Latest Developments in Cardiometabolic Therapies: EASD 2025 Spotlight on Orforglipron and Beyond

The European Association for the Study of Diabetes (EASD) meeting, set to take place from September 15 to 19 in Vienna, Austria, comes at a crucial juncture for the cardiometabolic space. Recent high-profile readouts have reshaped the landscape, particularly in obesity treatment, with Eli Lilly's orforglipron taking center stage amid both promise and setbacks.

Orforglipron: Efficacy vs. Safety Concerns

Eli Lilly's orforglipron, widely regarded as the leading oral weight loss pill in development, has shown mixed results in its Phase III ATTAIN-1 trial. While the candidate outperformed placebo in reducing body weight for patients with overweight or obesity, regardless of type 2 diabetes status, safety concerns have emerged.

Graig Suvannavejh, senior biotechnology and biopharmaceuticals analyst at Mizuho Securities, noted that the initial negative reaction to orforglipron's 72-week data was due to "surprisingly high levels of adverse events." Placebo-adjusted nausea rates increased from 11-16% at 40 weeks to 18-25.5% at 72 weeks, with vomiting rates also rising over time.

"Usually the side effects for GLP-1s occur in the earlier stages of taking the drug," Suvanjavejh explained, highlighting that orforglipron's toxicities appear later in its treatment course. This pattern "wouldn't be ideal if the goal was to take the pill as a maintenance therapy for the rest of your life," he added.

The EASD presentation is expected to provide more clarity on orforglipron's safety and tolerability profile, particularly regarding the timing of adverse events during the 72-week treatment period.

Beyond Weight Loss: Cardiovascular Benefits and Emerging Therapies

While obesity remains a central focus, the EASD conference is set to explore the broader therapeutic potential of incretin therapies beyond weight loss. Mihail Zilbermint, associate professor of Clinical Medicine at the Johns Hopkins School of Medicine, emphasized that the meeting will likely recognize obesity as a chronic, treatable disease while also addressing other topics such as devices, digital health, artificial intelligence, and nutrition.

A key highlight will be Novo Nordisk's SOUL trial, which examines the cardiovascular outcomes of oral semaglutide (Rybelsus) in patients with type 2 diabetes. The trial, involving over 9,600 patients, showed a significant reduction in major adverse cardiovascular events (MACE). However, analysts have noted that the data were "complicated" and pointed to an "inconsistent benefit" across different MACE components.

The conference will feature several presentations on SOUL, potentially clarifying its implications for long-term cardiometabolic protection. This aligns with a broader industry push to demonstrate the cardiovascular benefits of GLP-1 therapies, as evidenced by Novo Nordisk's recent STEER trial results, which showed a 57% drop in MACE risk for injectable semaglutide compared to Lilly's tirzepatide in patients with established cardiovascular disease.

Emerging Competitors and Future Directions

While Eli Lilly's orforglipron has faced challenges, competitors are also navigating hurdles. Viking Therapeutics reported a 10.9% placebo-adjusted weight reduction for its investigational pill VK2735 at 13 weeks, but tolerability issues and high dropout rates have dampened investor enthusiasm.

Meanwhile, Novo Nordisk has emerged as a potential frontrunner, anticipating approval of an oral version of its blockbuster GLP-1 Wegovy by year's end. The company is also developing amycretin, an analog of the amylin hormone, with both oral and subcutaneous formulations showing promise in early-stage trials.

As the cardiometabolic space continues to evolve, the EASD meeting will provide crucial insights into the ongoing development of more effective and better-tolerated treatments. With a focus on both immediate weight loss outcomes and long-term cardiovascular benefits, the conference is poised to advance both the scientific understanding and public health conversation around obesity and diabetes care.