Summary table: the 3 molecules head-to-head
Semaglutide (Novo Nordisk, brands Ozempic/Wegovy/Rybelsus): mono-receptor GLP-1 agonist, EMA and AEMPS approved, available in Spanish pharmacies by prescription. Mean weight loss: -14.9% at 68 weeks in obesity (STEP-1). Tirzepatide (Eli Lilly, brands Mounjaro/Zepbound): dual GLP-1/GIP agonist, EMA 2022 and AEMPS 2024 approval, available in Spanish pharmacies by prescription. Mean weight loss: -22.5% at 72 weeks (SURMOUNT-1). Retatrutide (Eli Lilly, LY3437943): triple GLP-1/GIP/glucagon agonist, phase III TRIUMPH, NOT yet approved by EMA or AEMPS (expected 2027-2028). Mean weight loss: -24.2% at 88 weeks in phase II data (Jastreboff et al., NEJM 2023).
Key difference 1: receptor targets
Semaglutide acts only on the GLP-1 receptor (insulinotropic + satiety). Tirzepatide adds the GIP receptor, which potentiates postprandial insulin response and modulates adipocyte lipogenesis. Retatrutide also adds the glucagon receptor, which activates hepatic lipolysis and resting energy expenditure. This explains why each generation surpasses the previous in weight loss: glucagon adds a thermogenic component the first two lack.
Key difference 2: HbA1c efficacy (type-2 diabetes)
Comparable data at 40-72 weeks: Semaglutide 1.0 mg weekly → -1.4 HbA1c points (SUSTAIN-7). Tirzepatide 15 mg weekly → -2.3 HbA1c points (SURPASS-2). Retatrutide 12 mg weekly → -2.1 HbA1c points (TRIUMPH-4 preliminary). In high-A1c type-2 diabetes, retatrutide and tirzepatide are already equivalent; the gap is wider in obesity without diabetes.
Key difference 3: safety profile
All three share the classic transient GI adverse-event pattern (nausea, vomiting, diarrhea, constipation) most frequent during titration. Reported rates: semaglutide 44% any GI AE; tirzepatide 56%; retatrutide 65%. Clinically significant gastroparesis: <2% in all three. Acute pancreatitis: rates similar to placebo in all pivotal trials. Thyroid tumors: absolute contraindication in MEN2 / familial medullary thyroid cancer for all three due to rodent findings.
Key difference 4: availability in Spain
Semaglutide — listed in CIMA. Ozempic with intermittent shortage since 2023; Wegovy marketed but limited access due to AEMPS off-label restrictions. Medical prescription required. Tirzepatide — Mounjaro AEMPS-approved 2024, available in pharmacy by private prescription. High open-market price. Retatrutide — NOT available in Spain as medicine. Its entry to the Spanish market depends on EMA approval (expected 2027-2028) plus the national pricing & reimbursement procedure.
Implications for research
Synthetic material of all three molecules exists as a research reagent with HPLC ≥99% purity and external CoA. It is the format used in preclinical pharmacokinetic studies, biochemical assay validation, chromatography calibration, and aqueous stability studies. NOT the human-use form, which requires pharmaceutical presentation and medical prescription.
What's coming 2027-2028
Eli Lilly expects EMA approval for retatrutide in 2027-2028, marking the first triple agonist on the European market. Boehringer is working on survodutide (another dual GLP-1/glucagon) with phase III data expected Q2 2026. Amgen continues MariTide (dual GLP-1R/GIPR antagonist) in phase III. Novo Nordisk pushes amycretin (oral peptide combining GLP-1 agonism with amylin activation). 2027 will be the most intense year in the GLP-1 segment in a decade.
Source: NEJM / Lancet