What you need to know about Eli Lilly's investigational oral GLP-1 and how it compares to injectable therapies

The landscape of weight loss medication is shifting from needles to pills. While Novo Nordisk's oral Wegovy received FDA approval in December 2025, Eli Lilly's orforglipron is making headlines as a potential game-changer in the oral GLP-1 space. Here's what the latest clinical data tells us about this investigational medication and what it means for your health.

What is Orforglipron?

Orforglipron is an investigational once-daily oral GLP-1 receptor agonist developed by Eli Lilly. Unlike currently available oral semaglutide (which uses the same molecule as injectable Wegovy), orforglipron represents an entirely new molecular approach—it's a small molecule, non-peptide compound that works differently from traditional GLP-1 medications.

Current FDA Status: Orforglipron is not yet FDA approved. Eli Lilly submitted a New Drug Application (NDA) to the FDA in late 2025 and received a "Commissioner's National Priority Voucher," which expedites the review process. This means FDA approval could come within weeks to months, rather than the standard 6-10 month timeline. The company anticipates potential approval in 2026.

How Orforglipron Compares to Injectable GLP-1s

Weight Loss Efficacy

Orforglipron's Performance:

• 12.4% average weight loss at highest dose (36mg) over 72 weeks in the ATTAIN-1 trial

• 59.6% of participants achieved >10% weight loss

• 39.6% achieved >15% weight loss

How It Stacks Up:

• Injectable semaglutide (Wegovy): ~16.9% weight loss

• Injectable tirzepatide (Zepbound): 15-22% weight loss

• Oral semaglutide 25mg: 16.6% weight loss over 64 weeks

The Reality: Orforglipron produces less total weight loss than injectable options or the high-dose oral semaglutide, but it still delivers clinically meaningful results comparable to injectable liraglutide (9.2% weight loss).

Head-to-Head: Orforglipron vs. Oral Semaglutide

In the ACHIEVE-3 trial—a direct comparison study—orforglipron demonstrated superior results:

Weight Loss:

• Orforglipron 36mg: 19.7 lbs (9.2%)

• Oral semaglutide 14mg: 11.0 lbs (5.3%)

• 73.6% greater relative weight loss with orforglipron at the highest dose

Blood Sugar Control (A1C reduction):

• Orforglipron 36mg: -2.2%

• Oral semaglutide 14mg: -1.4%

Near-Normal Blood Sugar Achievement:

• 37.1% with orforglipron (highest dose)

• 12.5% with oral semaglutide (highest dose)

• Nearly 3x more participants reached near-normal blood sugar with orforglipron

The Convenience Factor: Why Orforglipron Stands Out

No Food or Water Restrictions

Here's where orforglipron has a major advantage over oral semaglutide:

Oral Semaglutide (Wegovy pill):

• Must be taken on an empty stomach

• Only 4 ounces of water allowed

• Must wait 30 minutes before eating, drinking, or taking other medications

• This restriction has historically limited adoption of Rybelsus (the diabetes version)

Orforglipron:

• Can be taken any time of day

• No food restrictions

• No water restrictions

• Significantly more convenient for daily life

This flexibility could be a decisive factor in long-term adherence—a critical component of successful weight management.

Weight Maintenance: A Novel Use Case

One of the most promising findings comes from the ATTAIN-MAINTAIN trial, which studied orforglipron as a maintenance therapy after initial weight loss with injectable GLP-1s.

The Results:

• Patients who switched from Wegovy to orforglipron gained only 0.9 kg (2 lbs) over 52 weeks

• Patients who switched from Zepbound to orforglipron gained 5 kg (11 lbs) over 52 weeks

• Both groups ended at the same average weight

• Placebo groups regained over 9 kg (20 lbs)

What This Means: Orforglipron could serve as a convenient oral maintenance therapy after achieving initial weight loss with more potent injectables, offering a stepping-down strategy for long-term weight management.

Side Effects: What to Expect

Like all GLP-1 medications, orforglipron's most common side effects are gastrointestinal:

• Nausea, diarrhea, vomiting

• Generally mild-to-moderate in severity

• Consistent with the GLP-1 class overall

Discontinuation Rates (due to side effects):

• Orforglipron: 8.7-9.7% (depending on dose)

• Oral semaglutide: 4.5-4.9%

• The study wasn't powered to directly compare safety profiles between drugs

Important Safety Note: The drug showed no hepatic (liver) safety signals in clinical trials—a finding consistent with evidence showing GLP-1 medications may actually improve liver health in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Pricing: More Accessible Than Injectables

Under agreements with the Trump administration in November 2025:

• Starting dose: $149/month

• Higher doses: Up to $399/month for cash-pay patients

For comparison:

• Injectable Zepbound: $299/month (starting dose, cash pay)

• Injectable Wegovy: $349/month (cash pay)

• Oral Wegovy: $149/month (starting dose)

Pills are easier to manufacture at scale, which could improve availability and potentially lower long-term costs.

Why Biomarker Tracking Matters on GLP-1 Medications

Whether you choose an injectable or oral GLP-1, understanding what's happening inside your body is crucial. Here's why regular biomarker monitoring is essential:

Key Markers to Track:

1. Metabolic Markers

• HbA1c and fasting glucose: Track glycemic control

• Fasting insulin: Understand insulin sensitivity improvements

• Expected outcome: Improved glucose regulation

2. Liver Health

• ALT (Alanine Aminotransferase)

• AST (Aspartate Aminotransferase)

• Why it matters: GLP-1s often improve liver enzyme levels, particularly in patients with fatty liver disease. Studies show an average ALT reduction of ~10 U/L

3. Cardiovascular Risk

• Lipid panel (LDL, HDL, triglycerides)

• High-sensitivity CRP (inflammation marker)

• Why it matters: Weight loss should correlate with improved cardiovascular markers, but individual responses vary

4. Kidney Function

• Creatinine and eGFR

• Why it matters: GI side effects can cause dehydration, potentially stressing kidneys

5. Nutritional Status

• Vitamin D, B12, iron, magnesium

• Why it matters: Reduced appetite can lead to nutrient deficiencies if dietary quality isn't maintained

6. Body Composition

• Muscle mass preservation

• Why it matters: Rapid weight loss can include muscle loss. GLP-1 users may lose 25-40% of weight from lean mass rather than just fat

The Mito Health Approach

At Mito Health, we believe the future of GLP-1 therapy isn't just about weight on a scale—it's about comprehensive metabolic optimization. Here's what smart monitoring looks like:

Before Starting:

• Baseline comprehensive metabolic panel

• Liver function tests

• Lipid panel

• Body composition analysis

During Treatment:

• Monthly for first 3 months: Glucose, HbA1c, liver enzymes

• Quarterly: Full metabolic panel, lipids, and inflammatory markers

• Every 6 months: Comprehensive nutrient panel, body composition

Why This Matters:

• Catch nutrient deficiencies before they become symptomatic

• Verify that cardiovascular risk factors are actually improving

• Ensure liver and kidney function remain optimal

• Track muscle mass preservation

• Adjust diet, supplementation, or exercise as needed

The Bottom Line

Orforglipron represents an exciting advancement in oral GLP-1 therapy. While it may not match the weight loss potency of high-dose injectables, it offers several compelling advantages:

✓ Superior convenience (no food/water restrictions)
✓ Outperforms currently available oral semaglutide
✓ Effective maintenance option after injectable therapy
✓ More accessible pricing
✓ Comparable side effect profile to other GLP-1s

Who might benefit most from orforglipron?

• Patients who prefer oral medications over injections

• Those seeking maintenance therapy after injectable GLP-1 weight loss

• Individuals with type 2 diabetes requiring both glycemic control and weight management

• People looking for convenience in daily medication routines

The Bigger Picture:

The arrival of effective oral GLP-1 options marks a turning point in obesity treatment. But medication is just one piece of the puzzle. Successful, sustainable weight management requires:

• Comprehensive biomarker tracking

• Nutritional optimization

• Strength training to preserve muscle mass

• Ongoing metabolic monitoring

The most successful outcomes come from treating weight management as a long-term metabolic optimization project, not just a number on the scale.

Track Your Progress with Precision

Whether you're on an injectable GLP-1, considering orforglipron when it launches, or exploring other metabolic health strategies, understanding your biomarkers is essential.

Mito Health offers comprehensive metabolic testing and personalized insights to help you:

• Monitor liver, kidney, and metabolic markers during GLP-1 therapy

• Catch nutrient deficiencies before they impact your health

• Verify that your cardiovascular risk is improving

• Track body composition changes, not just weight loss

• Optimize your longevity trajectory

Ready to take control of your metabolic health? Learn more about Mito Health's comprehensive testing and personalized health optimization.

References:

1. Eli Lilly ATTAIN-1 Trial Results (August 2025)

2. Eli Lilly ACHIEVE-3 Head-to-Head Trial (September 2025)

3. Eli Lilly ATTAIN-MAINTAIN Trial (December 2025)

4. Novo Nordisk OASIS-4 Trial, New England Journal of Medicine (September 2025)

5. FDA Oral Wegovy Approval (December 2025)

6. Meta-analysis: GLP-1 RAs and liver enzyme effects in NAFLD patients

7. JAMA Internal Medicine: GLP-1 RAs and cirrhosis risk reduction (November 2024)

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Orforglipron is an investigational medication not yet approved by the FDA. Consult with your healthcare provider before starting any weight loss medication.