Semaglutide: History & Discovery

The Discovery of GLP-1: Foundation for a Revolution

The story of semaglutide begins not in the 21st century, but in the 1970s with the discovery of glucagon-like peptide-1 (GLP-1), the hormone that semaglutide mimics. This discovery emerged from research into the "incretin effect"—the observation that oral glucose intake stimulates more insulin secretion than intravenous glucose administration, even when blood glucose levels are identical. This suggested that the gut produces hormones that enhance insulin secretion in response to food intake.

In 1983, researchers identified proglucagon, a precursor protein produced in intestinal L-cells and pancreatic alpha cells. When processed in the intestine, proglucagon yields several peptides, including GLP-1. Initial studies showed that GLP-1 potently stimulated insulin secretion in a glucose-dependent manner, making it an attractive target for diabetes treatment. However, native GLP-1 had a fatal flaw for therapeutic use: it was degraded within minutes by the enzyme dipeptidyl peptidase-4 (DPP-4), giving it a half-life of only 1-2 minutes.

This short half-life posed a significant challenge. Continuous intravenous infusion of GLP-1 could lower glucose in people with type 2 diabetes, but this was impractical for chronic treatment. Two strategies emerged to overcome this limitation: DPP-4 inhibitors (which prevent GLP-1 degradation) and GLP-1 receptor agonists (modified versions of GLP-1 resistant to degradation). Semaglutide represents the culmination of decades of work on the latter approach.

Early GLP-1 Agonists: Paving the Way

The development of GLP-1 agonists as therapeutic agents began in the 1990s with an unexpected source: the Gila monster, a venomous lizard native to the southwestern United States. Researchers discovered that Gila monster venom contained a peptide called exendin-4, which shared 53% amino acid sequence identity with human GLP-1 but was resistant to DPP-4 degradation. This peptide, developed as exenatide, became the first GLP-1 agonist approved by the FDA in 2005.

Exenatide required twice-daily injections due to its relatively short half-life of 2-3 hours. While effective for glucose lowering and producing modest weight loss (2-3 kg), the frequent dosing was burdensome. This spurred development of longer-acting GLP-1 agonists. Liraglutide, approved in 2010, required only once-daily injection due to its 13-hour half-life, achieved through fatty acid modification that enabled albumin binding. Liraglutide demonstrated superior glucose lowering compared to exenatide and produced greater weight loss (3-4 kg at diabetes doses).

These early GLP-1 agonists established several important principles. First, they demonstrated that GLP-1 receptor activation could safely and effectively lower glucose in type 2 diabetes with low hypoglycemia risk. Second, they showed that GLP-1 agonists produced weight loss rather than weight gain, distinguishing them from most other diabetes medications. Third, they suggested cardiovascular benefits, with liraglutide's LEADER trial showing reduced cardiovascular events. These successes set the stage for development of even longer-acting agents like semaglutide.

Novo Nordisk's Development Program

Novo Nordisk, a Danish pharmaceutical company with a century-long history in diabetes care, began developing semaglutide in the early 2000s. The company had already achieved success with liraglutide and sought to create a once-weekly GLP-1 agonist that would further improve convenience and potentially enhance efficacy. The goal was ambitious: develop a GLP-1 agonist with a half-life of approximately one week, enabling once-weekly dosing while maintaining or improving upon liraglutide's glucose-lowering and weight loss effects.

Molecular Engineering

Creating semaglutide required sophisticated molecular engineering. The starting point was the 31-amino acid sequence of native human GLP-1. Researchers made three key modifications. First, they substituted alanine with aminoisobutyric acid at position 8, protecting against DPP-4 cleavage. Second, they attached a C-18 fatty acid chain via a spacer to lysine at position 26, enabling strong albumin binding. Third, they substituted lysine with arginine at position 34, further enhancing stability.

These modifications were not arbitrary but based on years of structure-activity relationship studies. The fatty acid chain length was optimized—too short and albumin binding would be insufficient for weekly dosing; too long and the molecule might not reach GLP-1 receptors effectively. The spacer between the fatty acid and the peptide backbone was carefully designed to allow optimal albumin binding while maintaining receptor activation. The result was a molecule with 94% structural homology to native GLP-1 but a half-life of approximately 7 days—a 5,000-fold increase.

Preclinical Development

Preclinical studies in the mid-2000s demonstrated that semaglutide activated GLP-1 receptors with similar potency to native GLP-1 and produced robust glucose lowering and weight loss in animal models of diabetes and obesity. Importantly, the albumin binding strategy worked as intended, with semaglutide showing sustained drug levels after subcutaneous injection. Toxicology studies in rodents and non-human primates identified the thyroid C-cell tumor finding that would later lead to a boxed warning, though the relevance to humans remained uncertain.

Clinical Development: The SUSTAIN Program

Semaglutide entered clinical development in the late 2000s with a comprehensive program designed to establish its efficacy and safety for type 2 diabetes. The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) program would eventually include 10 major phase 3 trials enrolling over 8,000 participants.

Phase 1 and 2 Studies (2008-2012)

Early phase studies established semaglutide's pharmacokinetics, safety, and preliminary efficacy. Phase 1 studies in healthy volunteers confirmed the approximately 7-day half-life and demonstrated that steady-state concentrations were reached after 4-5 weeks of weekly dosing. Phase 2 dose-ranging studies in people with type 2 diabetes tested doses from 0.5 mg to 1.5 mg weekly, establishing that 0.5 mg and 1.0 mg were optimal doses balancing efficacy and tolerability.

These early studies revealed semaglutide's impressive glucose-lowering effects, with HbA1c reductions of 1.5-1.8% from baseline. Weight loss was also substantial, averaging 4-6 kg over 12-24 weeks. The side effect profile was consistent with other GLP-1 agonists, with gastrointestinal effects (nausea, vomiting, diarrhea) being most common but generally mild to moderate and improving with continued treatment.

SUSTAIN 1-5: Establishing Efficacy (2015-2016)

The core SUSTAIN trials compared semaglutide to placebo and active comparators in various patient populations and treatment contexts. SUSTAIN-1 (2015) compared semaglutide monotherapy to placebo in 388 participants with type 2 diabetes inadequately controlled with diet and exercise. Results were impressive: HbA1c reductions of 1.5% with 0.5 mg and 1.6% with 1.0 mg, compared to 0.1% with placebo. Weight loss was 3.7 kg and 4.5 kg respectively, compared to 1.0 kg with placebo.

SUSTAIN-2 (2016) compared semaglutide to sitagliptin (a DPP-4 inhibitor) in 1,231 participants inadequately controlled on metformin. Semaglutide demonstrated clear superiority, with HbA1c reductions of 1.3-1.6% versus 0.5% with sitagliptin. Weight loss was also superior: 4.3-6.1 kg versus 1.9 kg. SUSTAIN-3 compared semaglutide to exenatide extended-release (a once-weekly GLP-1 agonist), showing superior glucose lowering (1.5% vs 0.9% HbA1c reduction) and weight loss (5.6 kg vs 1.9 kg).

SUSTAIN-4 and SUSTAIN-5 compared semaglutide to insulin glargine and placebo (added to basal insulin), respectively. Both trials demonstrated semaglutide's superiority for glucose control and weight management. Notably, while insulin glargine caused weight gain (1.2 kg), semaglutide produced weight loss (5.2 kg), a crucial distinction for patients with type 2 diabetes and obesity.

SUSTAIN-6: Cardiovascular Outcomes (2016)

Perhaps the most important SUSTAIN trial was SUSTAIN-6, a cardiovascular outcomes trial required by FDA guidance for all new diabetes medications. This trial enrolled 3,297 participants with type 2 diabetes at high cardiovascular risk and followed them for 2 years. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

Results, published in the New England Journal of Medicine in 2016, showed that semaglutide reduced the primary endpoint by 26% (6.6% vs 8.9%, HR 0.74, p=0.02). This was driven primarily by reductions in non-fatal stroke (39% reduction) and non-fatal myocardial infarction (26% reduction). Semaglutide also reduced new or worsening nephropathy by 36%. These findings positioned semaglutide not just as a glucose-lowering agent but as a medication with cardiovascular and renal protective effects.

One unexpected finding was increased risk of diabetic retinopathy complications (3.0% vs 1.8%). This appeared related to rapid glucose lowering in people with pre-existing retinopathy, a phenomenon called "early worsening" that had been observed with intensive glucose control in other studies. This finding led to recommendations for ophthalmologic screening before starting semaglutide in people with pre-existing retinopathy.

SUSTAIN 7-10: Head-to-Head Comparisons (2017-2019)

Later SUSTAIN trials provided head-to-head comparisons with other diabetes medications. SUSTAIN-7 compared semaglutide to dulaglutide (another once-weekly GLP-1 agonist), showing superior glucose lowering and weight loss. SUSTAIN-8 compared semaglutide to canagliflozin (an SGLT2 inhibitor), again demonstrating semaglutide's superiority. SUSTAIN-9 examined semaglutide as add-on to SGLT2 inhibitors, showing additive benefits. SUSTAIN-10 compared semaglutide to liraglutide, demonstrating that the once-weekly agent was non-inferior to the once-daily agent.

FDA Approval for Diabetes (2017)

On December 5, 2017, the FDA approved semaglutide (brand name Ozempic) for treatment of type 2 diabetes in adults. The approval was based on the SUSTAIN clinical trial program demonstrating superior glucose lowering compared to placebo and multiple active comparators, along with cardiovascular benefits shown in SUSTAIN-6. Approved doses were 0.5 mg and 1.0 mg once weekly, with a starting dose of 0.25 mg weekly for 4 weeks to improve tolerability.

The approval included a boxed warning regarding thyroid C-cell tumors based on rodent findings, contraindications for personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2, and warnings about pancreatitis, diabetic retinopathy complications, and hypoglycemia when combined with insulin or sulfonylureas. Despite these warnings, the approval was seen as a major advance in diabetes treatment, offering superior efficacy with convenient once-weekly dosing.

Ozempic launched in the United States in early 2018 and quickly gained market share. By 2019, it had become one of the top-selling diabetes medications globally, with sales exceeding $3 billion annually. The medication's success was driven by its efficacy, convenient dosing, and growing recognition of the importance of weight loss in diabetes management.

Oral Semaglutide Development (2019)

While injectable semaglutide was achieving commercial success, Novo Nordisk was simultaneously developing an oral formulation—a significant technical challenge given that peptides are normally degraded in the gastrointestinal tract. The solution involved co-formulating semaglutide with an absorption enhancer called SNAC (sodium N-(8-[2-hydroxybenzoyl] amino) caprylate), which facilitates uptake across the gastric mucosa.

The PIONEER clinical trial program tested oral semaglutide in over 9,500 participants across 10 major trials. Results showed that oral semaglutide effectively lowered glucose (HbA1c reductions of 0.7-1.4% depending on dose) and produced weight loss (2-4 kg), though effects were somewhat less than injectable semaglutide due to lower bioavailability (approximately 1% for oral vs nearly 100% for subcutaneous).

The FDA approved oral semaglutide (brand name Rybelsus) in September 2019 for type 2 diabetes. This was the first oral GLP-1 agonist approved, offering an option for patients who preferred not to inject. However, the strict administration requirements (take on empty stomach with minimal water, wait 30 minutes before eating or taking other medications) limited its convenience advantage over injectable formulations.

The STEP Program: Pivoting to Obesity (2018-2021)

While semaglutide was approved for diabetes at doses up to 1.0 mg weekly, clinical observations suggested that higher doses might produce even greater weight loss. This led Novo Nordisk to initiate the STEP (Semaglutide Treatment Effect in People with obesity) program, testing semaglutide 2.4 mg weekly specifically for chronic weight management in people without diabetes.

STEP 1: Landmark Weight Loss Results (2021)

STEP-1, published in the New England Journal of Medicine in February 2021, was a game-changer. This trial enrolled 1,961 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity, but without diabetes. Participants received either semaglutide 2.4 mg weekly or placebo, both combined with lifestyle intervention (reduced-calorie diet and increased physical activity).

Results were unprecedented for a pharmaceutical weight loss intervention. After 68 weeks, the semaglutide group lost an average of 14.9% of body weight compared to 2.4% with placebo—a difference of 12.5 percentage points. Even more impressive, 86% of semaglutide participants lost at least 5% of body weight (vs 32% placebo), 69% lost at least 10% (vs 12% placebo), and 50% lost at least 15% (vs 5% placebo). Nearly one-third (32%) lost 20% or more of their body weight.

These results approached those typically seen with bariatric surgery, previously considered the gold standard for substantial, sustained weight loss. The weight loss was accompanied by improvements in cardiometabolic risk factors including blood pressure, lipids, inflammatory markers, and glycemic parameters. Quality of life measures also improved significantly. The findings generated enormous media attention and public interest, positioning semaglutide as a potential breakthrough in obesity treatment.

STEP 2-5: Confirming Efficacy Across Populations (2021)

STEP-2 examined semaglutide in people with obesity and type 2 diabetes, comparing 1.0 mg and 2.4 mg weekly doses. Results showed dose-dependent weight loss: 6.2% with 1.0 mg, 9.6% with 2.4 mg, and 3.4% with placebo. This confirmed that higher doses produced greater weight loss even in people with diabetes.

STEP-3 combined semaglutide with intensive behavioral therapy (low-calorie diet for first 8 weeks, frequent counseling sessions). Weight loss was 16.0% with semaglutide versus 5.7% with placebo, demonstrating that semaglutide's effects were additive to intensive lifestyle intervention.

STEP-4 examined weight loss maintenance. Participants first received open-label semaglutide for 20 weeks (losing an average of 10.6% of body weight), then were randomized to continue semaglutide or switch to placebo for 48 additional weeks. Those continuing semaglutide lost an additional 7.9% (total 17.4% from baseline), while those switched to placebo regained 6.9% (net loss of only 5.6% from baseline). This demonstrated that semaglutide's benefits were maintained with continued treatment but largely disappeared when stopped—a finding with important implications for treatment duration.

STEP-5 examined longer-term treatment (104 weeks), showing sustained weight loss of 15.2% with semaglutide versus 2.6% with placebo, confirming that benefits persisted for at least 2 years.

FDA Approval for Weight Management (2021)

On June 4, 2021, the FDA approved semaglutide 2.4 mg weekly (brand name Wegovy) for chronic weight management in adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity. This was the first new weight loss medication approved since 2014 and represented a paradigm shift in obesity treatment, offering pharmaceutical intervention with efficacy approaching bariatric surgery.

The approval was based on the STEP clinical trial program demonstrating substantial, sustained weight loss with improvements in cardiometabolic risk factors and quality of life. The indication specified that Wegovy should be used as an adjunct to reduced-calorie diet and increased physical activity, emphasizing that medication alone was insufficient—lifestyle modification remained essential.

Wegovy launched in the United States in June 2021 and immediately faced overwhelming demand. Within months, supply shortages developed as manufacturing capacity couldn't keep pace with prescriptions. The shortages persisted through 2022 and 2023, with Novo Nordisk investing billions in manufacturing expansion. The unprecedented demand reflected both the medication's efficacy and the enormous unmet need for effective obesity treatments.

The SELECT Trial: Cardiovascular Prevention (2023)

While semaglutide was approved for diabetes and weight management, questions remained about its cardiovascular effects in people without diabetes. The SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) trial, initiated in 2018, addressed this question.

SELECT enrolled 17,604 adults aged 45 or older with established cardiovascular disease (prior myocardial infarction, stroke, or peripheral artery disease) and overweight or obesity (BMI ≥27), but without diabetes. This was a massive undertaking—one of the largest cardiovascular outcomes trials ever conducted. Participants were randomized to semaglutide 2.4 mg weekly or placebo and followed for up to 4 years.

Results, presented at the American Heart Association Scientific Sessions in November 2023 and simultaneously published in the New England Journal of Medicine, showed that semaglutide reduced the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 20% (8.0% vs 9.5%, HR 0.80, p<0.001). The benefit emerged early (within 6 months) and persisted throughout the trial. Importantly, the benefit appeared consistent across subgroups and was evident even in participants who lost minimal weight, suggesting mechanisms beyond weight loss contributed to cardiovascular protection.

SELECT represented a paradigm shift in how obesity medications are viewed. Rather than simply treating obesity, semaglutide was now positioned as a cardiovascular protective agent for people with established cardiovascular disease and overweight or obesity. This expanded the potential patient population substantially and strengthened the case for insurance coverage and reimbursement.

Cultural Phenomenon and Societal Impact (2022-2024)

By 2022-2023, semaglutide had transcended its status as a prescription medication to become a cultural phenomenon. Media coverage was extensive, with major publications running features on "Ozempic" (the brand name became synonymous with GLP-1 agonists generally). Celebrities and public figures discussed their use of the medication, both openly and through speculation. Social media was filled with before-and-after photos, personal testimonials, and debates about the ethics and implications of pharmaceutical weight loss.

The cultural impact was complex and multifaceted. On one hand, semaglutide brought unprecedented attention to obesity as a medical condition requiring treatment, potentially reducing stigma. On the other hand, concerns emerged about trivializing obesity, promoting unrealistic body standards, and exacerbating health inequities given the medication's high cost and limited insurance coverage.

The supply shortages created a secondary market for compounded semaglutide—versions produced by compounding pharmacies that were not FDA-approved. While legally permitted during shortages, compounded products raised safety concerns due to variable quality, purity, and potency. Reports of adverse events from compounded semaglutide highlighted these risks. The FDA issued warnings about compounded products, but demand continued to exceed supply of brand-name formulations.

The economic impact was staggering. Semaglutide generated over $13 billion in sales for Novo Nordisk in 2023, making it one of the best-selling medications globally. The company's market capitalization soared, briefly making it the most valuable company in Europe. However, the high cost (over $1,000 per month in the United States) sparked debates about drug pricing, insurance coverage, and healthcare resource allocation. Many insurance plans covered Ozempic for diabetes but not Wegovy for weight management, leading to widespread off-label prescribing of Ozempic for weight loss.

Ongoing Research and Future Directions

As of 2024, semaglutide research continues to expand into new indications and populations.

NASH and Liver Disease

Phase 3 trials are examining whether semaglutide can prevent progression of non-alcoholic steatohepatitis (NASH) to cirrhosis. Phase 2 results showing NASH resolution in 59% of participants have generated optimism that semaglutide could become the first FDA-approved treatment for NASH, a condition affecting millions with no current approved therapies.

Heart Failure

The STEP-HFpEF trial is examining whether semaglutide improves symptoms and functional capacity in patients with heart failure with preserved ejection fraction (HFpEF), a condition strongly associated with obesity. If successful, this could open another major indication.

Chronic Kidney Disease

The FLOW trial examining semaglutide's effects on kidney disease progression in people with diabetes and chronic kidney disease was stopped early due to overwhelming efficacy, with semaglutide reducing kidney disease progression by 24%. This suggests semaglutide may join SGLT2 inhibitors as a cornerstone therapy for diabetic kidney disease.

Alzheimer's Disease

The EVOKE trials are examining whether semaglutide can prevent cognitive decline in people at high risk for Alzheimer's disease. This represents a completely new therapeutic avenue based on GLP-1 receptors' roles in neuroinflammation and neuroprotection.

Addiction

Clinical trials are examining whether semaglutide can reduce alcohol consumption in people with alcohol use disorder, based on preclinical evidence and anecdotal reports of reduced cravings. If successful, this could represent a novel approach to addiction treatment.

Pediatric Populations

Trials are examining semaglutide for weight management in adolescents with obesity, a population with limited treatment options. Balancing efficacy against potential effects on growth and development will be crucial.

Legacy and Impact on Medicine

Semaglutide's impact on medicine extends beyond its direct therapeutic effects. It has fundamentally changed how obesity is viewed and treated, shifting from a lifestyle issue to a medical condition requiring pharmacotherapy. It has demonstrated that substantial, sustained weight loss is achievable with medication, challenging the notion that bariatric surgery is the only effective intervention for severe obesity.

The medication has also influenced drug development strategies. The success of semaglutide has sparked intense interest in GLP-1-based therapies, with numerous pharmaceutical companies developing next-generation GLP-1 agonists and combination therapies. Tirzepatide (a dual GIP/GLP-1 agonist) has shown even greater weight loss than semaglutide. Triple agonists targeting GLP-1, GIP, and glucagon receptors are in development, with early results suggesting weight loss exceeding 20%.

Perhaps most importantly, semaglutide has demonstrated that targeting fundamental biological pathways regulating appetite and metabolism can produce clinically meaningful outcomes. This has reinvigorated obesity research and drug development, with the potential to transform treatment of metabolic diseases over the coming decades.