Mortality, Muscle, and a Crowded Tri-Agonist Race
Week Of April 11 – April 17, 2026
This week is dominated by Foundayo. Lilly’s oral GLP-1 hit its cardiovascular primary endpoint in Phase 3 ACHIEVE-4, showing MACE-4 (major adverse cardiovascular events) non-inferiority to insulin glargine plus a 57% reduction in all-cause mortality as a pre-planned secondary in people with type 2 diabetes and elevated CV risk. At the same time, the FDA asked Lilly for a post-marketing safety study on cardiovascular and liver signals from the obesity indication. Both stories will shape how Foundayo gets prescribed. Elsewhere, the tri-agonist race got significantly more crowded. Novo Nordisk is now running two tri-agonist programs in parallel, one in-house (NNC0662-0419) and one licensed from China (UBT251). Hanmi added a new Phase 2. I go into what the post-retatrutide landscape looks like in the Trial Spotlight. The Mechanism Explained covers lean mass preservation during GLP-1 therapy, which got newsworthy this week after a preprint claimed a muscle advantage for semaglutide over tirzepatide.
Separately, PrecisionLife and Ovation announced a pharmacogenomic GLP-1 response test launching in H2 2026 as both a physician-ordered LDT and a consumer DNA product. This follows last week’s 23andMe Nature paper on genetic predictors of GLP-1 response. Whether any of it is clinically actionable yet is an open question, but it’s worth noting that commercial pharmacogenomic stratification is arriving before we have robust clinical guidance.
Some interesting things I was reading this week touched on the breadth of the GLP-1 story. The New York Times piece on how GLP-1 experimentation is outrunning the evidence base was a useful reminder of how quickly these drugs are diffusing into adjacent use cases; I also revisited Daniel Drucker and Maria Gonzalez-Rellan’s review on the expanding benefits of GLP-1 medicines as a helpful frame for how wide the therapeutic conversation has already become.
🔥 THIS WEEK’S KEY DEVELOPMENTS
Lilly’s Foundayo meets CV primary endpoint in Phase 3 ACHIEVE-4 with 57% mortality reduction.
In the Phase 3 ACHIEVE-4 trial, Eli Lilly’s Foundayo (orforglipron) met its primary endpoint of non-inferiority to insulin glargine for major adverse cardiovascular events (MACE-4) in 2,749 adults with type 2 diabetes and elevated cardiovascular risk, with a 16% lower risk numerically (HR 0.84, 95% CI 0.59-1.20). A pre-planned analysis showed a 57% lower risk of all-cause death vs insulin glargine (HR 0.43, 95% CI 0.25-0.75, nominal p=0.002), sustained through 104 weeks alongside superior A1C and body weight reductions. Lilly plans to submit to the FDA for the T2D indication by end of Q2.
Press | Trials: NCT05803421 | Mechanism: oral non-peptide GLP-1 receptor agonist
FDA requests post-marketing safety study on Foundayo obesity indication.
Following the April 1 approval of Foundayo for weight management, the FDA has requested Lilly conduct a postmarketing clinical trial to further assess “serious” cardiovascular and liver safety signals, including unexpected MACE events and drug-induced liver injury (DILI). Lilly will submit the final report from the ongoing ACHIEVE-4 trial, now also assessing for DILI, by July. The request illustrates the tension running through this week: ACHIEVE-4 provides new favorable cardiovascular data, but the FDA’s obesity-indication concern predates ACHIEVE-4 and will take time to fully resolve.
Press | FiercePharma | Mechanism: oral non-peptide GLP-1 receptor agonist
Kailera closes $625M IPO, new benchmark for biotech IPOs.
Kailera Therapeutics closed its IPO at $625 million, the largest biotech IPO of 2026 and a new benchmark for obesity-focused offerings. Proceeds fund Kailera’s quartet of Chinese-origin obesity assets, led by GLP-1/GIP dual agonist ribupatide (KAI-9531, formerly HRS9531, licensed from Hengrui). The IPO tripled its originally targeted ~$200 million raise, reflecting strong investor demand for obesity pipeline exposure and continuing the trend of Chinese-origin metabolic assets entering the Western market.
Press | Mechanism: GLP-1/GIP dual agonist
📰 PRESS
Preprint claims semaglutide has muscle-sparing edge over tirzepatide.
Press | Mechanism: GLP-1 vs GLP-1/GIP dual
Foundayo launches with 1,390 prescriptions in first week, trailing Novo’s oral Wegovy launch pace.
Press | Mechanism: oral GLP-1
Inventors of tirzepatide and tri-agonists propose GIP+glucagon approach that drops GLP-1 entirely.
Richard DiMarchi and Matthias Tschop, the researchers behind semaglutide, tirzepatide, and the tri-agonist concept, published a peer-reviewed draft paper describing a GIP-receptor / glucagon-receptor co-agonist that excludes GLP-1 activity. In rodent and monkey studies, the molecule matched GLP-1-based weight loss while reportedly avoiding the nausea and vomiting profile typical of incretins. A preclinical result, but notable given the authors.
Novo Nordisk and OpenAI partner on AI for R&D, manufacturing, and corporate functions.
Press | Mechanism: AI/drug discovery
PrecisionLife and Ovation to launch GLP-1 pharmacogenomic stratification test in H2 2026.
A physician-ordered LDT and consumer DNA product aimed at predicting individual response to GLP-1 therapies. Builds on last week’s 23andMe Nature paper on genetic predictors of response.
Press | Mechanism: pharmacogenomics
Q1 2026 obesity-sector dealmaking already exceeds full-year 2025 total.
Press | Mechanism: market dynamics
FDA Pharmacy Compounding Advisory Committee to consider broader access to certain peptides (meeting Feb 2027).
Press | Mechanism: regulatory
USP adds Trulicity (dulaglutide) to vulnerable drug list over supply risks.
Press | Mechanism: supply chain
Lilly investing billions to prepare for overseas oral Foundayo launches.
Press | Mechanism: oral GLP-1
FDA issues 15+ warning letters to online pharmacies and compounding sites for unlawful sale of compounded semaglutide and tirzepatide.
Targets included Hims & Hers (Hers brand), Remedy Meds, SemaBio, and others. Published this week although dated 9/9/2025.
Example FDA letter | Mechanism: enforcement
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
Four Tri-Agonists, Two from Novo: Why the Post-Retatrutide Landscape Is More Crowded Than It Looks
Novo Nordisk’s initiation of a 45-patient Phase 1 drug-drug interaction study (NCT07525791) evaluating NNC0662-0419 alongside oral contraceptives is a meaningful structural signal that the company is preparing for broad Phase 3 populations, highlighting how fiercely contested the GLP-1 / GIP / glucagon tri-agonist race has become. By layering glucagon receptor agonism onto the established dual GLP-1 / GIP mechanism, these unimolecular compounds aim to drive higher weight loss via increased energy expenditure and hepatic lipid oxidation, though developers must carefully calibrate dosing to balance the thermogenic upside against glucagon’s tendency to raise hepatic glucose output. Eli Lilly’s retatrutide proved the viability of this biology by achieving up to 24.2% weight loss at 48 weeks in Phase 2, and the compound is now years ahead with over 13 active Phase 3 trials, including the massive 10,000-patient TRIUMPH-Outcomes study completing in early 2029.
What makes the current landscape strategically fascinating is Novo Nordisk’s deliberate decision to pursue a dual-track hedge to catch up; alongside NNC0662-0419’s expanding Phase 2 obesity and type 2 diabetes program, Novo is simultaneously advancing UBT251, a licensed tri-agonist that recently beat semaglutide on HbA1c reductions in a Chinese Phase 2 trial. With other competitors like Hanmi Pharmaceutical also launching concurrent mid-stage trials for their own candidate, HM15275, the tri-agonist class has rapidly evolved in under 18 months from a differentiated moonshot into a crowded space where companies are aggressively hedging their pipelines to secure the next frontier of twenty-percent-plus weight loss.
ClinicalTrials.gov: NCT07525791 (NNC0662-0419 DDI) | NCT07184632 (NNC0662-0419 Phase 2 Obesity) | NCT07395687 (UBT251 Phase 2 Obesity) | NCT06383390 (TRIUMPH-Outcomes) | NCT07527650 (HM15275 Phase 2 T2D)
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Lean Mass and GLP-1s: Sorting Signal from Narrative (Example drugs: Cagrilintide, Bimagrumab, Enobosarm)
The profound weight loss achieved with GLP-1 receptor agonists has surfaced a critical secondary concern: 25 to 40% of the total weight lost is typically fat-free lean mass, including skeletal muscle. A March 2026 meta-analysis in Diabetes, Obesity and Metabolism (20 RCTs, ~15,800 patients) was clarifying: incretins don’t cause disproportionate muscle wasting versus lifestyle-induced weight loss of similar magnitude. The absolute muscle loss is simply larger because GLP-1 drugs produce much more total weight loss. The real differentiator is exercise; resistance training cut lean mass loss to 17.5% of total weight lost, versus roughly 26% for both drugs and diet alone. Clinically, the concern is not the raw DEXA number but functional capacity, particularly in older patients and in those already at risk of obesity-related sarcopenia.
The pharmacological response is organized around two strategies. The first is amylin-based co-therapy: cagrilintide (in CagriSema) and Amgen’s maridebart cafraglutide are thought to spare muscle by regulating central appetite without the same degree of gut-motility-driven protein intake suppression seen with GLP-1 monotherapy. To formally test this “amylin signature” hypothesis, Novo Nordisk registered the Phase 1 RASMUS study this week, directly comparing CagriSema to its individual components. The second strategy targets muscle-anabolic pathways directly: Lilly’s bimagrumab (acquired via Versanis) is an activin type II receptor antagonist blocking myostatin and activin A signaling to drive muscle growth; Veru’s enobosarm is a selective androgen receptor modulator, now in the PLATEAU Phase 2 after the QUALITY Phase 2 completed last year; and Roche’s anti-myostatin emugrobart continues in obesity after discontinuing last month for spinal muscular atrophy. A preprint this week drew “Novo muscle advantage” headlines by reporting that semaglutide patients retained more lean mass than tirzepatide patients, though that observational comparison is confounded by the substantially larger weight loss under tirzepatide. Whether any amylin analog is intrinsically muscle-sparing or just benefits from lower overall weight loss, and whether expensive anti-myostatin monoclonals can justify their cost against plain resistance training, are the outstanding questions that these muscle-focused trials will need to answer.
ClinicalTrials.gov: NCT07527195 (RASMUS) | NCT06643728 (Bimagrumab + Tirzepatide) | NCT07446998 (Enobosarm PLATEAU) | Novo muscle preprint coverage
🆕 NEWLY REGISTERED TRIALS (10 in last week)
Elecoglipron Phase 1 drug-drug interaction study assessing its effect on rosuvastatin and atorvastatin in healthy participants (AstraZeneca, n=40)
[Safety/Tolerability]
Trials: NCT07534592 | Mechanism: oral non-peptide GLP-1 receptor agonist
AMAZE 2 Phase 3 investigating NNC0487-0111 (amycretin) for weight loss in adults with excess body weight and type 2 diabetes (Novo Nordisk, n=630)
[Weight Loss/Efficacy]
Trials: NCT07533175 (AMAZE 2) | Mechanism: GLP-1 + amylin combination
SYH2082 Phase 1 first-in-human single ascending dose study in healthy participants (CSPC ZhongQi Pharmaceutical, n=44)
[Safety/Tolerability]
Trials: NCT07532655 | Mechanism: Dual GLP-1/GIP agonist
NNC0662-0419 Phase 1 drug-drug interaction study assessing oral contraceptives and gastric emptying in women with excess body weight (Novo Nordisk, n=45)
[Safety/Tolerability]
Trials: NCT07525791 | Mechanism: GLP-1 / GIP / glucagon tri-agonist
HM15275 Phase 2 evaluating the drug in patients with type 2 diabetes (Hanmi Pharmaceutical, n=180)
[Weight Loss/Efficacy | New Indications]
Trials: NCT07527650 | Mechanism: GLP-1 / GIP / glucagon tri-agonist
Maridebart cafraglutide Phase 1 drug-drug interaction study assessing absorption of oral contraceptives in postmenopausal women with overweight or obesity (Amgen, n=45)
[Safety/Tolerability]
Trials: NCT07523711 | Mechanism: GLP-1 agonist + GIP antagonist (antibody-peptide conjugate)
HDM1005 Phase 2 head-to-head trial versus tirzepatide in adults with obesity without diabetes (Hangzhou Zhongmei Huadong Pharmaceutical, n=372)
[Weight Loss/Efficacy | Safety/Tolerability]
Trials: NCT07521631 | Mechanism: Dual GLP-1/GIP agonist
ALN-PNP Phase 2a evaluating the drug alone and in combination with a GLP-1R agonist in patients with homozygous PNPLA3-related MASLD (Regeneron/Alnylam, n=204)
[New Indications]
Trials: NCT07527910 | Mechanism: RNAi therapeutic (PNPLA3 silencing), with GLP-1 combination arm
HASHTAG Phase 2 evaluating semaglutide in adults with Cannabis Use Disorder (Rigshospitalet / University of Copenhagen, n=100)
[New Indications]
Trials: NCT07523633 (HASHTAG) | Mechanism: GLP-1 receptor agonist
RASMUS Phase 1 evaluating CagriSema vs individual components (cagrilintide and semaglutide) on muscle health (Novo Nordisk, n=100)
[Safety/Tolerability]
Trials: NCT07527195 (RASMUS) | Mechanism: GLP-1 + amylin combination
This newsletter compiles publicly available information from press releases, news sources, and trial registries. Not investment advice.
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