Retatrutide’s Results, Wegovy Gears Up For Europe
Week Of May 16 – May 22, 2026
Lilly’s retatrutide, the triple GIP/GLP-1/glucagon agonist, read out its flagship Phase 3 obesity trial: 28.3% weight loss at the top dose, in bariatric-surgery territory. An interesting part of the story is the dose ladder, where the lowest dose delivered nearly 20% weight loss with an adverse event discontinuation rate that actually fell below placebo. The Trial Spotlight goes into what TRIUMPH-1 confirms and the potential downsides of the top dose. In the Mechanism Explained, I cover how adding a third (potentially counterintuitive) lever, glucagon, lets a triple exceed the best dual agonists in terms of weight loss. Also this week: the Wegovy pill clears CHMP, the last major hurdle before EU approval.
Some interesting things I saw this week: this Wall Street Journal report on early signals that weight-loss drugs may help slow some cancers (paywalled) points to a intriguing, if still observational/preliminary, extension beyond metabolic disease; and the New York Times coverage of new retatrutide data was in line with the big readout of the week (covered below), and also mentioned Lilly’s ongoing suit against the FDA over reclassifying retatrutide as a biologic.
🔥 THIS WEEK’S KEY DEVELOPMENTS
Wegovy pill recommended for approval in the European Union.
Novo Nordisk announced that the EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the Wegovy® pill (once-daily oral semaglutide 25 mg) for weight management in the EU. The recommendation is based on the OASIS 4 trial, where the drug demonstrated a 16.6% mean weight loss, and also includes SELECT data showing a reduction in the risk of major adverse cardiovascular events (MACE). Novo Nordisk plans to launch the pill in select markets outside the US in the second half of 2026.
Press | Trials: NCT05564117 | NCT03574597 | Mechanism: oral GLP-1
Lilly’s retatrutide achieves 28.3% weight loss in Phase 3 trial.
In the Phase 3 TRIUMPH-1 trial, Eli Lilly’s retatrutide met its primary and key secondary endpoints for obesity. At 80 weeks, participants taking the 12 mg dose achieved an average weight loss of 28.3% (70.3 lbs), with 45.3% of participants achieving ≥30% weight loss. Lower doses also delivered strong results, with 25.9% loss at 9 mg and 19% at 4 mg. In a pre-specified extension to 104 weeks, participants with a baseline BMI ≥35 who continued on the 12 mg dose lost an average of 30.3% (85.0 lbs). See the Trial Spotlight below for the full dose-response picture.
Press | Trials: NCT05929066 | Mechanism: GIP, GLP-1, and glucagon triple receptor agonist
📰 PRESS
Mounjaro and Zepbound sales drive Lilly’s 56% Q1 revenue surge.
Press | Mechanism: tirzepatide era
FDA warns Chinese supplier over illegal GLP-1 imports.
Press | Mechanism: GLP-1 receptor agonist
Vincentage oral GLP-1 shows 12.4% weight loss in Phase 3.
Press | Mechanism: oral GLP-1 agonist
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
The 28% Drug, Now With a Dial: What TRIUMPH-1 Confirms and What It Costs
Eli Lilly recently reported eighty-week data from the flagship Phase 3 TRIUMPH-1 trial evaluating retatrutide, a once-weekly investigational GIP, GLP-1, and glucagon triple receptor agonist, across 2,300 adults with obesity or overweight and at least one weight-related comorbidity but without type 2 diabetes. The reason retatrutide can reach efficacy numbers that dual agonists cannot is this novel third lever of glucagon receptor agonism added on top of GIP and GLP-1. Readers should reference this week’s Mechanism Explained for how those three pathways combine.
TRIUMPH-1 confirmed a bariatric-surgery-like 28.3% weight loss at the top 12 mg dose, but its real strategic significance lies in revealing a highly titratable dose-response curve. An intermediate 9 mg dose dropped 25.9%, and a single-step 4 mg dose achieved nearly 20% weight reductions (about 47 pounds) with an adverse event discontinuation rate that actually fell below placebo. This dose ladder reframes the molecule from the “powerful but rough” reputation it acquired after the smaller TRIUMPH-4 osteoarthritis readout late last year, which saw top-dose discontinuation rates hover around 18%, into a much more flexible clinical tool that allows physicians to scale from a highly tolerable tirzepatide-like floor to a maximal-loss ceiling. Comparisons across distinct trial populations are directional rather than a clean head-to-head.
Pushing to that 12 mg ceiling still brings a notable side-effect burden, most distinctly a 12.5% incidence of dysesthesia, the dose-dependent burning or pins-and-needles skin sensitivity signal that remains a class-defining hurdle to watch. This specific rate is notably softer than the 21% incidence reported previously in the TRIUMPH-4 population.
A pre-specified 104-week extension showed even deeper weight loss for patients with a baseline body mass index of 35 or higher. Additional pre-specified analyses highlighted broad cardiovascular risk factor improvements and a substantial share of top-dose participants dropping below the obesity threshold, entirely absent multiplicity control. This primary cohort anchors a massive pipeline program that includes the upcoming TRIUMPH-2 diabetes and TRIUMPH-3 cardiovascular trials scheduled to read out later this year.
ClinicalTrials.gov: NCT05929066 (TRIUMPH-1, retatrutide flagship obesity) | NCT05929079 (TRIUMPH-2, obesity + type 2 diabetes) | NCT05882045 (TRIUMPH-3, established cardiovascular disease) | Lilly press release
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Three Levers at Once: Why GLP-1 / GIP / Glucagon Triple Agonists Reach 28% (Example drugs: Retatrutide, UBT251)
Anchored by this week’s TRIUMPH-1 readout, the clinical profile of retatrutide illustrates why triple hormone receptor agonists can achieve weight loss approaching 28%, pushing past the 16 to 21% ceiling where the best dual agonists currently plateau. They succeed by pairing the well documented energy-in suppression of GLP-1 and GIP with a completely distinct energy-out mechanism driven by the glucagon receptor.
The GLP-1 component functions as the foundational lever to slow gastric emptying and signal satiety to the brain. The GIP component acts synergistically to amplify postprandial insulin release while softening nausea via brainstem pathways. Adding a glucagon receptor target initially sounds biologically backwards, because the hormone natively raises blood sugar to prevent hypoglycemia. But the simultaneous insulin stimulation from both GLP-1 and GIP neutralizes this hyperglycemic risk.
With the glucose-raising effect counterbalanced by parallel insulin pathways, the glucagon component is free to act as a metabolic engine that elevates whole-body resting energy expenditure and directly stimulates hepatic fat oxidation, pulling lipid stores out of liver cells. That yielded the 82% hepatic fat reduction observed during the 24-week Phase 2 trials of retatrutide. Coupling this expenditure and fat mobilization mechanism with appetite suppression explains the efficacy jump, and defines a distinct competitive strategy compared to subtractive dual agonist approaches. Drugs like tirzepatide drop the glucagon lever entirely to simplify development, and alternatives like survodutide, mazdutide, and pemvidutide sacrifice the tolerability buffering of GIP.
Incorporating a third target demands a difficult pharmacological balancing act to optimize the activity ratios so that fat burns without unmasking diabetes, and it introduces extra clinical questions. These are evidenced by glucagon-linked heart rate elevations and a novel, dose-dependent dysesthesia skin sensation, the pins-and-needles burning that surfaced in the retatrutide Phase 3 safety data. Because navigating these trade-offs is complex, the late-stage pipeline remains thin, leaving retatrutide as the solitary Phase 3 asset. A sparse group of followers, notably UBT251 with its roughly 19.7% weight loss at 24 weeks in Phase 2, alongside Hanmi candidates efocipegtrutide for liver disease and HM15275 for diabetes, are attempting to replicate the receptor calibration required to combine intake reduction with enhanced metabolic output.
🆕 NEWLY REGISTERED TRIALS (6 in last week)
HRS9531 Phase 2 trial investigating the efficacy and safety of the oral tablet in participants with type 2 diabetes (Fujian Shengdi Pharmaceutical, n=240).
[Oral Formulations | Safety/Tolerability]
Trials: NCT07599410 | Mechanism: Dual GLP-1/GIP agonist
Berobenatide Phase 3 trial evaluating the efficacy and safety of the drug in adults with overweight or obesity (Pfizer, n=954)
[Weight Loss/Efficacy]
Trials: NCT07595549 | Mechanism: GLP-1 receptor agonist
HDM1002 Phase 1 thorough QT study assessing the drug’s effect on cardiac repolarization in healthy subjects (Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd., n=72)
[Safety/Tolerability]
Trials: NCT07594847 | Mechanism: GLP-1 receptor agonist
Cagrilintide Phase 1 trial comparing blood levels of different formulations in adults with overweight or obesity (Novo Nordisk, n=234)
[Novel Delivery]
Trials: NCT07597018 | Mechanism: Long-acting amylin analog (DACRA)
REGN20934 Phase 1 assessing safety and drug concentrations in adults with overweight or obesity (Regeneron Pharmaceuticals, n=90)
[Safety/Tolerability]
Trials: NCT07594093 | Mechanism: Mechanism not disclosed
Vascular and Neurocognitive Effects of Weight Loss Phase 4 trial investigating the impact of weight loss on blood vessel and brain health (Alain Dagher, n=240)
[Weight Loss/Efficacy]
Trials: NCT07592546 (THRIVE) | Mechanism: GLP-1 receptor agonist
This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.
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