With recent strong clinical trial results for its investigational oral weight-loss pill orforglipron, Eli Lilly is advancing its innovative pipeline in diabetes and obesity, building on the success of its groundbreaking injectable tirzepatide (Mounjaro/Zepbound) to offer comprehensive solutions for patients.
Eli Lilly and Company is at the forefront of a paradigm shift in how type 2 diabetes and obesity are treated. Their strategic investments in novel incretin-based therapies have yielded significant breakthroughs, most notably with the dual GIP and GLP-1 receptor agonist tirzepatide, marketed as Mounjaro and Zepbound. Now, the pharmaceutical giant is poised to introduce another potential game-changer: orforglipron, an investigational oral GLP-1 drug that recently demonstrated impressive results in late-stage clinical trials.
Tirzepatide: The Dual Incretin Breakthrough
The journey for tirzepatide (initially known as LY3298176) began with promising early-stage results. In October 2018, data from a Phase 2b clinical trial showcased “unprecedented” reductions in blood sugar (HbA1c) and body weight for people with type 2 diabetes. Average HbA1c reductions reached up to 2.4 percentage points, and participants experienced an average weight reduction of up to 11.3 kg (12.7 percent), as detailed in findings published in The Lancet.
This investigational drug integrates the actions of two natural incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)—into a single molecule. This dual-action mechanism distinguishes it from earlier selective GLP-1 receptor agonists like Lilly’s own dulaglutide (Trulicity) and Novo Nordisk’s semaglutide (Ozempic).
Following these encouraging results, Lilly initiated a large Phase 3 clinical program, dubbed SURPASS. The SURPASS-1 trial, which randomized 478 type 2 diabetics, further validated tirzepatide’s efficacy, showing significant drops in both HbA1c (up to 2.07% from baseline) and body weight (up to 9.5 kg or 11% reduction) over 40 weeks. The success of these trials culminated in the U.S. Food and Drug Administration (FDA) approval of tirzepatide under the brand name Mounjaro for type 2 diabetes in May 2022. The drug’s remarkable weight-loss effects also led to its subsequent approval as Zepbound for chronic weight management in November 2023.
Orforglipron: Advancing with an Oral Option
Building on the success of tirzepatide, Eli Lilly is now making significant strides with orforglipron, an investigational oral GLP-1 weight-loss drug. The convenience of a pill, compared to injectables, could greatly expand access and adherence for patients.
Recent Phase 3 trials, the results of which were announced on October 15, 2025, demonstrated that orforglipron met its primary and all key secondary endpoints for people with type 2 diabetes. In one trial, orforglipron showed superior blood sugar control, lowering HbA1c by up to 1.7% compared to a 0.8% reduction with AstraZeneca’s dapagliflozin (Farxiga/Forxiga). Another trial confirmed its efficacy when used alongside insulin glargine, achieving an additional 2.1% HbA1c reduction. Across both studies, orforglipron also delivered significant weight loss and improvements in multiple cardiovascular risk factors.
These findings reinforce earlier head-to-head trials where orforglipron outperformed Novo Nordisk’s oral GLP-1 drug, Rybelsus, in both blood sugar and weight reduction. Lilly plans to submit orforglipron for obesity treatment to global regulatory agencies by the end of 2025, with submission for type 2 diabetes treatment expected in 2026.
The Science Behind Incretin Agonists
The efficacy of both tirzepatide and orforglipron lies in their ability to mimic or enhance the action of incretin hormones. GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide) are natural gut hormones released after eating, which play crucial roles in metabolic regulation. They:
- Stimulate insulin secretion in a glucose-dependent manner, helping to lower blood sugar without causing severe hypoglycemia.
- Delay gastric emptying, promoting a feeling of fullness and reducing food intake.
- Suppress appetite in the brain, leading to reduced caloric consumption.
- May regulate blood lipid metabolism.
Tirzepatide’s dual action taps into both pathways, offering a synergistic effect that has led to its profound impact on HbA1c and weight loss. Orforglipron, as a GLP-1 receptor agonist, focuses on the proven benefits of GLP-1, delivering them in a convenient oral form.
Safety and Tolerability
Across both the tirzepatide and orforglipron clinical trials, the safety profiles were generally consistent with the known GLP-1 receptor agonist class. The most commonly reported side effects were gastrointestinal-related, including:
- Nausea
- Diarrhea
- Vomiting
These events were typically mild to moderate in severity, dose-dependent, and transient, often occurring during the initial titration period. Crucially, no participants in any of the treatment groups experienced severe hypoglycemia, a significant advantage in diabetes management. Lilly has indicated that studies are ongoing to optimize titration schedules to help manage these initial gastrointestinal effects.
Market Implications and Eli Lilly’s Vision
Eli Lilly’s robust pipeline, featuring both tirzepatide and orforglipron, positions the company as a dominant force in the rapidly expanding metabolic health market. With Trulicity (dulaglutide) facing patent expiration in 2027, these new drugs are critical for Lilly’s future growth and its competitive stance against rivals like Novo Nordisk, which markets Ozempic and Wegovy (semaglutide).
The introduction of highly effective injectable and oral treatments provides clinicians with more tools to address the complex needs of people with type 2 diabetes and obesity, conditions that affect millions worldwide. The potential for oral medications like orforglipron to simplify treatment regimens could dramatically improve patient access and adherence, driving a new era in chronic disease management.
These advancements reflect Lilly’s century-long commitment to diabetes care and its ongoing dedication to discovering and delivering life-changing medicines that make a real difference for patients globally.
