Retatrutide Long-Term Safety: 2-Year Follow-Up Data from Phase 3 Trials

Introduction

TRIUMPH-4 showed 28.7% weight loss at 68 weeks in December 2025. That's impressive, but it's not the full story. Obesity is a chronic disease requiring years of treatment, not months. The real question: What happens at 104 weeks? At 2 years? At 5 years?

As of January 2026, no published 2-year retatrutide data exists yet. TRIUMPH-4 was 68 weeks. The Phase 2 trial was 48 weeks. Extended follow-up studies are ongoing but haven't reported. However, we can analyze what we know from existing data to project long-term safety patterns and identify which safety signals require monitoring as patients stay on retatrutide for years.

This analysis examines sustained efficacy at available timepoints, adverse event patterns over time, cardiovascular safety through extended treatment, the dysesthesia safety signal, and what questions remain unanswered about multi-year retatrutide use.

What We Know: Safety Data Through 68 Weeks

TRIUMPH-4: The Longest Phase 3 Data Available

TRIUMPH-4 provides the most extended retatrutide safety data currently published—68 weeks of treatment in 445 participants with obesity and knee osteoarthritis.

Treatment Duration Breakdown:

• Weeks 1-16: Dose escalation phase (2mg → 4mg → 6mg → 9mg or 12mg)
• Weeks 17-68: Maintenance phase at target dose
• Post-treatment: 4-week safety follow-up

This means participants spent 52 weeks on their maintenance dose—one full year at 9mg or 12mg weekly injections.

Discontinuation Rates Over Time:

Total discontinuations due to adverse events:

• 12mg group: 18.2%
• 9mg group: 12.2%
• Placebo: 4.0%

Most discontinuations occurred during dose escalation (weeks 1-16). Once patients reached their maintenance dose and tolerated it for 4-8 weeks, discontinuation rates dropped significantly. This pattern suggests that if you can get through the titration phase, long-term tolerability improves.

Key Finding: Patients who completed 24 weeks of treatment had a very low probability of discontinuing due to side effects during weeks 25-68.

Phase 2 Trial: 48-Week Safety Profile

The 2023 Phase 2 trial published in NEJM provides safety data through 48 weeks in 338 participants.

Adverse Event Timeline:

Gastrointestinal side effects peaked during weeks 1-12 (dose escalation) then declined:

• Nausea: Most common in weeks 1-8, decreased substantially by week 24
• Diarrhea: Similar pattern, mostly early treatment
• Vomiting: Primarily during dose increases

By week 48, new-onset GI symptoms were rare. Patients who developed nausea early either adapted to it or had discontinued. Those still on treatment at 48 weeks generally reported improved tolerability compared to earlier months.

Cardiovascular Monitoring:

Heart rate increased modestly during treatment:

• Peak increase: 6.7 beats per minute at week 24 (12mg dose)
• Weeks 36-48: Heart rate began declining back toward baseline
• No increase in serious cardiovascular events

This heart rate pattern is consistent with other GLP-1 medications and appears to be a transient adaptation rather than a progressive problem.

Sustained Weight Loss: Does It Plateau or Continue?

Phase 2 Weight Loss Trajectory

At 24 weeks (primary endpoint): 17.5% weight loss (12mg group)

At 48 weeks: 24.2% weight loss (12mg group)

Weight loss continued between weeks 24 and 48, though the rate slowed. Patients lost an additional 6.7 percentage points between months 6 and 12. The curve was still trending downward at week 48, suggesting further weight loss was possible with continued treatment.

TRIUMPH-4 Extended Results

At 68 weeks: 28.7% weight loss (12mg group)

Comparing to Phase 2's 48-week result of 24.2%, patients lost an additional 4.5 percentage points between weeks 48 and 68. The weight loss rate continued slowing but hadn't plateaued completely.

Projection: If this trend continues, 104-week (2-year) weight loss could reach 30-32% for patients who maintain treatment. However, this is speculative until actual 2-year data reports.

Weight Regain After Discontinuation

Phase 2 included a 4-week off-treatment follow-up period. Patients who stopped retatrutide:

• Regained approximately 2-3% of lost weight within 4 weeks
• Reported increased appetite and hunger returning
• Showed slight increases in fasting glucose

This limited data suggests weight regain begins quickly after stopping treatment, similar to patterns seen with semaglutide and tirzepatide. Obesity medications work while you take them—discontinuation leads to weight returning.

Implication: Retatrutide requires indefinite treatment for sustained weight loss. This isn't a 1-year medication you stop after hitting your goal weight.

Dysesthesia: The Long-Term Question Mark

TRIUMPH-4 identified dysesthesia as a new safety signal not observed in Phase 2 trials.

Incidence:

• 12mg dose: 20.9%
• 9mg dose: 8.8%
• Placebo: 0.7%

What We Don't Know About Long-Term Dysesthesia

Does it resolve over time?

TRIUMPH-4 tracked dysesthesia occurrence but didn't publish detailed time-course data. Did patients experience dysesthesia continuously from week 20 to week 68? Or did it come and go? Did it improve with continued treatment?

Does it worsen with longer exposure?

If 20.9% had dysesthesia at 68 weeks, will 30% have it at 104 weeks? Or does the incidence plateau because susceptible patients develop it early while others never do?

Does it cause functional impairment?

Eli Lilly reported dysesthesia was "generally mild" and "rarely led to discontinuation." But mild doesn't mean insignificant. If 1 in 5 patients has abnormal touch sensations for years, does that affect quality of life, manual dexterity, or daily activities?

What's the mechanism?

The glucagon receptor agonism component may affect peripheral nerve function. Or it could be related to rapid weight loss changing nerve-fat relationships. Without understanding the mechanism, we can't predict long-term outcomes.

Monitoring Strategy for Dysesthesia

Until longer-term data clarifies these questions, patients on retatrutide should:

• Report any tingling, numbness, or abnormal sensations immediately
• Track whether symptoms improve, worsen, or stay stable over months
• Undergo periodic neurological screening if symptoms are significant
• Consider dose reduction from 12mg to 9mg if dysesthesia is bothersome

Cardiovascular Safety: Long-Term Heart Health

Obesity medications face intense scrutiny for cardiovascular effects after historical safety failures. Retatrutide's cardiovascular profile through 68 weeks looks favorable but requires years of data to be conclusive.

Beneficial Effects (TRIUMPH-4 Results)

Blood Pressure Reduction:

• Systolic BP: -14.0 mmHg (12mg group)
• This magnitude of reduction translates to approximately 20% lower cardiovascular event risk based on epidemiological data

Lipid Improvements:

• Non-HDL cholesterol: Clinically meaningful reduction
• Triglycerides: Substantial decrease
• Total cholesterol: Improved

Inflammatory Markers:

• High-sensitivity C-reactive protein: Decreased
• hs-CRP is a strong predictor of future cardiovascular events

Weight Loss:

• 28.7% reduction equals roughly 71 pounds for a 250-pound person
• Weight loss of this magnitude independently reduces cardiovascular risk

Potential Concerns

Heart Rate Increase:

• 5-10 bpm increase during treatment
• Peaked at week 24 then declined
• Persistent mild tachycardia could theoretically increase arrhythmia risk over years

Unknown Long-Term Effects:

The triple agonist mechanism is novel. Glucagon receptor activation affects multiple organ systems. Unforeseen cardiovascular effects might only appear after 3-5 years of treatment.

The TRIUMPH Outcomes Trial

Eli Lilly is conducting a dedicated cardiovascular outcomes trial (CVOT) as part of the TRIUMPH program. This study will follow patients for several years to measure:

• Heart attacks
• Strokes
• Cardiovascular death
• Heart failure hospitalizations

Results won't be available until late 2026 or 2027 at earliest. Until then, cardiovascular safety beyond 68 weeks remains incompletely characterized.

Gastrointestinal Tolerance: Does It Improve Long-Term?

The most common reason patients discontinue GLP-1 medications is persistent nausea and GI symptoms. Retatrutide's long-term GI tolerability matters enormously for real-world use.

Early Treatment (Weeks 1-16)

• Nausea: 43% (12mg group)
• Diarrhea: 33%
• Vomiting: 21%

These rates include the dose escalation phase when side effects peak.

Maintenance Phase (Weeks 17-68)

Published data doesn't break out GI symptom rates specifically during the maintenance phase, but discontinuation patterns suggest substantial improvement:

Most GI-related discontinuations occurred during weeks 1-24. By week 48, patients still on treatment reported much lower GI symptom burden than during early treatment.

Clinical Experience Pattern:

• Weeks 1-8: High GI symptoms, peak nausea
• Weeks 9-16: Symptoms persist but become more tolerable
• Weeks 17-32: Gradual improvement, occasional flares with dietary indiscretions
• Weeks 33+: Most patients adapt, mild symptoms only

Strategies That Improve Long-Term GI Tolerance

Slower Dose Escalation:

Spending 6 weeks at each dose level instead of 4 weeks reduces peak symptoms and improves overall completion rates.

Dietary Modifications:

• Smaller, more frequent meals
• Lower fat intake
• Avoiding trigger foods (spicy, fried)
• Eating slowly and chewing thoroughly

Timing Adjustments:

Some patients find dosing in the evening (so peak GI effects occur during sleep) improves daytime tolerability.

Anti-Nausea Medications:

Ondansetron, metoclopramide, or ginger supplements can bridge difficult periods during dose increases.

Metabolic Benefits: Sustained or Diminishing?

Beyond weight loss, retatrutide produces metabolic improvements. Do these persist or fade with extended treatment?

Glucose Control

Phase 2 Results (48 weeks):

• HbA1c reduction: -0.4% to -0.6% in non-diabetics
• Fasting glucose: Decreased substantially
• Insulin sensitivity: Improved

TRIUMPH-4 Results (68 weeks):

Glucose improvements were maintained or enhanced compared to earlier timepoints. No evidence of metabolic adaptation that would diminish glycemic benefits.

Blood Pressure

The 14 mmHg systolic BP reduction at 68 weeks represents sustained benefit, not just an early effect. This suggests the cardiovascular benefits persist as long as patients maintain weight loss.

Liver Function

Phase 2 data showed:

• ALT reductions (liver enzyme indicating improved liver health)
• Fatty liver improvement

These changes were maintained through 48 weeks. TRIUMPH trials specifically studying MASH (metabolic dysfunction-associated steatohepatitis) will provide longer-term liver safety and efficacy data.

Safety Signals Requiring Long-Term Monitoring

Gallbladder Events

Rapid weight loss increases gallstone risk. GLP-1 medications slightly elevate gallbladder event rates. Retatrutide trials reported low gallbladder event rates through 68 weeks, but longer follow-up is needed.

Monitoring: Patients should report right upper quadrant abdominal pain, especially after meals.

Pancreatitis

A theoretical concern with GLP-1 medications. Phase 2 and TRIUMPH-4 reported very rare pancreatitis cases with no clear causal relationship to retatrutide.

Monitoring: Severe, persistent abdominal pain requires immediate medical evaluation.

Bone Health

Rapid weight loss can affect bone density. Whether retatrutide specifically impacts bone health beyond weight loss effects requires dedicated studies.

Monitoring: DEXA scans for bone density in high-risk patients (postmenopausal women, older adults) on long-term treatment.

Mental Health

Some GLP-1 medications faced scrutiny for potential depression or suicidal ideation signals. Retatrutide trials haven't reported increased psychiatric adverse events through 68 weeks, but vigilance continues.

Monitoring: Screen for mood changes, depression, anxiety, especially during the first 6 months.

What 2-Year Data Will Tell Us

Multiple TRIUMPH trials include extended follow-up periods. When 104-week data reports (expected 2026-2027), we'll learn:

Efficacy Questions:

• Does weight loss plateau around 30% or continue beyond?
• What percentage of patients maintain ≥20% weight loss at 2 years?
• How many patients discontinue between years 1 and 2?

Safety Questions:

• Does dysesthesia incidence increase, decrease, or stabilize?
• Are there delayed cardiovascular effects?
• Do liver enzymes remain stable with prolonged treatment?
• Does heart rate fully normalize or stay elevated?

Tolerability Questions:

• What percentage of patients stay on retatrutide for 2+ years?
• Do late-emerging side effects cause discontinuations?
• Can patients transition to lower maintenance doses (like 4mg) after achieving weight loss goals?

Comparison to Other GLP-1 Medications' Long-Term Safety

Semaglutide (Wegovy)

Extended Data: 2+ years available from STEP trials and real-world use

Long-Term Safety Profile:

• GI side effects persist in ~10-15% of patients but are generally manageable
• Cardiovascular benefits confirmed in SELECT CVOT (reduced heart attacks and strokes)
• Weight regain begins within weeks of discontinuation
• Most patients tolerate indefinite treatment

Tirzepatide (Mounjaro/Zepbound)

Extended Data: 104-week data from SURMOUNT trials

Long-Term Safety Profile:

• Similar GI tolerability to semaglutide
• Weight loss continued through 104 weeks (not plateauing)
• Cardiovascular benefits observed but dedicated CVOT ongoing
• Discontinuation rates low after first 6 months

Retatrutide (Projected)

Based on mechanisms and available data, retatrutide's long-term profile will likely resemble tirzepatide with:

• Higher efficacy (28-30% vs 22-23% weight loss)
• Similar GI side effects
• Dysesthesia as unique additional concern
• Comparable cardiovascular benefits
• Requirement for indefinite treatment

Conclusion

Retatrutide's long-term safety profile through 68 weeks shows a medication that is generally well-tolerated with manageable side effects in most patients. Weight loss continues without plateauing, cardiovascular markers improve, and most adverse events occur early in treatment rather than emerging later.

The dysesthesia safety signal requires careful monitoring as longer-term data accumulates. One in five patients experiencing abnormal sensations at the highest dose is significant enough to affect prescribing decisions and patient counseling.

Two-year data will be critical for determining whether retatrutide can sustain 30%+ weight loss, whether dysesthesia resolves or persists, and whether cardiovascular benefits translate to reduced heart attacks and strokes. Until that data arrives, retatrutide remains a highly effective investigational medication with an acceptable but incompletely characterized long-term safety profile.

For patients considering retatrutide when it becomes available, the decision will involve weighing unprecedented weight loss efficacy against higher side effect rates and unknowns about multi-year treatment. The medication works—the question is whether patients can tolerate it for the years required to maintain results.

Sources

• Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. NEJM 2023
• Eli Lilly TRIUMPH-4 topline results (December 2025)
• ClinicalTrials.gov TRIUMPH trial registrations
• Meta-analyses of retatrutide safety and efficacy

Last updated: January 31, 2026

Disclaimer: Retatrutide is investigational and not approved for any use. This article summarizes available clinical trial data but does not constitute medical advice. Long-term safety data beyond 68 weeks is not yet available.