The Major Discovery Papers, Pivotal Trials, and Headline-Making Findings in Date Order
GLP-1 drugs did not appear overnight. The field developed over more than four decades, starting with basic hormone discovery work, then early human physiology studies, then diabetes drug trials, then cardiovascular-outcome trials, and finally the modern obesity era led by semaglutide and tirzepatide. Today, the pipeline has expanded into oral GLP-1s, dual- and triple-agonists, heart-failure trials, kidney-outcome trials, sleep-apnea studies, and liver-disease programs.
1983 — Proglucagon and the Birth of GLP-1 Biology
The modern GLP-1 story begins in 1983, when Graeme Bell and colleagues characterized the proglucagon gene, revealing peptide sequences that eventually led to identification of GLP-1 and GLP-2. This was the foundational molecular discovery that made the entire drug class possible. Later historical reviews consistently cite Bell’s 1983 work as the starting point of modern GLP-1 science.
Why it mattered
- It showed GLP-1 was part of the proglucagon system.
- It opened the door to studying GLP-1 as a metabolic hormone, not just a biochemical curiosity.
1983 was a monumental year for GLP-1 research and biology, when the cloning of the proglucagon gene revealed that the hormone glucagon was encoded within a much larger precursor molecule containing two additional “glucagon-like” sequences, designated GLP-1 and GLP-2. This pivotal discovery, produced by top researchers such as Graeme Bell, shifted focus from just “gut glucagon” to the potential physiological actions of these newly identified peptides, essentially marking the “birth” of GLP-1 biology and laying the foundation for modern incretin-based therapies.
Graeme Bell and colleagues cloned the hamster preproglucagon gene (soon followed by human sequences), revealing that one gene encodes glucagon, GLP-1, and GLP-2.The Prohormone Structure: Proglucagon is a 180-amino acid precursor that is post-translationally cleaved into different products in the pancreas vs. the intestine. Researchers realized that the intestinal L-cells produce a version of proglucagon that releases GLP-1, rather than glucagon. While initial studies in 1983-1984 on the 37-amino acid form of GLP-1 did not show strong insulinotropic effects, the identification of the gene set the stage for finding the shorter, active forms of GLP-1 (7–36/7–37) later in the 1980s, which are potent stimulators of insulin secretion
1987 — First Key Human GLP-1 Physiology Study
A landmark 1987 human study by Kreymann et al. demonstrated that GLP-1(7-36) amide acts as a physiological incretin in humans. In practical terms, this study showed that GLP-1 levels rise after oral glucose and meals, and that GLP-1 infusion increases insulin while lowering glucose and glucagon. This paper is one of the most important foundation stones in the field.
Key finding:
GLP-1 was not just a lab peptide — it had a real, measurable blood-sugar regulatory role in humans.
The 1987 study by Kreymann et al., published in The Lancet, was a landmark human trial that established GLP-1 (7-36) amide as a potent physiological incretin. It demonstrated that intravenous infusion of GLP-1 in humans stimulates insulin release, lowers glucagon, and reduces blood glucose levels, proving its potential for treating diabetes
1993 — GLP-1 Still Works in Type 2 Diabetes
A pivotal 1993 human study by Nauck et al. showed that GLP-1 retained much of its insulinotropic activity in mild type 2 diabetes, whereas GIP did not perform as well. This mattered because it suggested GLP-1 could become a viable treatment target in diabetes.
Key finding:
GLP-1 not only worked in healthy volunteers, but also retained clinically useful glucose-lowering effects in patients with type 2 diabetes.
One of the foundational human studies underlying the modern development of GLP-1 medications such as Ozempic, Wegovy, Mounjaro, and Zepbound was conducted in 1993 by German endocrinologist Michael A. Nauck and colleagues. The study is widely regarded as one of the pivotal early demonstrations that glucagon-like peptide-1 (GLP-1) could significantly improve glucose regulation in human patients with type 2 diabetes.
The research was conducted primarily through investigators affiliated with Ruhr University Bochum and associated German metabolic research centers specializing in endocrinology and diabetes physiology. During the early 1990s, scientists were attempting to better understand the so-called “incretin effect,” a biological process in which hormones released from the intestine after eating stimulate insulin secretion from the pancreas.
1995 — Early Dose/Mechanism Studies Show Benefit and Tolerability Limits
By the mid-1990s, pharmacokinetic and dose-response studies showed that GLP-1 infusion could increase insulin secretion and improve glucose handling, but also cause dose-related side effects such as nausea and vomiting at higher exposures. These early mechanistic studies foreshadowed the adverse-effect profile of modern GLP-1 drugs.
Key finding
The benefits and side-effect pattern of the GLP-1 class were visible before modern branded GLP-1 drugs even existed.
Early–Mid 1990s to 2005 — Exendin-4 and the First Drug Era
The discovery of exendin-4 in Gila monster venom led to development of exenatide, the first GLP-1 receptor agonist to reach the market. Historical reviews trace a direct path from exendin-4 discovery to the launch of exenatide/Byetta. By 2005, exenatide had become the first approved GLP-1–based diabetes drug.
Why it mattered
- Exenatide proved a GLP-1 drug could work in the real world.
- It established the commercial and clinical feasibility of the class.
One of the most important milestones in the history of GLP-1 medications occurred in 2005 with the approval of exenatide, marketed as Byetta, which became the first GLP-1 receptor agonist approved for clinical use in the United States. The approval marked the transition of GLP-1 science from experimental endocrinology into mainstream pharmaceutical therapy and laid the foundation for later drugs such as Ozempic, Wegovy, Mounjaro, and Zepbound.
Exenatide was developed through collaborative efforts involving Amylin Pharmaceuticals and Eli Lilly and Company. The drug received approval from the U.S. Food and Drug Administration in April 2005 for treatment of type 2 diabetes mellitus.
2005 — Pivotal Exenatide Clinical Trial
An early randomized exenatide trial in patients with type 2 diabetes inadequately controlled on metformin showed that exenatide reduced HbA1c versus placebo and promoted modest weight loss, helping secure its role as the first major GLP-1 therapy.
Key finding
Exenatide improved glycemic control and introduced the now-familiar combination of:
- lower A1c
- weight reduction
- GI side effects.
In 2005, a series of pivotal clinical trials involving exenatide led to the approval of Byetta, the first GLP-1 receptor agonist ever approved for clinical use in the United States. These studies represented a turning point in diabetes treatment and ultimately laid the scientific and commercial foundation for later GLP-1 drugs such as Ozempic, Wegovy, Mounjaro, and Zepbound. Exenatide was developed by Amylin Pharmaceuticals in collaboration with Eli Lilly and Company and was approved by the U.S. Food and Drug Administration in April 2005 for treatment of type 2 diabetes mellitus.
The pivotal exenatide clinical trials were conducted between approximately 2002 and 2005 through a multinational network of endocrinology and diabetes research centers. The studies primarily evaluated exenatide as an adjunct therapy in patients whose type 2 diabetes remained inadequately controlled despite treatment with standard oral medications such as metformin and sulfonylureas.
Researchers found that exenatide significantly improved glycemic control by lowering hemoglobin A1c levels while also reducing fasting and postprandial blood glucose levels. Importantly, the studies demonstrated that exenatide stimulated insulin secretion in a glucose-dependent manner, meaning its insulin-enhancing effects occurred primarily when blood glucose levels were elevated. This characteristic reduced the risk of severe hypoglycemia compared with some older diabetes medications.
2008–2010 — The LEAD Program Establishes Liraglutide
Yes. The LEAD (Liraglutide Effect and Action in Diabetes) clinical trial program was the pivotal Phase III development program for Liraglutide. The LEAD studies evaluated liraglutide across multiple settings in type 2 diabetes, including:
- as monotherapy,
- in combination with oral antidiabetic drugs,
- versus comparators such as insulin glargine, sulfonylureas, and exenatide,
- and across outcomes like HbA1c reduction, weight change, and hypoglycemia risk.
The program’s results supported regulatory approval of liraglutide for type 2 diabetes treatment under the brand Victoza. The LEAD trial program was the major clinical development platform for liraglutide.
Important studies included:
2009 — LEAD-3 Mono
Liraglutide monotherapy outperformed glimepiride in glycemic control, helping establish liraglutide as a strong once-daily GLP-1 option in type 2 diabetes.
2009 — LEAD-6
Liraglutide once daily was more effective than exenatide twice daily for glycemic control and was generally better tolerated in some respects, marking an important “second-generation GLP-1 vs first-generation GLP-1” comparison.
2010 — Liraglutide vs Sitagliptin
Liraglutide beat sitagliptin as add-on therapy to metformin, reinforcing the potency of injectable GLP-1 receptor agonism relative to DPP-4 inhibition.
2009 — Early Obesity Signal With Liraglutide
A 2009 Lancet study showed liraglutide produced meaningful weight loss and reduced the prevalence of prediabetes, helping set the stage for the later obesity indication.
2015 — SCALE and Modern Anti-Obesity GLP-1 Therapy
A landmark NEJM trial in 2015 showed that liraglutide 3.0 mg produced significant weight loss in adults with obesity when added to diet and exercise. This was one of the defining studies that moved GLP-1 therapy from “diabetes drug with weight loss” to “serious obesity medicine.” The landmark Liraglutide 3.0 mg trial published in the New England Journal of Medicine in 2015 was the SCALE Obesity and Prediabetes study. It evaluated liraglutide (a GLP-1 receptor agonist) for chronic weight management in people with obesity or overweight, many with prediabetes.
The 2015 SCALE trial was a major milestone in obesity treatment because it showed that the GLP-1 drug liraglutide could help people lose significant weight when combined with diet and exercise. In the study, participants taking liraglutide lost much more weight than those taking placebo, while also improving blood pressure, blood sugar, and other metabolic health markers. The trial helped change medical thinking about obesity by showing it is a chronic biological disease that can be treated with hormone-based therapy rather than just willpower alone. SCALE also laid the foundation for today’s newer and more powerful GLP-1 medications, such as semaglutide and tirzepatide, which produce even greater weight loss.
The trial established that liraglutide 3.0 mg produces clinically significant weight loss and can reduce progression from prediabetes to diabetes, helping cement GLP-1 therapy as a major option for obesity management
Key finding
Liraglutide 3.0 mg led to clinically meaningful weight loss and improved metabolic measures in obesity treatment.
2016 — Cardiovascular Outcomes Become Central
LEADER (Liraglutide)
The 2016 LEADER trial was a turning point. In patients with type 2 diabetes at high cardiovascular risk, liraglutide reduced major adverse cardiovascular events versus placebo. The 2016 LEADER trial (published in The New England Journal of Medicine) was a large cardiovascular outcomes study evaluating the GLP-1 receptor agonist Liraglutide in over 9,300 adults with Type 2 Diabetes who were at high risk for cardiovascular disease. Participants were randomly assigned to receive liraglutide or placebo in addition to standard care and were followed for a median of about 3.8 years. The study found that liraglutide significantly reduced the risk of major adverse cardiovascular events (MACE)—a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke—with a hazard ratio of 0.87 compared with placebo. This benefit was driven largely by reductions in cardiovascular and all-cause mortality, while effects on nonfatal heart attack and stroke individually were less pronounced. The trial also showed a modest reduction in overall mortality without a significant increase in severe hypoglycemia, pancreatitis, or pancreatic cancer. Overall, LEADER was a landmark study establishing that liraglutide not only improves glycemic control but also provides meaningful cardiovascular protection in high-risk type 2 diabetes patients.
SUSTAIN-6 (Semaglutide)
Also in 2016, SUSTAIN-6 showed semaglutide significantly reduced cardiovascular events in high-risk type 2 diabetes patients.
Why 2016 mattered
After 2016, GLP-1 drugs were no longer viewed only as glucose-lowering agents. They became cardiometabolic therapies with outcome benefits.
2017 — Kidney Signal With Liraglutide and CV Safety With Exenatide
Liraglutide Renal Outcomes
A 2017 NEJM analysis from LEADER showed liraglutide also improved certain renal outcomes, suggesting broader organ-protective potential.
EXSCEL (Exenatide Once Weekly)
The 2017 EXSCEL trial found once-weekly exenatide was noninferior for cardiovascular safety, though it did not deliver the same strength of superiority signal seen with liraglutide and semaglutide.
2019 — REWIND and Oral Semaglutide Arrive
REWIND (Dulaglutide)
The 2019 REWIND trial showed dulaglutide reduced major cardiovascular events in a broad type 2 diabetes population, notable because a relatively low proportion had established prior cardiovascular disease compared with earlier CVOTs.
PIONEER-6 (Oral Semaglutide)
Also in 2019, PIONEER-6 showed oral semaglutide was noninferior to placebo for cardiovascular safety, supporting the first oral GLP-1 product class entry.
Related 2019 Renal Signal
A REWIND renal outcomes analysis also found dulaglutide reduced composite renal outcomes, extending the pattern of cardiometabolic and renal benefit across the class.
2020 — Broader Functional Outcomes With Dulaglutide
A 2020 Lancet Neurology analysis from REWIND suggested dulaglutide reduced cognitive impairment in type 2 diabetes, adding to the expanding list of outcomes being examined beyond glycemia and weight.
2021 — The Modern Obesity Era Truly Begins
STEP 1 (Semaglutide 2.4 mg in Obesity)
The 2021 NEJM STEP 1 trial was historic. Once-weekly semaglutide 2.4 mg led to a mean weight loss of about 14.9% at 68 weeks in adults with overweight or obesity without diabetes, dramatically shifting expectations for obesity pharmacotherapy.
SURPASS-2 (Tirzepatide vs Semaglutide in Type 2 Diabetes)
Also in 2021, SURPASS-2 showed tirzepatide was noninferior and superior to semaglutide for A1c reduction, with greater weight loss as well. This introduced the idea that dual GIP/GLP-1 agonism could outperform GLP-1 alone.
AMPLITUDE-O (Efpeglenatide)
NEJM in 2021 also reported that efpeglenatide improved cardiovascular and renal outcomes, reinforcing that the benefits of the GLP-1 pathway extended beyond just the biggest brand names.
Semaglutide in NASH/MASH (Phase 2)
A 2021 NEJM phase 2 trial found subcutaneous semaglutide improved histologic outcomes in patients with NASH, opening a major new disease area beyond diabetes and obesity.
2022 — Tirzepatide Redefines Obesity Pharmacotherapy
SURMOUNT-1
The 2022 NEJM SURMOUNT-1 trial showed tirzepatide produced substantial and sustained weight loss in obesity, with the highest dose approaching ~21% mean weight loss at 72 weeks. This placed tirzepatide at the very top of medical obesity therapy.
2021–2023: SURMOUNT-2 Trial — Tirzepatide (Mounjaro/Zepbound) for Obesity and Type 2 Diabetes
One of the earliest landmark GLP-1-related studies to emerge during this period was the SURMOUNT-2 trial, whose principal findings were published in 2023. The study evaluated tirzepatide, a dual GIP/GLP-1 receptor agonist marketed by Eli Lilly as Mounjaro and Zepbound, in adults suffering from obesity and type 2 diabetes. Sponsored by Eli Lilly and Company, the randomized phase-3 trial was conducted through an international network of obesity and endocrinology clinics, including major participation from Weill Cornell Medicine and Yale School of Medicine.
The principal investigators included Louis J. Aronne and Ania Jastreboff. The trial enrolled more than 900 participants who were followed for approximately 72 weeks. Researchers found that higher doses of tirzepatide produced approximately 15% to 22% body-weight reduction, together with major improvements in blood glucose control and insulin sensitivity. Many participants achieved weight-loss levels that had previously been associated primarily with bariatric surgery.
The findings were considered highly significant because they demonstrated that dual-hormone therapies may outperform earlier GLP-1 drugs in weight reduction. The study also contributed to a growing scientific consensus that obesity is a neurohormonal and metabolic disease rather than simply a behavioral condition. A clinical summary of the SURMOUNT-2 trial is available through the American College of Cardiology SURMOUNT‑2 Summar
STEP 5 (Two-Year Semaglutide Data)
The 2022 STEP 5 trial showed semaglutide’s weight-loss effect could be sustained over 104 weeks, addressing concerns about durability.
Adolescent Obesity
A 2022 NEJM trial in adolescents with obesity found semaglutide produced significantly greater BMI reduction than placebo, expanding the age range and clinical relevance of GLP-1 obesity therapy.
GRADE
The 2022 GRADE study found liraglutide and insulin glargine were more effective than glimepiride and sitagliptin in maintaining glycemic targets after metformin in relatively early type 2 diabetes.
2023 — Outcomes Beyond Weight and Glucose Expand Fast
2018–2023 (Findings Released 2023–2024): SELECT Trial — Semaglutide and Cardiovascular Disease Prevention, SELECT (Semaglutide in Obesity, No Diabetes)
The 2023 SELECT trial was a landmark because it showed semaglutide reduced major adverse cardiovascular events in people with overweight/obesity and established cardiovascular disease but without diabetes. That was a major expansion of the GLP-1 narrative. One of the most consequential obesity and cardiovascular studies ever conducted was the SELECT trial, formally titled “Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity.” Sponsored by Novo Nordisk , the study began in 2018 and publicly released its landmark findings in August and November 2023, with additional analyses continuing into 2024 and 2025.
The trial involved approximately 17,604 participants across 41 countries and represented one of the largest obesity-focused cardiovascular outcome studies ever undertaken. The research was coordinated through a multinational network involving investigators from Cleveland Clinic, University College London, and University of Washington. Lead researchers included A. Michael Lincoff, John Deanfield, and Steven E. Kahn. The SELECT trial examined whether semaglutide could reduce cardiovascular events in overweight or obese adults who already had cardiovascular disease but did not have diabetes. Participants were randomly assigned semaglutide or placebo injections and followed for a mean duration of approximately 40 months.
Researchers found that semaglutide reduced the combined risk of heart attack, stroke, and cardiovascular death by approximately 20% compared with placebo. The findings were especially important because investigators observed cardiovascular benefits earlier than would normally be expected from weight loss alone. This led researchers to conclude that semaglutide may directly influence vascular inflammation, endothelial function, systemic inflammatory signaling, and cardiac metabolism independent of weight reduction itself.
The SELECT trial significantly altered the medical and regulatory perception of obesity medications by positioning GLP-1 drugs not merely as weight-loss agents, but as broad cardiometabolic therapies capable of reducing major adverse cardiovascular events. Trial summaries and abstracts are available through the American College of Cardiology SELECT Summary and the New England Journal of Medicine.
STEP-HFpEF
The 2023 NEJM STEP-HFpEF trial showed semaglutide improved symptoms, physical limitations, exercise function, and weight loss in obesity-related heart failure with preserved ejection fraction.
Retatrutide Phase 2
A 2023 NEJM phase 2 trial showed the triple agonist retatrutide produced substantial weight loss in adults with obesity, instantly making it one of the most watched next-generation candidates.
Orforglipron Phase 2
In 2023, a NEJM phase 2 obesity trial showed the oral small-molecule GLP-1 orforglipron produced substantial weight loss, helping establish oral nonpeptide GLP-1 agonism as a serious future direction.
2024 — Kidney, Sleep Apnea, HFpEF, and Liver Disease Move Center Stage
2019–2024: FLOW Trial — Semaglutide and Chronic Kidney DiseaseFLOW (Semaglutide in CKD + T2D)
In 2024, the FLOW trial showed semaglutide reduced clinically important kidney outcomes and cardiovascular death in patients with type 2 diabetes and chronic kidney disease. This was a major renal milestone for the class. In late 2023 and continuing into 2024, another major semaglutide study known as the FLOW trial generated substantial attention within nephrology and diabetes medicine. Sponsored by Novo Nordisk, the FLOW trial began in 2019 and evaluated semaglutide in patients suffering from type 2 diabetes and chronic kidney disease. The study involved approximately 3,533 participants in a randomized phase-3 trial conducted across multiple international nephrology and endocrinology centers, including researchers affiliated with UNSW Sydney, University of Edinburgh, and additional global renal disease networks. Principal investigators included Vlado Perkovic, Peter Rossing, and George Bakris.
The FLOW trial was stopped early in October 2023 after interim analysis demonstrated statistically significant clinical benefit. Participants receiving semaglutide experienced an approximately 24% reduction in kidney disease progression, kidney failure, cardiovascular death, and sustained decline in kidney filtration function compared with placebo. Researchers also observed slower deterioration in estimated glomerular filtration rate (eGFR), lower urinary protein leakage, and delayed progression toward dialysis. The study was considered highly influential because it suggested semaglutide may directly protect renal tissue by reducing inflammation, fibrosis, oxidative stress, and vascular injury in the kidneys.
The FLOW findings expanded scientific understanding of GLP-1 medications beyond glucose regulation and obesity treatment into renal protection and chronic disease modification. Additional details and summaries are available through the American College of Cardiology FLOW Trial Summary
2022–2024: Comparative Effectiveness Research — Tirzepatide Versus Semaglutide for Weight Loss
By 2024, researchers increasingly turned toward comparative effectiveness studies examining whether newer GLP-1 therapies produced superior outcomes compared with earlier agents. One influential comparative study published in 2024 evaluated tirzepatide versus semaglutide for weight reduction using large-scale real-world electronic health record data from U.S. healthcare systems. The study examined approximately 41,222 patient records, with roughly 18,386 matched participants included in the final comparative analysis. Researchers found that patients using tirzepatide were substantially more likely than semaglutide users to achieve at least 5%, 10%, and 15% body-weight reduction over time.
At approximately 12 months, tirzepatide users experienced roughly 6.9% greater average weight reduction than semaglutide users. Importantly, gastrointestinal side effects appeared generally similar between the two groups despite tirzepatide’s stronger weight-loss efficacy. The study contributed to a growing scientific consensus that tirzepatide may currently represent the most potent pharmaceutical weight-loss therapy available, while semaglutide retains the strongest long-term cardiovascular and kidney outcome evidence. A summary of this comparative analysis is available through the American College of Cardiology Comparative Study Summary
2021–2025: EVOKE and EVOKE+ Trials — Semaglutide and Alzheimer’s Disease Research
Throughout 2024 and 2025, GLP-1 research expanded into additional disease areas, including neurodegenerative disorders such as Alzheimer’s disease. Novo Nordisk
sponsored large phase-3 Alzheimer’s studies known as EVOKE and EVOKE+, which evaluated whether oral semaglutide could slow cognitive decline and progression of Alzheimer’s disease.
These studies involved multinational neurology and dementia research centers beginning in approximately 2021 and continuing through 2025. Although semaglutide did not ultimately demonstrate sufficient cognitive improvement to meet primary Alzheimer’s endpoints, researchers observed possible favorable changes in inflammatory biomarkers, vascular markers, and metabolic indicators associated with neurodegeneration. As a result, investigators continue studying whether GLP-1 therapies may still prove beneficial in dementia prevention, vascular cognitive impairment, or brain insulin-resistance syndromes.
2024–2026: Expanding GLP-1 Research Into Additional Chronic Diseases
Between 2024 and 2026, GLP-1 research expanded dramatically into additional medical conditions beyond obesity and diabetes. Researchers and pharmaceutical companies began studying GLP-1 therapies for fatty liver disease, obstructive sleep apnea, osteoarthritis, addiction biology, alcohol cravings, systemic inflammation, cardiovascular aging, and metabolic dysfunction.
Collectively, the research conducted between 2023 and 2026 fundamentally changed scientific and medical understanding of GLP-1 medications. Initially developed as diabetes therapies, semaglutide and tirzepatide are now increasingly viewed by researchers as broad-spectrum cardiometabolic drugs with potential applications in obesity medicine, cardiovascular disease prevention, chronic kidney disease management, inflammatory disorders, and possibly additional systemic diseases. At the same time, researchers continue evaluating important unresolved questions involving long-term safety, gastrointestinal side effects, muscle loss during rapid weight reduction, medication discontinuation, insurance coverage limitations, and weight regain following cessation of therapy.
SURMOUNT-OSA (Tirzepatide in Obstructive Sleep Apnea)
Also in 2024, the NEJM SURMOUNT-OSA trials showed tirzepatide reduced apnea–hypopnea index, body weight, hypoxic burden, hsCRP, and systolic blood pressure in people with obesity and obstructive sleep apnea. The SURMOUNT-OSA clinical trial demonstrated that tirzepatide significantly reduces the severity of obstructive sleep apnea (OSA) in adults with obesity, leading directly to the U.S. FDA approval of Zepbound (tirzepatide) for this indication. Published in the New England Journal of Medicine, this Phase 3 trial established tirzepatide as the first effective pharmacological treatment targeting the root cause of obesity-driven OSA.
SUMMIT / Tirzepatide in HFpEF + Obesity
A 2024 NEJM trial showed tirzepatide reduced a composite of worsening heart-failure events or cardiovascular death in patients with HFpEF and obesity, extending metabolic therapy into heart-failure care. The SUMMIT clinical trial (NCT04847557) demonstrated that tirzepatide significantly reduces the risk of worsening heart failure and improves quality of life in patients suffering from Heart Failure with Preserved Ejection Fraction (HFpEF) and obesity. Published in the New England Journal of Medicine (NEJM), SUMMIT is the first trial of its kind where heart failure outcomes were examined as the primary prespecified endpoint for this specific patient population
Tirzepatide in MASH
In 2024, NEJM reported tirzepatide was more effective than placebo for resolution of MASH without worsening fibrosis, another signal that incretin-based therapies may reshape hepatology as well as endocrinology. In June 2024, The New England Journal of Medicine (NEJM) published the results of the SYNERGY-NASH phase 2 trial, which demonstrated that weekly subcutaneous injections of tirzepatide are highly effective at achieving the resolution of metabolic dysfunction–associated steatohepatitis (MASH) without worsening liver fibrosis.
STEP-HFpEF DM
A 2024 NEJM study extended semaglutide HFpEF findings into patients who also had type 2 diabetes, again showing improved symptoms and weight loss. The STEP-HFpEF DM clinical trial was a landmark randomized, double-blind, placebo-controlled study published in the New England Journal of Medicine (NEJM) in April 2024. The trial evaluated the efficacy of once-weekly subcutaneous semaglutide (2.4 mg) (the active ingredient in Wegovy) over 52 weeks in patients living with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes
2025 — Oral Semaglutide Strengthens and Combination Therapy Advances
Oral Semaglutide CV Outcomes
In 2025, NEJM reported that oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events than placebo in a high-risk type 2 diabetes population, a stronger finding than the earlier safety-only PIONEER-6 result.
Semaglutide in MASH, Phase 3
A 2025 NEJM phase 3 trial found semaglutide improved liver histologic outcomes in patients with MASH and moderate or advanced fibrosis, pushing the drug class deeper into liver disease treatment.
CagriSema / Cagrilintide + Semaglutidewhat is nejm
In 2025, NEJM published data on coadministered cagrilintide and semaglutide, highlighting the growing movement toward combination metabolic therapies intended to improve on single-pathway GLP-1 treatment.
Orforglipron Longer-Duration Obesity Data
A 2025 NEJM study of orforglipron in obesity showed significantly greater weight reduction than placebo over 72 weeks, strengthening the case for an eventual oral GLP-1 alternative to injections.
Tirzepatide and Diabetes Prevention in Obesity
A 2024/2025 NEJM analysis from SURMOUNT-1 showed tirzepatide reduced progression toward type 2 diabetes in adults with obesity or overweight, reinforcing its preventive metabolic potential.
2026 —
Researchers who are employees of the Veterans’ Affairs distributed data in JAMA Network Open, which apaprently confirms prior findings associating GLP-1 drugs with a higher isk of non-arteritic anterior ischemic optic neuropathy (NAION). Researchers with the VA St. Louis Health Care System in Missouri examined national electronic VA health records. The research compared the three-year chance of NAION between GLP-1 prescription holders and patients who have a prescription for sodium-glucose cotransporter-2 (SGLT2) inhibitors such as farxiga. “Out of 588,168 participants, 139,546 started GLP-1 treatment, while 448,622 took a form of SGLT2 inhibitors. According to the findings, three years of follow-up revealed that NAION affected 39 per 10,000 persons taking drugs like Ozempic and Mounjaro, compared to just 29 per 10,000 persons taking Jardiance or Invokana and similar drugs, resulting in what researchers determined was a 35% increased risk among GLP-1 users. They concluded that GLP-1 use was linked to a “modestly increased risk of NAION,” though they noted that the absolute risk remained low. The researchers called for heightened vigilance among health care providers for early signs of NAION among GLP-1 users.” About lawsuits
2026 and Beyond — The Pipeline Story Is Now Bigger Than GLP-1 Alone
By 2026, the field had clearly moved beyond single-pathway GLP-1 drugs. Reviews in Nature, Diabetes, and other journals describe a rapidly expanding pipeline that now includes:
- oral small-molecule GLP-1 agonists
- GLP-1 + amylin combinations
- dual GLP-1/GIP agonists
- GLP-1/glucagon co-agonists
- triple agonists like retatrutide.
This means the literature is no longer just about diabetes control. It now spans:
- obesity
- cardiovascular disease
- kidney disease
- heart failure
- sleep apnea
- liver disease
- prevention of diabetes.
What the Timeline Shows
Across four decades, the GLP-1 field progressed through five broad phases:
- Discovery phase
From proglucagon biology to GLP-1’s role as a human incretin.
- Proof-of-concept phase
Studies showed GLP-1 could lower glucose and still work in type 2 diabetes.
- First drug phase
Exenatide and liraglutide established the GLP-1 agonist class in diabetes.
- Outcome phase
LEADER, SUSTAIN-6, REWIND, FLOW, and SELECT demonstrated cardiovascular and kidney benefits, not just glucose control.
- Obesity and multi-agonist phase
STEP, SURMOUNT, retatrutide, and orforglipron redefined obesity pharmacotherapy and pushed the field into next-generation drug design.
Related
The GLP-1 story starts in the early 1980s with hormone discovery, becomes clinically meaningful in the late 1980s and early 1990s, enters drug therapy in the 2000s, proves cardiovascular benefit in the 2010s, and then explodes into obesity, kidney, heart-failure, sleep-apnea, and liver-disease treatment in the 2020s. The most important modern studies include LEADER, SUSTAIN-6, REWIND, STEP 1, SURMOUNT-1, SELECT, FLOW, STEP-HFpEF, SURMOUNT-OSA, and the emerging retatrutide and orforglipron trials.