GLP-1 drugs for obesity: oral semaglutide, tirzepatide and what is coming in 2026-2027

For decades, chronic obesity lacked truly effective pharmacological treatments. GLP-1 (glucagon-like peptide-1) receptor agonists radically changed that equation: first with liraglutide, then with injectable semaglutide, and more recently with tirzepatide. But 2025-2027 represent perhaps the most dizzying leap of all: obesity pharmacology has entered a phase of unprecedented innovation ranging from the first weight-loss pill approved by the FDA to molecules that produce weight loss exceeding 25-28%, figures until recently reserved for bariatric surgery.

In this article, we analyse each drug with scientific rigour: molecular mechanism, efficacy data from pivotal trials, safety profile, current regulatory status, and outlook for Spain and community pharmacy. There is no advertising, there are no extrapolations: only clinical evidence.

The context: why GLP-1 changed everything

GLP-1 is an incretin secreted by the L-cells of the ileum and colon in response to food intake. Its physiological effects are multiple: it stimulates glucose-dependent insulin secretion, inhibits glucagon, slows gastric emptying, reduces appetite by acting on hypothalamic and brainstem receptors, and produces a feeling of early satiety. This cascade of effects makes its receptor agonists simultaneously antidiabetic and anorexigenic.

Subcutaneous semaglutide 2.4 mg weekly (Wegovy, approved by the FDA in 2021) demonstrated in the STEP programme mean weight loss of 14.9-17.4% of body weight, with one-third of patients achieving reductions ≥20%. Those data placed obesity pharmacotherapy in the same range of efficacy as some restrictive bariatric procedures.

What came next has been even more impressive: tirzepatide outperformed semaglutide in a head-to-head trial, and the next-generation pipeline points to 25-30% weight loss with completely oral molecules or combinations that act on three receptors simultaneously.

Oral semaglutide: the first obesity pill approved by the FDA

The problem with oral semaglutide: the gastrointestinal barrier

Semaglutide is a 31-amino acid peptide. Proteins and peptides administered orally undergo enzymatic degradation (gastric and intestinal proteases) and have poor epithelial permeability, which makes their oral bioavailability practically nil under normal conditions. Novo Nordisk solved this problem with the excipient SNAC (sodium N-(8-[2-hydroxybenzoyl]amino)caprylate), which acts through a dual mechanism:

Tirzepatide: the dual agonist that outperformed semaglutide

The dual mechanism: what does GIP add to GLP-1?

Tirzepatide is a synthetic molecule designed to simultaneously activate GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors. Unlike GLP-1, GIP is an incretin secreted by K cells of the duodenum and jejunum, with effects that for years were considered merely anabolic. Its inclusion in tirzepatide generates synergistic effects on energy balance:

Activation of the GIP receptor in adipose tissue enhances lipolysis and regulates lipid storage in a coordinated manner with the anorexigenic effect of GLP-1. In the central nervous system, the combined GLP-1 + GIP activation on hypothalamic nuclei (arcuate nucleus, NTS) produces a more marked suppression of appetite than the individual activation of each receptor. The end result is a greater weight reduction than that of pure GLP-1 agonists, especially at the 15 mg dose.

SURMOUNT-5: the definitive head-to-head

The SURMOUNT-5 trial (NEJM, January 2025) was the first direct non-inferiority and superiority trial between tirzepatide (10-15 mg) and semaglutide 2.4 mg, involving 751 participants over 72 weeks. It was designed with the hypothesis that tirzepatide was at least as effective as semaglutide, and the results not only confirmed non-inferiority but showed statistically significant superiority:

Tirzepatide produced a mean body weight loss of 20.2% compared to 13.7% for semaglutide (difference of −6.5 percentage points; p<0.001). In terms of kilograms, the difference was approximately 10 kg in favour of tirzepatide. The reduction in body fat mass was 33.9% with tirzepatide versus 24.5% with semaglutide, with differences also in body composition (greater preservation of relative lean mass). Adverse effects were comparable between groups.

Why is there a shortage of Mounjaro in pharmacies?

Tirzepatide was approved by the EMA in 2023 for type 2 diabetes (Mounjaro) and in September 2024 for obesity (as Mounjaro, since the EU did not market the Zepbound brand). Demand has repeatedly exceeded Eli Lilly's production capacity. Industrial-scale peptide manufacturing is a complex process (solid-phase synthesis, chromatographic purification, lyophilisation or solution formulation) that cannot be scaled up in months. In Spain, the Spanish regulatory agency AEMPS managed priority access through compassionate use protocols and the limitation of new prescriptions in 2024 (please check your own national regulator for regulatory status).

The 2026-2027 pipeline: beyond semaglutide and tirzepatide

Innovation in pharmacological obesity treatment does not stop. Below is an analysis of the most advanced candidates that could reach Spanish pharmacies between 2026 and 2028.

Orforglipron is qualitatively different from oral semaglutide: it is not a peptide, but a small non-peptide molecule that activates the GLP-1 receptor allosterically. This fundamentally resolves the oral bioavailability issues of peptides: as a low molecular weight organic molecule, it is efficiently absorbed through the intestinal epithelium without the need for facilitating excipients and without food administration restrictions.

In the ATTAIN programme (phase 3), the 36 mg dose produced a 12.4% reduction in body weight at 36 weeks in patients with obesity without diabetes. In an indirect comparative substudy, orforglipron showed efficacy similar to or greater than oral semaglutide 25 mg with better gastrointestinal tolerability. Eli Lilly submitted the NDA to the FDA in early 2026; if the review proceeds without requests for additional information (Complete Response Letter), approval could occur in the second half of 2026 in the US.

Retatrutide adds glucagon receptor (GCGR) activation to dual agonism (GLP-1 + GIP). This third mechanism is not without controversy: glucagon is a hyperglycaemic hormone, and its chronic activation in patients without diabetes requires meticulous balancing. However, in the context of triple agonism, the net effect on blood glucose is neutral or even favourable (GLP-1 and GIP compensate for the hyperglycaemic effect of glucagon), whilst GCGR activation provides unique effects:

The glucagon receptor in the liver stimulates fatty acid oxidation and increases basal energy expenditure. In brown adipose tissue, GCGR activation promotes thermogenesis. The result is a medicine that not only reduces appetite and food intake, but also increases calorie burning, tackling obesity from both sides of the energy balance. Data from the phase 3 TRIUMPH-4 trial are the most impressive published to date for an incretin receptor agonist: mean body weight loss of 28.7% (12 mg, 48 weeks), with 72% of patients achieving reductions ≥15% and 47% achieving ≥25%. An additional finding from the TRIUMPH programme is the significant reduction in joint pain in knee osteoarthritis (mean improvement of 4.2 points on the WOMAC scale), an effect independent of weight loss that suggests direct anti-inflammatory activity.

CagriSema combines semaglutide 2.4 mg and cagrilintide 2.4 mg in a single weekly injection. Cagrilintide is a long-acting analogue of amylin, a hormone co-secreted with insulin by pancreatic beta cells whose receptor acts on the area postrema and the NTS of the brainstem. Amylin produces short-term (postprandial) satiety whilst GLP-1 acts more on basal satiety and hunger reduction. The combination generates a dual-phase satiety signal that results in greater overall appetite suppression.

In REDEFINE 1, the largest published cohort to date (3,400 participants, 68 weeks), CagriSema produced a mean weight loss of 20.4% (ITT) and 23% in the per-protocol analysis, with 46.5% of patients achieving reductions ≥20%. Novo Nordisk submitted the NDA to the FDA in December 2025 and the application to the EMA in the first quarter of 2026.

Comparative table: all candidates at a glance

Weight loss data are expressed as percentage change from baseline weight in pivotal trials, intention-to-treat analysis unless otherwise stated. Trials have varying durations (36-72 weeks) and different populations, so direct comparisons between rows should be made with caution. Only SURMOUNT-5 offers a statistically validated direct comparison (tirzepatide vs s.c. semaglutide).

Situation in Spain: shortages, access and the role of the pharmacy

Spanish community pharmacies have been on the front line of the GLP-1 receptor agonist supply crisis since 2023. According to data from SEFAR (Sociedad Española de Farmacia Rural - Spanish Rural Pharmacy Society), semaglutide accounted for 10.7% of shortages in community pharmacies during the first quarter of 2025, making it the active ingredient with the greatest impact on dispensing after ibuprofen. This situation has led to clinically delicate scenarios: patients with type 2 diabetes well controlled with Ozempic (semaglutide) who have had to switch treatments, with the resulting glycaemic impact, and patients with obesity on treatment with Wegovy (semaglutide) who have interrupted therapy due to lack of product. Please check your own national regulator (such as the MHRA in the UK) for regulatory guidance.

Chronology of regulatory access in Spain

What the pharmacist needs to know at the counter

Community pharmacists are frequently the first healthcare professionals whom patients ask about these medicines. Some practical keys for dispensing and pharmacy advice:

Regarding oral semaglutide (if it arrives in Spain): Adherence to administration instructions is critical. The patient must take the tablet on an empty stomach, with no more than 120 ml of water, and wait 30 minutes before consuming any food, drink or medication. A common mistake will be taking it with the usual morning glass of water alongside other medicines. This instruction must be reinforced at every dispensing.

Regarding dose escalation: All these medicines require gradual dose escalation (weeks to months) to reduce the incidence of gastrointestinal adverse effects. Patients who start at full doses have much higher dropout rates. The pharmacist can verify that the prescription includes the correct dose according to the week of treatment.

Regarding nausea and vomiting: These are the most frequent adverse effects, especially in the first weeks. They are generally moderate and transient. The advice to take the weekly injectable on the same day of the week and not on an empty stomach (for injectables) can reduce symptoms. Persistent nausea or vomiting that prevents eating should be referred to the prescribing doctor.

Regarding shortages: If a product is not available, the patient must never autonomously substitute it with another GLP-1 receptor agonist or change to a different dose. Treatment interruption must be communicated to the doctor, who will assess options. There is no dose equivalence between semaglutide and tirzepatide that can be established generically.