From the “miracle” injection to the “everyday” pill
Over the last five years, injectable incretins (mainly GLP-1 agonists and GLP-1/GIP combinations) have radically reshaped how medicine approaches obesity. For the first time, randomized trials showed average weight loss in the range of 15–20%, making it fully legitimate to treat obesity as a metabolic disease with targeted pharmacotherapy. A landmark was the STEP-1 trial with once-weekly semaglutide 2.4 mg, where an average of ~15% weight loss was achieved over 72 weeks. New England Journal of Medicine Today, the “second act” of this revolution is being written with oral regimens. If a once-daily pill achieves efficacy comparable to the injections, access will expand dramatically: better adherence, less infrastructure, and the possibility of large-scale use in primary care. Analysts estimate that the global anti-obesity market could reach or exceed 100 billion dollars by 2030—with pills acting as a demand accelerator. Goldman Sachs+2JPMorgan Chase+2 Why a pill? The three layers of argument 1.1 Clinical / behavioral There is a significant proportion of patients who avoid needles; for them, a pill is often a prerequisite even to consider starting therapy. Market analyses show that the availability of an oral regimen can bring “new entrants” into treatment—populations who previously refused injectables. This is not just about convenience: acceptance and adherence are key determinants of real-world effectiveness. 1.2 Operational / supply In principle, pills are easier to distribute and take. However, when the active substance is a peptide (e.g., semaglutide), the oral route requires multiple times the amount of active ingredient compared with the injection—burdening manufacturing and cost. Novo Nordisk, by acquiring Emisphere (SNAC technology), managed to “break” the gastric barrier, but there is still a practical price to pay: strict dosing routines and increased API requirements.Reuters 1.3 Public health / market The expansion of access through pills can change clinical practice: more prescriptions from primary-care clinics, wider geographic coverage, and better “social acceptability”. Leading houses (Goldman Sachs, J.P. Morgan) place the AOM (anti-obesity medication) market around 95–130 billion dollars in 2030 (with revisions depending on pricing, reimbursement, and supply), emphasizing that pills are a critical growth lever. Bloomberg+3Goldman Sachs+3JPMorgan Chase+3 The “stomach” barrier & Novo Nordisk’s SNAC technology Peptide drugs (such as semaglutide) are destroyed by gastric acid and enzymes, and are poorly absorbed through the gastrointestinal mucosa. Emisphere developed Eligen® SNAC, an absorption enhancer that increases local pH and permeability, helping the peptide cross into systemic circulation “intact”. Novo Nordisk fully acquired Emisphere in 2020 for 1.8 billion dollars, securing the crucial “pipeline” for oral semaglutide. Reuters The price? Dosing discipline. The official label/instructions for Rybelsus (oral semaglutide for type 2 diabetes) require taking it in the morning with up to 4 oz (~120 ml) of plain water and waiting at least 30 minutes before any food, drink, or other oral medication—any deviation reduces effectiveness. The same “protocol” is expected to accompany higher-dose regimens for obesity. FDA Access Data+2FDA Access Data+2 Proof of efficacy: OASIS-1 and related data The OASIS-1 trial (The Lancet) in adults with obesity/overweight without diabetes showed that oral semaglutide 50 mg/day achieved a −15.1% mean weight loss at 68 weeks versus −2.4% with placebo. More than 50% of participants achieved ≥15% weight loss. PubMed+1 Beyond the “scale”, the OASIS program shows improvements in glycemic and lipid parameters and other cardiometabolic endpoints, while recent presentations (ObesityWeek) demonstrated trends comparable to injectable semaglutide in certain secondary outcomes—important for reimbursement and health-policy decisions. Nature A critical compliance factor is the “water–pill–30 minutes” rule. For patients with multiple morning medications or irregular schedules, this can be a barrier. Success will depend on how easily this routine becomes a habit. FDA Access Data Eli Lilly’s counterattack: orforglipron, the “small-molecule” GLP-1 Lilly chose a different chemical route: instead of a peptide, it is developing orforglipron, a small-molecule GLP-1 agonist. Theoretical advantages include easier chemical synthesis, scalable manufacturing, and the absence of strict fasting/water rules like those of Rybelsus. - Phase 3 (ATTAIN-1, 72 weeks, without type 2 diabetes): at the maximum dose of 36 mg, mean weight loss was −12.4%. The study met its primary endpoint but underperforms compared with top-tier injectable regimens. Financial Times+4Reuters+4Reuters+4 - Phase 3 (ATTAIN-2, 72 weeks, with type 2 diabetes): mean weight loss of ~−10.5% at the maximum dose, with ~10% discontinuation due to adverse events in the high-dose group—a safety profile consistent with the class. Reuters According to Reuters, Lilly states it will file for approval of the pill in 2025, having invested billions of dollars in new manufacturing plants in the US—a sign that it is betting on the mass scale of the small molecule. Reuters Comparison with oral sema 50 mg: Based on current data, orforglipron lags by ~3–5 percentage points in mean weight loss compared with oral semaglutide, but gains on “freedom of dosing” and potentially production cost. PubMed+2The Lancet+2 It’s not a two-player game: AstraZeneca and the “combinations” AstraZeneca acquired from Eccogene ECC5004/AZD5004, an oral small-molecule GLP-1RA (once-daily, low-dose), with $185 million upfront and up to $1.825 billion in milestones. The program is running in Phase 2b (VISTA/SOLSTICE), and the company is integrating it strategically into its CVRM platform for combination therapies (e.g., with SGLT2 inhibitors/aldosterone agents). AstraZeneca+4AstraZeneca+4Reuters+4 CEO Pascal Soriot has publicly emphasized two goals: lowering cost/improving accessibility and preserving muscle mass (i.e., more fat loss – less lean-mass loss), which is critical for healthy weight reduction. The Guardian Injectables vs pills: the “cold” comparison - Injectable semaglutide 2.4 mg (STEP-1): ~−15% at 72 weeks, with proven cardiovascular benefit in people with obesity without type 2 diabetes (SELECT: HR 0.80, 20% relative reduction in MACE). New England Journal of Medicine+1 - Oral semaglutide 50 mg (OASIS-1): −15.1% at 68 weeks in overweight/obese adults without type 2 diabetes; requires the water–pill–30 minutes routine. PubMed+2The Lancet+2 - Orforglipron (36 mg, Phase 3): ~−12.4% (without type 2 diabetes) and ~−10.5% (with type 2 diabetes) at 72 weeks; flexible dosing, ~10% discontinuation at high dose. Reuters TL;DR: In terms of pure weight loss, oral semaglutide “hits” typical injectable semaglutide levels (~15%); orforglipron delivers double-digit weight loss with simpler dosing but a lower ceiling. PubMed+2The Lancet+2 Beyond kilos: cardio-renal and metabolic benefits The SELECT trial (17,604 patients, ~3 years) showed that semaglutide reduces MACE by 20% in adults with obesity/overweight without diabetes—a finding that shifts the narrative from “cosmetic weight loss” to hard clinical outcomes. Subgroup analyses show improvements in ischemic and heart-failure endpoints. Over a 4-year horizon, weight decreases initially up to ~65 weeks and then is maintained with continuous therapy. New England Journal of Medicine+2The Lancet+2 For pills, full long-term data are still emerging. In Phase 3 studies of orforglipron, there are improvements in HbA1c, lipids, and blood pressure, while some patients appear to plateau after ~72 weeks—a reminder of the need for maintenance strategies (behavioral/nutritional and potentially pharmacological personalization). Reuters Adherence, routine, and the “human” side Simplicity of dosing is highly valuable. Orforglipron does not require the ritual of “water only + 30 minutes fasting”, which in real life makes a difference—especially when a patient is taking multiple morning medications. On the other hand, oral semaglutide, when taken strictly according to instructions, has excellent efficacy. The dilemma here is individualized: biology + lifestyle schedule = regimen choice. FDA Access Data Manufacturing, cost, reimbursement: where the “battle” will be decided - API requirements: Oral semaglutide needs multiple times more active ingredient per tablet compared with the injection—potentially limiting availability and pushing costs up. Reuters - Small molecules = factory “comfort”: As a small molecule, orforglipron promises easier manufacturing scale-up. Lilly has already announced major investments in new plants in the US. Reuters - Reimbursement/pricing: Final pricing and reimbursement decisions will determine adoption speed. Analysts have already revised some market estimates downward (e.g., Goldman from 130 → 95 billion), factoring in cost, pricing policies, and possible treatment discontinuations. Goldman Sachs+1 The strategy of “combinations” and multimorbidity Obesity is rarely a “lone” disease. It coexists with type 2 diabetes, hypertension, dyslipidemia, MASLD (NAFLD/MASLD), and CKD. This is why companies are targeting combinations: oral GLP-1 + SGLT2 inhibitor, and later perhaps amylin, etc. AstraZeneca is already positioning AZD5004 within a broader CVRM platform with a view to “plugging it in” to polypharmacy—simpler regimens for complex patients. AstraZeneca Risks of oversimplification & the real world There is no “magic pill”. Incretins—injectable or oral—are tools that work best within a system: nutritional and behavioral support, exercise, monitoring of adverse events, and management of comorbidities. In orforglipron studies, ~10% of the high-dose group discontinued due to adverse events; plateau after 12–18 months was also observed in many participants. Honest communication here is key to prevent expectations from derailing. Reuters Historical context – and a necessary correction There is often a narrative link made between the “Canary Girls” of World War I and “slimming pills”. Historically, the Canary Girls turned yellow due to TNT exposure in British munitions factories; this was occupational exposure to explosives, not a weight-loss drug. This is well documented by museums and historical archives. Imperial War Museums+1 DNP (2,4-dinitrophenol), indeed, was used in the 1930s as a “calorie-burning” pill because it uncoupled oxidative phosphorylation—raising metabolism and thermogenesis but with a very narrow therapeutic window and fatal toxicity. Modern reviews and toxicology profiles (ATSDR, NIH) are clear: it has no place in therapy. Remembering this history is useful: it shows why we insist today on large RCTs, regulatory oversight, and long-term safety. PMC+2ATSDR+2 A brief “guide” to choosing (always with medical advice) Target and intensity of weight loss: - “I want maximum weight loss and can realistically follow a strict morning routine” → oral semaglutide 50 mg (where and when approved/available) or injectable semaglutide 2.4 mg. The Lancet+1 - “I want ease of dosing without the water–pill–30 minutes rule, and steady double-digit weight loss” → orforglipron (once approved), acknowledging that the “ceiling” is lower. Reuters Comorbidities / risk: - If someone has type 2 diabetes or high cardiovascular risk, priority will be given to regimens with proven CV benefit (today we have this for semaglutide from SELECT). New England Journal of Medicine Cost / access: - Initially, prices may mirror injectables; reality will be shaped by reimbursement and availability (especially for oral sema, given higher API needs). Reuters The above does not constitute medical advice. Treatment choice is made by a physician based on medical history, comorbidities, and individual goals. Market scenarios to 2030: the “size of the dream” - Goldman Sachs (2023): $100 billion by 2030 (later revised closer to $95 billion). Goldman Sachs+1 - J.P. Morgan (2023): >$100 billion, roughly split between diabetes and obesity. JPMorgan Chase - Other estimates: $130 billion (Bloomberg/Goldman 2024) and scenarios up to $150 billion (Reuters analyses 2024). More extreme forecasts (e.g., $500 billion) are considered overly optimistic by most observers. Bloomberg+2BioSpace+2 The common denominator: if a highly effective, well-tolerated non-peptide pill emerges, supply and pricing problems will ease and the market will explode. This is precisely where small molecules (orforglipron, AZD5004) are placing their bet. Regulatory horizon 2025–2026 - Oral semaglutide for obesity: Available data and the accompanying dossier (based on OASIS) have paved the way for regulatory decisions in the US. The Lancet - Orforglipron: Lilly has announced it will file by the end of 2025 for obesity (and in 2026 for diabetes), backed by major manufacturing investments. Reuters - AZD5004/ECC5004: In Phase 2b, with a clear CVRM/combination plan and a focus on patients with type 2 diabetes and comorbidities.AstraZeneca+1 Real-world case studies – what payers will be looking at - Weight maintenance at 2–4 years: Semaglutide data (SELECT and related analyses) show that weight loss is maintained with continuous treatment; the question is whether oral formulations will show similar profiles over comparable durations. Nature - Adverse events & discontinuations: 10% discontinuation in the high-dose orforglipron arm is manageable but requires “education” (dose titration, diet, management of GI symptoms). διαχειρίσιμες, αλλά θέλουν «εκπαίδευση» (τιτλοποίηση, διατροφή, υποστήριξη GI συμπτωμάτων). Reuters - Comorbidities & value-based reimbursement: Payers will look for outcomes (fewer CV events, hospitalizations, better HbA1c/NAFLD control), not just kilos. The clear CV benefit of semaglutide is a strong selling point. New England Journal of Medicine Communication & ethics: speaking honestly Oversimplification (“one pill and you’re done”) does a disservice both to drugs and to patients. We need clear information on: - Realistic expectations (e.g., plateau, need for maintenance). - Supporting interventions (nutrition, exercise, behavioral strategies). - Open discussion about adverse events (mainly GI) and when dose/regimen changes are needed. The goal is not just a number on the scale, but reduced cardiovascular risk, better metabolic control, and quality of life. “Where we’re heading” towards 2030 - Oral semaglutide 50 mg has shown in RCTs that it can match injectable semaglutide in efficacy (~−15%), at the cost of a strict routine and higher active-ingredient needs (and thus potentially limited availability at first). PubMed+2The Lancet+2 - Orforglipron promises easier production and dosing convenience (no fasting/water-only ritual), with ~−12.4% mean loss over 72 weeks— a figure that, if paired with the right pricing and access, could capture a large share of patients. Reuters - AstraZeneca and combination strategies (e.g., AZD5004 + CVRM agents) open the door to more holistic, oral regimens for obesity with comorbidities. AstraZeneca Looking back, from the Canary Girls (TNT) and the dangerous DNP “slimming pills” of the 1930s to the “smart” GLP-1 pills of 2030, we see the same constant ambition: safer, more effective, more practical control of weight and metabolic risk—without myths, without exaggeration, with science, routine, and transparency. Imperial War Museums+1 Indicative references / sources - OASIS-1 (oral semaglutide 50 mg): The Lancet (abstract) & PubMed. - Rybelsus – dosing instructions (FDA label 2024 & 2025 update, official website): 30-minute wait with up to 4 oz water. FDA Access Data - Emisphere/SNAC acquisition by Novo Nordisk (2020): Reuters, BioSpace. - Orforglipron (Lilly): Reuters (12.4% at 72 weeks; ~10% discontinuation at high dose), more recent reports on plateau, filing plans for 2025, manufacturing investments. - AstraZeneca – ECC5004/AZD5004: official press release (license), clinical trials, IR deck, Reuters. - SELECT (CV outcomes with semaglutide): NEJM (primary publication & PubMed) and The Lancet (pre-specified analyses). - Market 2030: Goldman Sachs, J.P. Morgan, Bloomberg, Reuters, BioSpace. - Historical DNP/Canary Girls: Imperial War Museums, ATSDR/NIH DNP reviews. Read the full article