Eloralintide

What is Eloralintide?

Eloralintide (LY3841136) is a once-weekly, selective amylin receptor agonist developed by Eli Lilly. Amylin is a hormone co-secreted with insulin from pancreatic beta cells that promotes satiety and slows gastric emptying — similar to GLP-1 but through a distinct receptor pathway. Eloralintide's selectivity for the amylin receptor (rather than also activating calcitonin receptors) and its long half-life of approximately two weeks contribute to improved tolerability compared to older amylin analogs like pramlintide. In Phase 2 trials published in The Lancet, eloralintide achieved up to 20% body weight loss at 48 weeks — rivaling tirzepatide — with a side effect profile notable for fatigue rather than the severe nausea typical of GLP-1 drugs. The Phase 3 ENLIGHTEN program began with ENLIGHTEN-2 in type 2 diabetes (NCT07282600, December 2025) and expanded in February 2026 to ENLIGHTEN-1 in obesity without diabetes (NCT07321886), ENLIGHTEN-3 in obstructive sleep apnea (NCT07369011, 800 patients, primary completion March 2028; co-primary measures are body weight change and AHI (apnea-hypopnea index) change at week 64), ENLIGHTEN-4 in knee osteoarthritis pain (NCT07353931), and ENLIGHTEN-6 in people with persistent obesity on a weekly incretin (NCT07392190). Lilly is running two combination tracks. With tirzepatide, the 48-week Phase 2b of 'EloraTZP' (NCT06603571; 367 adults with obesity or overweight and type 2 diabetes) reported in September 2026 up to 23.3% weight loss with eloralintide 9 mg + tirzepatide 15 mg vs 14.8% with tirzepatide 15 mg alone (efficacy estimand), and the Phase 3 programme for the co-formulation (internally LY900043) is now registered and under way as AMPLIFY-2 (NCT07881458), which began recruiting on 16 October 2026 in obesity or overweight with type 2 diabetes, with AMPLIFY-1 (NCT07881432) to follow in obesity without diabetes. With Lilly's own macupatide — a long-acting GIP receptor agonist, not a dual GIP/GLP-1 agent — two Phase 2 trials are under way (NCT07215559, now closed to enrollment, and NCT07589608).

What Eloralintide Is Investigated For

Eloralintide is investigated primarily for weight management in overweight and obese adults, with a pharmacological story built around selective amylin receptor agonism — a distinct pathway from the GLP-1/GIP mechanisms of semaglutide and tirzepatide. The strongest evidence is the Phase 2 trial published in The Lancet (263 participants, 48 weeks, 46 US sites) showing dose-dependent weight loss from 9% at 1 mg to 20% at 9 mg — a magnitude rivaling tirzepatide — along with cardiometabolic improvements across all doses. The Phase 3 ENLIGHTEN-3 program began February 2026 (NCT07369011, 800 patients, primary completion March 2028) and notably tests eloralintide in obesity-plus-OSA with dual co-primary endpoints (body weight change and AHI change at week 64). The honest caveats remain substantial: long-term safety beyond 48 weeks is uncharacterized, no cardiovascular outcomes trial exists, and the combination data are still early — the 48-week EloraTZP Phase 2b with tirzepatide (NCT06603571) showed up to 23.3% weight loss vs 14.8% for tirzepatide 15 mg in obesity plus type 2 diabetes, but with more GI adverse events and higher adverse-event discontinuation in the combination arms, and the parallel combination with Lilly's in-house GIP receptor agonist macupatide (NCT07215559, NCT07589608) is still in Phase 2. The tolerability differentiation claim — fatigue rather than severe nausea — is supported but not absolute, with dose-dependent nausea still present at 6–9 mg arms. Eloralintide is a promising investigational compound, not an available therapy, and FDA approval would not be expected before 2028–2029 if Phase 3 succeeds.

History & Discovery

Eloralintide (LY3841136) was developed at Eli Lilly as a long-acting, selectivity-engineered amylin receptor agonist intended to overcome the limitations of pramlintide — the first-generation amylin analog approved in 2005, whose mealtime dosing burden, mixed amylin/calcitonin receptor activity, and amyloid aggregation tendencies limited adoption. The discovery program is described in a 2025/2026 paper covering the medicinal-chemistry optimization that yielded improved AMY1 receptor selectivity over the calcitonin receptor and a half-life supporting once-weekly dosing. Lilly published Phase 1 proof-of-concept in Diabetes, Obesity and Metabolism, followed by a 48-week Phase 2 trial in The Lancet (263 participants, 46 US sites) showing dose-dependent weight loss reaching approximately 20% at the 9 mg dose. The Phase 3 ENLIGHTEN program began with ENLIGHTEN-2 in type 2 diabetes (NCT07282600) in December 2025 and widened in February 2026 to ENLIGHTEN-1 (obesity without diabetes), ENLIGHTEN-4 (knee osteoarthritis pain), ENLIGHTEN-6 (persistent obesity on a weekly incretin) and ENLIGHTEN-3 (NCT07369011, 800 participants), which has co-primary endpoints of body weight change and apnea-hypopnea index change at week 64 in adults with obesity and moderate-to-severe obstructive sleep apnea, with primary completion targeted March 2028. The combination strategy runs on two tracks. The eloralintide-plus-tirzepatide Phase 1 combination (NCT06916065) completed in January 2026, and the 48-week Phase 2b of the pairing, branded EloraTZP (NCT06603571, 367 adults with obesity or overweight and type 2 diabetes), was presented at EASD on September 30, 2026: up to 23.3% weight loss vs 14.8% with tirzepatide 15 mg alone (efficacy estimand). The co-formulation, LY900043, moved into Phase 3 the following month: AMPLIFY-2 (NCT07881458) began recruiting on 16 October 2026, pairing EloraTZP against tirzepatide in 1,000 adults with type 2 diabetes over a 100-week primary endpoint, with AMPLIFY-1 (NCT07881432) registered in 2,115 adults without diabetes. In parallel, Lilly is testing eloralintide with macupatide, its in-house long-acting GIP receptor agonist, in two Phase 2 trials (NCT07215559 and NCT07589608) — stacking complementary metabolic mechanisms inside its own pipeline. Macupatide is a GIPR mono-agonist rather than a dual incretin: a Phase 1b deliberately paired it against dulaglutide precisely to separate GIP from GLP-1 effects.

How It Works

Eloralintide mimics amylin, a natural hormone your pancreas releases alongside insulin after meals. Amylin tells your brain you're full and slows down stomach emptying. As a selective amylin receptor agonist, eloralintide activates this satiety signal without triggering related calcitonin receptors — which may explain why it's better tolerated than older amylin drugs.

Eloralintide is an AMY1-preferring amylin receptor agonist. Amylin receptors are the calcitonin receptor (CTR) complexed with receptor activity-modifying proteins (RAMPs), giving the AMY1, AMY2 and AMY3 subtypes. The discovery work is more specific than the usual description: eloralintide preferentially activated human AMY1R by 12-fold over the calcitonin receptor and 11-fold over AMY3R, with roughly 8-fold higher binding affinity at AMY1R than at either. Two nuances matter. The selectivity is one of potency, not efficacy — eloralintide reaches full agonism (Emax above 80%) at all three human receptors. And the profile is species-dependent: in rats both AMY1R and AMY3R are activated more potently than CTR, so rodent tolerability results do not map cleanly onto humans. Structurally it is a 37-amino-acid analog with three non-coded residues, the native disulfide replaced by a methylene thioacetal bridge, and Lys26 acylated with a two-γ-glutamate linker and a C20 fatty diacid that binds albumin to give a terminal half-life of roughly 310 to 366 hours, or about two weeks. Amylin receptors in the area postrema and nucleus tractus solitarius mediate satiety signaling, slowed gastric emptying, and suppressed postprandial glucagon secretion. Eloralintide's engineered long half-life (~2 weeks) enables once-weekly subcutaneous dosing. Phase 2 data (263 participants, 48 weeks) showed dose-dependent weight loss: -9% (1 mg), -12% (3 mg), -18% (6 mg), and -20% (9 mg) vs -0.4% placebo, with improvements in waist circumference, blood pressure, lipid profiles, glycemic control, and inflammatory markers. Phase 1 (100 participants, 12 weeks) confirmed dose-proportional pharmacokinetics with 2.6-11.3% weight loss.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Eloralintide:

• 01Cardiovascular outcomes — no cardiovascular outcomes trial has been conducted for eloralintide or for any amylin receptor agonist, so whether the class reduces MACE is unknown. ENLIGHTEN-10 (NCT07900633) will enroll 3,000 people with type 2 diabetes and increased cardiovascular risk from December 2026, but its co-primary endpoints are body weight at week 64 and HbA1c at week 36 — not MACE — so it is a CV-risk-enriched efficacy trial rather than a CVOT, a distinction worth keeping straight as the result is reported.
• 02Long-term safety and efficacy beyond 48 weeks — Phase 3 data will be the first to characterize multi-year exposure.
• 03Body composition effects — no dedicated sub-study on lean mass preservation, bone density or resistance-training mitigation has been published. The preclinical work and an independent 2026 review both describe preferential fat mass loss, which is encouraging but is not the same as a human DXA sub-study, and the resistance-training question is entirely open.
• 04Combination pharmacology — the EloraTZP Phase 2b (NCT06603571) showed additive weight loss with tirzepatide (up to 23.3% vs 14.8%) but higher adverse-event discontinuation (10.8–27.0% vs 2.9%), and it has not yet been peer-reviewed. Whether the optimized escalation schedule planned for the Phase 3 co-formulation narrows that tolerability gap, and whether the parallel macupatide combination (NCT07215559, NCT07589608) performs differently, are open questions.
• 05Effects in T1D and advanced T2D, where pramlintide has the strongest historical evidence base — eloralintide's selectivity profile may or may not preserve those benefits.
• 06Direct head-to-head comparisons with petrelintide, cagrilintide, and the GLP-1 class.
• 07Response variability and predictors — Phase 2 reported mean weight loss, but the distribution of individual responses, the proportion of high responders versus non-responders, and any baseline predictors (BMI, sex, ethnicity, baseline metabolic markers) of response have not been characterized.
• 08OSA-specific efficacy independent of weight loss — ENLIGHTEN-3's apnea-hypopnea index co-primary endpoint will help disentangle whether amylin signaling contributes to airway physiology beyond the indirect effect of fat mass reduction.

Forms & Administration

Eloralintide is administered as a once-weekly subcutaneous injection. Phase 2 tested doses from 1 mg to 9 mg with various escalation schedules. Slower dose escalation (3 mg → 9 mg) improved tolerability compared to starting at higher doses. It is currently only available through clinical trials.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

Eloralintide is investigational and not approved by the FDA or any other regulatory authority. The doses cited reflect clinical trial protocols rather than prescribing guidance. Use outside an authorized trial carries unquantified risk.

Timeline of Effects

Monitoring & Measurement

Common Questions

Who Eloralintide Is NOT For

Drug & Supplement Interactions

Documented drug-interaction data for eloralintide in humans are still limited, but this is actively changing: Lilly has four dedicated Phase 1 studies under way covering the exact questions the class raises — co-administration with acetaminophen as the standard gastric-emptying and oral-absorption probe (NCT07738614), co-administration with a combined oral contraceptive (NCT07808060), and pharmacokinetics in hepatic (NCT07401862) and renal (NCT07426380) impairment. Until those report, the class-level interactions known from pramlintide remain the best proxies. The class-level interactions known from pramlintide and from broader appetite-suppressing peptides are the best available proxies. Insulin and insulin secretagogues materially raise hypoglycemia risk when combined with amylin agonists, and downward titration of those agents at eloralintide initiation is the expected mitigation. Slowed gastric emptying alters absorption rate and peak concentrations of orally administered medications, with particular relevance for narrow-therapeutic-index agents (warfarin, levothyroxine, oral contraceptives, antiepileptics, and oral antibiotics). The EloraTZP Phase 2b with tirzepatide reported more GI adverse events in the combination arms than with either drug alone, and the Phase 3 co-formulation program will characterize dual-agent pharmacology further; combined use outside a trial is not appropriate. Anyone enrolling in an eloralintide trial while taking chronic medication should disclose all concurrent agents to the trial team.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions