liver inflammation.

Chronic Kidney Disease

Trials are examining whether tirzepatide slows progression of chronic kidney disease in people with diabetes and kidney disease.

Legacy and Impact on Medicine

Tirzepatide has established dual incretin agonism as a superior approach to pure GLP-1 agonism for diabetes and obesity. The medication has set new standards for what's achievable with pharmaceutical obesity treatment, producing weight loss that rivals bariatric surgery. This has fundamentally changed expectations for obesity medications and sparked a new wave of drug development.

The success has validated the concept of multi-receptor agonism, leading to development of triple agonists (GIP/GLP-1/glucagon) that may produce even greater weight loss. Retatrutide, the most advanced triple agonist, produced 24% weight loss in phase 2 trials. If successful in phase 3, triple agonists could represent the next evolution beyond tirzepatide.

Perhaps most importantly, tirzepatide has demonstrated that targeting fundamental biological pathways regulating appetite and metabolism can produce transformative outcomes. This has reinvigorated obesity research and drug development, with the potential to transform treatment of metabolic diseases over the coming decades.