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.
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.
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.
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.
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.
2008–2010 — The LEAD Program Establishes Liraglutide
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.”
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.
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.
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
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.
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
FLOW (Semaglutide in CKD + T2D)
In 2024, the NEJM 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.
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.
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.
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.
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.
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 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.