Newfound Mechanism Rewires Cellular Energy Processing for Drastic Weight Loss
Beyond Ozempic: Research Outlines Pathways for Future Obesity Solutions
NEW YORK, May 21, 2025 /PRNewswire/ — Mice genetically engineered to lack the ability to make the amino acid cysteine, and fed a cysteine-free diet, lost 30 percent of their body weight in just one week, a new study shows.
Published online May 21 in Nature, the work found that cysteine depletion disrupts the normal metabolic pathways used by mammalian cells to convert food into energy, forcing the animals to rapidly burn fat stores in a futile attempt to meet energy demands.
Led by researchers at NYU Grossman School of Medicine, the study reveals key details about how cells process fuels like carbohydrates and fats (metabolism), and how cysteine depletion affects tissues. Experiments showed that lowering cysteine levels caused a drop in levels of the small molecule called coenzyme A (CoA), which rendered inefficient mechanisms that convert carbohydrates and fats into energy.
Despite CoA being involved in more than 100 intermediate metabolic reactions and serving as a partner (cofactor) for 4% of all enzymes in the body, scientists had previously been unable to study its function directly. This is because mice with defective CoA synthesis typically do not survive beyond three weeks of age. The current findings detail, for the first time, how CoA shapes metabolism in adult mice.
'Our surprising findings reveal that low cysteine levels triggered rapid fat loss in our study mice by activating a network of interconnected biological pathways,' said co-senior study author Evgeny Nudler, PhD, the Julie Wilson Anderson Professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, and an investigator with the Howard Hughes Medical Institute. 'While driving weight loss in the clinic remains a key future mission, we are most excited for the moment about the profound, fundamental aspects of metabolism revealed in this study,' added Dr. Nudler.
The current finding does not immediately suggest a new approach to weight loss, the authors caution, as cysteine is found in nearly all foods. Achieving a truly cysteine-free diet would require patients to consume a specially formulated solution that would be challenging for most. Moreover, because cysteine is involved in numerous cellular pathways, eliminating it – such as through a drug that inhibits cysteine production – could make organs more vulnerable to everyday toxins, including medications.
That said, the study authors say it is worth considering that fruits, vegetables, and legumes contain much lower levels of cysteine and its precursor, the sulfur-containing amino acid methionine, than red meat. While earlier studies have linked low sulfur amino acid intake to health benefits, this study clarifies that these benefits are due to cysteine depletion specifically, and not methionine restriction.
'Given that achieving maximum cysteine deprivation weight loss in the mice was dependent on both diet and deletion of the gene, moving forward we can now restore cysteine production genetically in specific cells or tissues and determine the role of each in the dramatic weight loss we observed,' said co-senior author Dan L. Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Department of Pathology, and a professor in the Department of Cell Biology, at NYU Grossman School of Medicine. 'We hope in the future to hijack parts of this process to induce a similar weight loss in humans but without completely removing cysteine,' added Dr. Littman, who is also an investigator with the Howard Hughes Medical Institute.
Overlapping MechanismsThe study is the first to examine the effects of removing cysteine, or any of the nine of the essential amino acids, which must be obtained through diet and are required for building proteins that make up most of the body's enzymes, tissues, and signaling molecules. The findings revealed that eliminating cysteine from the mammalian body led to far greater weight loss than the removal of any other essential amino acid.
Specifically, cysteine deprivation disrupted oxidative phosphorylation, the main process for producing adenosine triphosphate (ATP), the molecule that serves as cells' energy currency. Oxidative phosphorylation is known to be tightly dependent on CoA. As a result, sugar-derived intermediate molecules (carbon skeletons) such as pyruvate, orotate, citrate, and α-ketoglutarate were no longer used efficiently, and were instead lost in the urine. In response, the body turned to stored lipids (fats) to make energy.
Further, the team found that cysteine restriction activates both the integrated stress response (ISR), a signaling network that restores cellular balance after stress, and the oxidative stress response (OSR), which is triggered by higher levels of reactive oxygen species (ROS) following depletion of glutathione, the body's primary antioxidant. ROS can oxidize (take away electrons from) and damage sensitive cell parts like DNA.
Remarkably, this simultaneous activation of ISR and OSR—previously observed only in cancer cells—was shown to occur in normal tissues in mice in the cysteine-restriction group, with the two stress responses reinforcing each other. The study also shows that ISR and OSR, acting independently of CoA depletion, increase production of the stress hormone GDF15, which contributes to food aversion and degradation of acetyl-CoA-carboxylase, a key enzyme in lipid synthesis. This increased weight loss further in the study mice by preventing the replenishment of their fat stores.
Along with Drs. Evgeny Nudler and Dan Littman, the study's co-senior authors, co-first authors were Alan Varghese, a joint student in labs of Drs Littman and Nudler in the Department of Cell Biology, and Ivan Gusarov in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine. Additional NYU Langone contributors included Daria Dolgonos, Yatin Mankan, and Mydia Phan from the Department of Cell Biology; Ilya Shamovsky and Drew Jones from the Department of Biochemistry and Molecular Pharmacology; Begoña Gamallo-Lana and Adam Mar from the Department of Neuroscience; Rebecca Jones from the Division of Advanced Research Technologies; Thales Papagiannakopoulos from the Department of Pathology, and Michael Pacold from the Department of Radiation Oncology and Perlmutter Cancer Center. Other study authors were Maria Gomez-Jenkins and Eileen White of Rutgers Cancer Institute of New Jersey, and Rui Wang of the Department of Biology at York University in Toronto.
The study was supported by the long-term funding from the Howard Hughes Medical Institute (HHMI) and the Blavatnik Family Foundation. Additional support was provided by the National Institutes of Health grants S10OD010584-01A1, S10OD018338-01, 1OT2CA278609-01, R35GM147119, and R01AI158687. The research was also funded by the American Cancer Society (grant RSG-21-115-01-MM), the Natural Sciences and Engineering Research Council of Canada (grant RGPIN-2023-05099), and Cancer Research UK (grant CGCATF-2021/100022).
About Howard Hughes Medical Institute (HHMI)HHMI is one of the largest private funders of biomedical research, with an endowment exceeding $27 billion. Through its Investigator Program, HHMI supports approximately 300 leading scientists across the United States, selected for their bold and fundamental approaches to scientific discovery. Each investigator receives unrestricted annual funding through renewable seven-year terms, granting them the freedom to pursue high-risk, high-reward research that often falls outside the scope of traditional funding mechanisms.
About the Blavatnik Family Foundation The Blavatnik Family Foundation provides many of the world's best researchers, scientists, and future leaders with the support and funding needed to solve humankind's greatest challenges. Led by Sir Leonard Blavatnik, founder and chairman of Access Industries, the Foundation advances and promotes innovation, discovery, and creativity to benefit the whole of society. Over the past decade, the Foundation has contributed more than US$1 billion to more than 250 organizations.
About NYU Langone HealthNYU Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked NYU Langone the No. 1 comprehensive academic medical center in the country for three years in a row, and U.S. News & World Report recently placed nine of its clinical specialties among the top five in the nation. NYU Langone offers a comprehensive range of medical services with one high standard of care across 7 inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. With $14.2 billion in revenue this year, the system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.
Contact: Gregory Williams, gregory.williams@nyulangone.org
Hashtags
Try Our AI Features
Explore what Daily8 AI can do for you:
Comments
No comments yet...
Related Articles
Malaysian Reserve
21 hours ago
- Malaysian Reserve
Lilly's once-weekly insulin efsitora alfa demonstrated A1C reduction and a safety profile consistent with daily insulin in multiple Phase 3 trials
Results from the fixed-dose QWINT-1 study, along with the QWINT-3 and QWINT-4 studies, reinforce efsitora's potential to simplify insulin management with weekly dosing Lilly plans to submit efsitora for the treatment of adults with type 2 diabetes to global regulatory agencies by the end of this year INDIANAPOLIS, June 22, 2025 /PRNewswire/ — Eli Lilly and Company (NYSE: LLY) today announced detailed results from QWINT-1, QWINT-3, and QWINT-4 Phase 3 clinical trials evaluating the safety and efficacy of investigational once-weekly insulin efsitora alfa (efsitora) in adults with type 2 diabetes who used insulin for the first time, previously used daily basal insulin, and previously used daily basal insulin and mealtime insulin, respectively. In each trial, once-weekly efsitora met the primary endpoint of non-inferior A1C reduction compared to daily basal insulin. The complete results from these studies were presented at the American Diabetes Association (ADA) 85th Scientific Sessions 2025. Simultaneously, results from QWINT-1, a first-of-its-kind fixed-dose study, were published in The New England Journal of Medicine, while results from QWINT-3 and QWINT-4 were published in The Lancet. In QWINT-1, efsitora reduced A1C by 1.31% compared to 1.27% for insulin glargine at week 52 for the efficacy estimand.1,2 In the trial, efsitora was titrated to four fixed doses at four-week intervals, as needed for blood glucose control.3 In QWINT-3, efsitora reduced A1C by 0.86% compared to 0.75% for insulin degludec at week 26 for the efficacy estimand.4 In QWINT-4, efsitora reduced A1C by 1.07% compared to 1.07% for insulin glargine at week 26 for the efficacy estimand.5 In these two trials, efsitora was administered using traditional insulin dosing with adjustments based on each patient's glucose level. 'The novel fixed-dose regimen used in QWINT-1 for once-weekly efsitora, which consisted of only four single-dose titration options, has the potential to facilitate and simplify insulin therapy, reducing the hesitation often associated with starting insulin to treat type 2 diabetes,' said Dr. Julio Rosenstock, senior scientific advisor for Velocity Clinical Research at Medical City Dallas, clinical professor of medicine, University of Texas Southwestern Medical Center, and lead trial investigator for QWINT-1. 'A simpler, once-weekly regimen with efsitora may help people with type 2 diabetes initiate and manage insulin therapy with the goal of improving blood sugar levels. Across all QWINT trials, the results showed that once-weekly efsitora controlled glucose as effectively as the most popular once-daily basal insulins.' QWINT-1 Primary Endpoint Efficacy Estimand Treatment-RegimenEstimand6 Primary Endpoint – A1C Reduction (Resulting A1C) at Week 52 Efsitora -1.31 % (6.92 %) -1.19 % (7.05 %) Glargine -1.27 % (6.96 %) -1.16 % (7.08 %) QWINT-3 Primary and Key Secondary Endpoints Efficacy Estimand Treatment-RegimenEstimand Primary Endpoint – A1C Reduction (Resulting A1C) at Week 26 Efsitora -0.86 % (6.93 %) -0.81 % (6.99 %) Degludec -0.75 % (7.03 %) -0.72 % (7.08 %) Key Secondary Endpoint – Rates of Clinically Significant or Severe Nocturnal Hypoglycemic Events Per Patient-Year of Exposure up to Week 787,8 Efsitora 0.11 Degludec 0.10 Key Secondary Endpoint – Percent Time in Range (70-180 mg/dL) During the FourWeeks Prior to Week 26 Efsitora 62.8 % 61.4 % Degludec 61.3 % 61.0 % QWINT-4 Primary and Key Secondary Endpoints Efficacy Estimand Treatment-Regimen Estimand Primary Endpoint – A1C Reduction (Resulting A1C) at Week 26 Efsitora -1.07 % (7.12 %) -1.01 % (7.17 %) Glargine -1.07 % (7.11 %) -1.00 % (7.18 %) Key Secondary Endpoint – Participants Achieving A1C <7% at Week 26 Without Nocturnal Hypoglycemia Efsitora 39.5 % 38.6 % Glargine 36.6 % 35.9 % Key Secondary Endpoint – Rates of Clinically Significant or Severe NocturnalHypoglycemic Events Per Patient-Year of Exposure up to Week 26 Efsitora 0.67 Glargine 1.00 'Building on Lilly's legacy of innovation in insulin therapy, once-weekly efsitora may offer a significant advancement for people with type 2 diabetes who need insulin by eliminating over 300 injections per year,' said Jeff Emmick, M.D., Ph.D., senior vice president of product development at Lilly. 'These results reinforce the potential for once-weekly efsitora to help reduce the overall burden of insulin therapy through a simplified treatment approach. We look forward to working with regulatory agencies to bring this innovation to patients around the world.' Across the three trials, efsitora demonstrated an overall safety profile similar to two of the most commonly used daily basal insulin therapies for the treatment of type 2 diabetes. In QWINT-1, efsitora resulted in approximately 40% fewer hypoglycemic events compared to insulin glargine, with estimated combined rates of severe or clinically significant hypoglycemic events per patient-year of exposure of 0.50 with efsitora vs. 0.88 with insulin glargine at 52 weeks. In QWINT-3, these rates were 0.84 with efsitora vs. 0.74 with insulin degludec at 78 weeks. In QWINT-4, estimated combined rates of severe or clinically significant hypoglycemic events per patient-year of exposure were 6.6 with efsitora vs. 5.9 with insulin glargine at 26 weeks. Lilly plans to submit efsitora for the treatment of adults with type 2 diabetes to global regulatory agencies by the end of this year. About the QWINT clinical trial programThe QWINT Phase 3 global clinical development program for insulin efsitora alfa (efsitora) in diabetes began in 2022 and has enrolled more than 3,000 people living with type 2 diabetes across four global registration studies. QWINT-1 (NCT05662332) was a parallel-design, open-label, treat-to-target, randomized controlled clinical trial comparing the efficacy and safety of efsitora as a once-weekly basal insulin using a fixed dose escalation to daily insulin glargine for 52 weeks in insulin-naïve adults with type 2 diabetes. The trial randomized 795 participants across the U.S., Argentina and Mexico to receive efsitora once weekly or insulin glargine once daily, administered subcutaneously. Participants treated with efsitora received a starting dose of 100 units of insulin, followed by escalation to fixed dosages of 150 units, 250 units and 400 units every four weeks, as needed, until achieving a target fasting blood glucose of 80-130 mg/dL. Participants with fasting blood glucose greater than 130 mg/dL on or after 16 weeks were transferred to flexible dosing. The primary objective of the trial was to demonstrate non-inferiority in reducing A1C at week 52 with efsitora compared to daily use of insulin glargine. QWINT-3 (NCT05275400) was a multicenter, randomized, parallel-design, open-label trial comparing the efficacy and safety of efsitora as a once-weekly basal insulin to insulin degludec for 78 weeks after a three-week lead-in followed by a five-week safety follow up period, in adults with type 2 diabetes who are currently treated with basal insulin. The trial randomized 986 participants across the U.S., Argentina, Hungary, Japan, Korea, Poland, Puerto Rico, Slovakia, Spain and Taiwan to receive efsitora once weekly or insulin degludec once daily, administered subcutaneously. The primary objective of the study was to demonstrate non-inferiority in reducing A1C at week 26 with efsitora compared to insulin degludec. QWINT-4 (NCT05462756) was a parallel-design, open-label, treat-to-target, randomized controlled clinical trial comparing the efficacy and safety of efsitora as a weekly basal insulin to insulin glargine for 26 weeks in adults with type 2 diabetes who have previously been treated with basal insulin and at least two injections per day of mealtime insulin. The trial randomized 730 participants across the U.S., Argentina, Germany, India, Italy, Mexico, Puerto Rico and Spain to receive efsitora once weekly or insulin glargine once daily, both of which were administered subcutaneously along with insulin lispro. The primary objective of the trial was to demonstrate non-inferiority in reducing A1C at week 26 with efsitora compared to insulin glargine. About insulin efsitora alfaInsulin efsitora alfa (efsitora) is a once-weekly basal insulin, a fusion protein that combines a novel single-chain variant of insulin with a human IgG2 Fc domain. It is specifically designed for once-weekly subcutaneous administration, and with its low peak-to-trough ratio, it has the potential to provide more stable glucose levels (less glucose variability) throughout the week. About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit and or follow us on Facebook, Instagram, and LinkedIn. P-LLY The efficacy estimand represents the treatment effect on all participants who adhered to the study drug without initiating rescue therapy for persistent severe hyperglycemia. From a baseline of 8.20% for efsitora and 8.28% for insulin glargine. Participants treated with efsitora received a starting dose of 100 units of insulin, followed by escalation to fixed dosages of 150 units, 250 units and 400 units every four weeks, as needed, until achieving a target fasting blood glucose of 80-130 mg/dL. Participants with fasting blood glucose greater than 130 mg/dL on or after 16 weeks were transferred to flexible dosing. From a baseline of 7.80% for both efsitora and insulin degludec. From a baseline of 8.18% for both efsitora and insulin glargine. The treatment-regimen estimand represents the estimated average treatment effect regardless of treatment discontinuation or introduction of rescue therapy for persistent severe hyperglycemia. Blood glucose <54 mg/dL. Nocturnal hypoglycemia was defined as any event that occurred at night between midnight and 6 a.m. Cautionary Statement Regarding Forward-Looking StatementsThis press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about insulin efsitora alfa as a potential treatment for people with type 2 diabetes and the timeline for future readouts, presentations, and other milestones relating to insulin efsitora alfa and its clinical trials and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that future study results will be consistent with study results to date, that insulin efsitora alfa will prove to be a safe and effective treatment for type 2 diabetes, that insulin efsitora alfa will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. Trademarks and Trade NamesAll trademarks or trade names referred to in this press release are the property of the company, or, to the extent trademarks or trade names belonging to other companies are referenced in this press release, the property of their respective owners. Solely for convenience, the trademarks and trade names in this press release are referred to without the ® and ™ symbols, but such references should not be construed as any indicator that the company or, to the extent applicable, their respective owners will not assert, to the fullest extent under applicable law, the company's or their rights thereto. We do not intend the use or display of other companies' trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies. Refer to: Niki Biro; niki_biro@ 317-358-9074 (Media) Michael Czapar; czapar_michael_c@ 317-617-0983 (Investors)
Sinar Daily
2 days ago
- Sinar Daily
New T-Rex ancestor discovered in drawers of Mongolian institute
The fossils were first dug up in southeastern Mongolia in the early 1970s but at the time were identified as belonging to a different tyrannosaur, Alectrosaurus. 21 Jun 2025 06:00pm This handout artist's illustration made available by University of Calgary on June 6, 2025, shows the newly discovered dinosaur species Khankhuuluu mongoliensis, an ancestor of Tyrannosaurus Rex. Misidentified bones that languished in the drawers of a Mongolian institute for 50 years belong to a new species of tyrannosaur that rewrites the family history of the mighty T-Rex, scientists said on June 11, 2025. (Photo by Julius CSOTONYI / University of Calgary / AFP) PARIS - Misidentified bones that languished in the drawers of a Mongolian institute for 50 years belong to a new species of tyrannosaur that rewrites the family history of the mighty T-Rex, scientists said Wednesday. This slender ancestor of the massive Tyrannosaurus Rex was around four metres (13 feet) long and weighed three quarters of a tonne, according to a new study in the journal Nature. "It would have been the size of a very large horse," study co-author Darla Zelenitsky of Canada's University of Calgary told AFP. The fossils were first dug up in southeastern Mongolia in the early 1970s but at the time were identified as belonging to a different tyrannosaur, Alectrosaurus. For half a century, the fossils sat in the drawers at the Institute of Paleontology of the Mongolian Academy of Sciences in the capital Ulaanbaatar. Then PhD student Jared Voris, who was on a trip to Mongolia, started looking through the drawers and noticed something was wrong, Zelenitsky said. It turned out the fossils were well-preserved, partial skeletons of two different individuals of a completely new species. "It is quite possible that discoveries like this are sitting in other museums that just have not been recognised," Zelenitsky added. 'Messy' family history They named the new species Khankhuuluu mongoliensis, which roughly means the dragon prince of Mongolia because it is smaller than the "king" T-Rex. Zelenitsky said the discovery "helped us clarify a lot about the family history of the tyrannosaur group because it was really messy previously". The T-Rex represented the end of the family line. It was the apex predator in North America until 66 million years ago, when an asteroid bigger than Mount Everest slammed into the Gulf of Mexico. Three quarters of life on Earth was wiped out, including all the dinosaurs that did not evolve into birds. Around 20 million years earlier, Khankhuuluu -- or another closely related family member -- is now believed to have migrated from Asia to North America using the land bridge that once connected Siberia and Alaska. This led to tyrannosaurs evolving across North America. Then one of these species is thought to have crossed back over to Asia, where two tyrannosaur subgroups emerged. One was much smaller, weighing under a tonne, and was nicknamed Pinocchio rex for its long snout. The other subgroup was huge and included behemoths like the Tarbosaurus, which was only a little smaller than the T-rex. One of the gigantic dinosaurs then left Asia again for North America, eventually giving rise to the T-Rex, which dominated for just two million years -- until the asteroid struck. - AFP
Malaysian Reserve
2 days ago
- Malaysian Reserve
Lilly's oral GLP-1, orforglipron, showed compelling efficacy and a safety profile consistent with injectable GLP-1 medicines, in complete Phase 3 results published in The New England Journal of Medici
The investigational once-daily pill lowered A1C by an average of 1.3% to 1.6% across doses, with improvements seen as early as four weeks, in adults with type 2 diabetes In ACHIEVE-1, orforglipron also led to an average weight loss of 16.0 lbs (7.9%) at the highest dose by week 40 in a key secondary endpoint The safety profile of orforglipron was consistent with the established GLP-1 class INDIANAPOLIS, June 21, 2025 /PRNewswire/ — Eli Lilly and Company (NYSE: LLY) today announced detailed results from ACHIEVE-1, a Phase 3 trial evaluating the safety and efficacy of orforglipron compared to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone. Orforglipron is the first oral small molecule (non-peptide) glucagon-like peptide-1 (GLP-1) receptor agonist, taken without food and water restrictions, to successfully complete a Phase 3 trial. At 40 weeks, all three doses (3 mg, 12 mg, 36 mg) of orforglipron achieved the primary endpoint of superior A1C reduction. In addition, the 12 mg and 36 mg doses showed clinically meaningful and statistically significant reductions in body weight vs. placebo. In the study, orforglipron had a safety profile similar to the established GLP-1 class, and the most frequently reported adverse events were gastrointestinal-related. The results were presented at the American Diabetes Association (ADA) 85th Scientific Sessions 2025 and simultaneously published in The New England Journal of Medicine. In the study, orforglipron met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks, lowering A1C by 1.3% to 1.6% from a baseline of 8.0%, for the efficacy estimand.1 In key secondary endpoints, up to 76.2% of participants taking orforglipron achieved the ADA treatment target A1C of <7%, 66.0% achieved an A1C of ≤6.5%, and 25.8% achieved <5.7%, defined as a normal A1C value.2,3 Improvements in A1C were observed as early as four weeks and were accompanied by similar reductions in fasting serum glucose. In another key secondary endpoint, participants taking the highest dose of orforglipron lost an average of 16.0 lbs (7.9%). While participants in ACHIEVE-1 did not appear to reach a weight plateau, longer-duration trials, such as the ATTAIN trials, will provide a comprehensive evaluation of the safety and efficacy of orforglipron for the treatment of obesity. 'The ACHIEVE-1 trial demonstrated that orforglipron, a novel oral small-molecule GLP-1, achieved clinically meaningful reductions in A1C and body weight over 40 weeks in adults with type 2 diabetes,' said Dr. Julio Rosenstock, senior scientific advisor for Velocity Clinical Research at Medical City Dallas, clinical professor of medicine, University of Texas Southwestern Medical Center, and lead trial investigator. 'The early onset of glycemic improvement, observed as soon as four weeks, reinforces the therapeutic potential of orforglipron as an effective, oral GLP-1 therapy for early type 2 diabetes treatment. These findings support further investigation in broader populations and longer-duration studies.' Full Results Orforglipron 3 mg Orforglipron 12 mg Orforglipron 36 mg Placebo Primary Endpoint A1C reduction from baseline of 8.0 %i Efficacy estimand 1.3 % 1.6 % 1.5 % 0.1 % Treatment-regimen estimand4 1.2 % 1.5 % 1.5 % 0.4 % Key Secondary Endpointsii Percent weight reduction from baseline of 90.2 kg (198.9 lbs)i,iii Efficacy estimand 4.7 % 6.1 % 7.9 % 1.6 % Treatment-regimen estimand 4.5 % 5.8 % 7.6 % 1.7 % Weight reduction from baseline of 90.2 kg (198.9 lbs)i,iii Efficacy estimand 4.4 kg (9.7 lbs) 5.5 kg (12.2 lbs) 7.3 kg (16.0 lbs) 1.3 kg (2.9 lbs) Treatment-regimen estimand 4.2 kg (9.3 lbs) 5.2 kg (11.5 lbs) 7.2 kg (15.8 lbs) 1.5 kg (3.4 lbs) Percent of participants achieving A1C <7 %i Efficacy estimand 72.9 % 76.2 % 74.9 % 28.0 % Treatment-regimen estimand 68.1 % 72.9 % 72.7 % 33.0 % Percent of participants achieving A1C ≤6.5 %i,ii Efficacy estimand 61.5 % 62.3 % 66.0 % 13.5 % Treatment-regimen estimand 56.9 % 58.1 % 61.9 % 14.9 % Percent of participants achieving A1C <5.7 %iii Efficacy estimand 17.7 % 25.8 % 23.9 % 3.8 % Treatment-regimen estimand 16.8 % 23.9 % 21.5 % 3.8 % Fasting serum glucose reduction from baseline of 147.5 mg/dLi Efficacy estimand 30.6 mg/dL 37.4 mg/dL 37.8 mg/dL 1.1 mg/dL Treatment-regimen estimand 30.7 mg/dL 36.5 mg/dL 34.7 mg/dL 10.8 mg/dL iSuperiority test was adjusted for from the full list of key secondary endpoints are available in the of participants achieving A1C <5.7% across all orforglipron doses and body weight for orforglipron 3 mg were not controlled for Type 1 error. 'This convenient once-daily pill with no restrictions on food and water intake could be an option for millions of people with type 2 diabetes who prefer oral medications over injectables,' said Jeff Emmick, M.D., Ph.D., senior vice president of product development at Lilly. 'The positive ACHIEVE-1 results position orforglipron as a potential treatment option with meaningful A1C and weight reduction, and a safety profile similar to injectable GLP-1 therapies. We look forward to the four remaining global readouts from the ACHIEVE program, as well as results of the ATTAIN program in obesity, and working with regulators to bring this once-daily oral GLP-1 to people around the world.' The overall safety profile of orforglipron in ACHIEVE-1 was consistent with the established GLP-1 class. The most common adverse events for participants treated with orforglipron (3 mg, 12 mg and 36 mg, respectively) were diarrhea (19%, 21% and 26%) vs. 9% with placebo, nausea (13%, 18% and 16%) vs. 2% with placebo, dyspepsia (11%, 20% and 15%) vs. 7% with placebo, constipation (8%, 17% and 14%) vs. 4% with placebo, and vomiting (5%, 7% and 14%) vs. 1% with placebo. These gastrointestinal-related adverse events were generally mild-to-moderate in severity and occurred primarily during dose escalation. Overall treatment discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg) and 8% (36 mg) for orforglipron vs. 1% with placebo. No hepatic safety signal was observed. Later this year, Lilly expects to share topline results from ACHIEVE-2, evaluating orforglipron compared with dapagliflozin, and ACHIEVE-3, evaluating orforglipron compared to oral semaglutide, both in adults with type 2 diabetes inadequately controlled with metformin. ATTAIN-1 and ATTAIN-2, evaluating orforglipron for weight management, will also be shared in the third quarter of this year. Lilly remains on track to submit orforglipron for weight management to global regulatory agencies by the end of this year and for the treatment of type 2 diabetes in 2026. About orforglipron Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.5 Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together.6 Lilly is running Phase 3 studies on orforglipron for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea and hypertension in adults with obesity. About ACHIEVE-1 and the ACHIEVE clinical trial program ACHIEVE-1 (NCT05971940) is a Phase 3, 40-week, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of orforglipron 3 mg, 12 mg and 36 mg as monotherapy to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone. The trial randomized 559 participants across the U.S., China, India, Japan and Mexico in 1:1:1:1 ratio to receive either 3 mg, 12 mg or 36 mg orforglipron or placebo. The primary objective of the study was to demonstrate that orforglipron (3 mg, 12 mg, 36 mg) is superior in A1C reduction from baseline after 40 weeks, compared to placebo, in people with type 2 diabetes who have not taken any anti-diabetic medications for at least 90 days prior to visit 1, and are naïve to insulin therapy. Study participants had a HbA1c between ≥7.0% and ≤9.5% and a BMI of ≥23 kg/m2. All participants in the orforglipron treatment arms started the study at a dose of orforglipron 1 mg once-daily and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 3 mg (via a 1 mg step), 12 mg (via steps at 1 mg, 3 mg and 6 mg) or 36 mg (via steps at 1 mg, 3 mg, 6 mg, 12 mg and 24 mg). Flexible dosing was not permitted. The ACHIEVE Phase 3 global clinical development program for orforglipron has enrolled more than 6,000 people with type 2 diabetes across five global registration trials. The program began in 2023 with results anticipated later this year and into 2026. About LillyLilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit and or follow us on Facebook, Instagram and LinkedIn. P-LLY The efficacy estimand represents the treatment effect had on all participants who adhered to the study drug (with possible dose interruptions) for 40 weeks without initiating additional antihyperglycemic medications (>14 days of use). American Diabetes Association. Standards of Care in Diabetes—2020 Abridged for Primary Care Providers. Clinical Diabetes 2020; 38(1):10–38. Percent of participants achieving A1C <5.7% across all doses was not controlled for Type 1 error. The treatment-regimen estimand represents the estimated average treatment effect regardless of treatment discontinuation or initiation of additional antihyperglycemic medications. Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Ther. 2024 Apr;15(4):819-832. Epub 2024 Feb 24. PMID: 38402332; PMCID: PMC10951152. T. Kawai, B. Sun, H. Yoshino, D. Feng, Y. Suzuki, M. Fukazawa, S. Nagao, D.B. Wainscott, A.D. Showalter, B.A. Droz, T.S. Kobilka, M.P. Coghlan, F.S. Willard, Y. Kawabe, B.K. Kobilka, & K.W. Sloop, Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist, Proc. Natl. Acad. Sci. U.S.A. 117 (47) 29959-29967, (2020). Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about orforglipron as a potential treatment for adults with type 2 diabetes, and the timeline for future readouts, presentations, and other milestones relating to orforglipron and its clinical trials and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that orforglipron will prove to be a safe and effective treatment for type 2 diabetes, that orforglipron will receive regulatory approval, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. Trademarks and Trade Names All trademarks or trade names referred to in this press release are the property of the company, or, to the extent trademarks or trade names belonging to other companies are referenced in this press release, the property of their respective owners. Solely for convenience, the trademarks and trade names in this press release are referred to without the ® and ™ symbols, but such references should not be construed as any indicator that the company or, to the extent applicable, their respective owners will not assert, to the fullest extent under applicable law, the company's or their rights thereto. We do not intend the use or display of other companies' trademarks and trade names to imply a relationship with, or endorsement or sponsorship of us by, any other companies. Refer to: Brooke Frost; 317-432-9145 (Media) Michael Czapar; czapar_michael_c@ 317-617-0983 (Investors)
