In a 51-year-old male who lost approximately 75 lb using semaglutide (Ozempic), what is the most likely cause of the new multiple firm, mobile subcutaneous nodules on his forearms and right leg?

What is causing the new subcutaneous nodules after significant weight loss with semaglutide?

The most likely cause of these new firm, mobile subcutaneous nodules on the bilateral forearms and right leg is lipohypertrophy from repeated semaglutide injections, not lipomas from weight loss. This patient has been using Ozempic 1 mg weekly for 4 months with injections into subcutaneous tissue, and the nodules appeared specifically after starting this therapy 1.

Primary Diagnosis: Injection-Site Lipohypertrophy

Lipohypertrophy is the most common form of lipodystrophy associated with repeated subcutaneous injections of GLP-1 receptor agonists like semaglutide. The condition presents as palpable subcutaneous nodules or swelling at injection sites, caused by enlargement of adipocytes from repeated insulin or GLP-1 RA delivery into the same skin area 1.

Key Distinguishing Features Supporting This Diagnosis:

• Timing: The nodules developed specifically after 4 months of semaglutide therapy, not gradually during the weight loss period 1
• Location pattern: Bilateral forearms and anterior right leg are common self-injection sites for subcutaneous medications 1
• Size and characteristics: Multiple 2-4mm nodules with one 5mm nodule match the typical presentation of lipohypertrophy 1
• Firm and movable: These physical characteristics are consistent with subcutaneous fat tissue changes from repeated injections 1

Mechanism of Lipohypertrophy with GLP-1 Receptor Agonists:

While lipohypertrophy risk is considerably less with noninsulin injectables compared to insulin, palpable injection site subcutaneous nodules have been specifically reported following delivery of once-weekly semaglutide. The condition arises from repeated delivery into one skin site without adequate rotation 1.

Alternative Differential Diagnoses (Less Likely)

True Lipomas from Weight Loss:

This is unlikely because:

• Lipomas typically develop slowly over years, not acutely over 4 months 2
• The bilateral symmetric distribution on injection-accessible sites (forearms, anterior leg) is atypical for spontaneous lipomas 2
• Weight loss does not cause new lipoma formation; existing lipomas may become more apparent with fat loss, but this patient had no prior history 2, 3

Dercum's Disease (Adiposis Dolorosa):

This is excluded because:

• The patient explicitly denies pain, whereas Dercum's disease is characterized by multiple painful subcutaneous lipomas 3
• Dercum's disease selectively affects postmenopausal women; this is a 51-year-old male 3
• The acute onset after medication initiation does not fit the chronic progressive nature of Dercum's disease 3

Diagnostic Confirmation and Management

Immediate Assessment:

1. Detailed injection-site history: Document exactly where the patient has been injecting semaglutide over the past 4 months—this should correlate precisely with nodule locations 1
2. Visual and palpation examination: Inspect all documented injection sites for swelling, nodules, and skin changes consistent with lipodystrophy 1
3. Ultrasound imaging (if diagnosis uncertain): Can confirm subcutaneous fat tissue changes and exclude other pathology 3

Management Protocol:

Instruct the patient to immediately cease injecting into sites with palpable nodules. Injection into areas of lipodystrophy causes erratic medication absorption, potentially increasing risk of hypoglycemia, hyperglycemia, and glucose variability 1.

Implement systematic injection-site rotation:

• Rotate between at least 4 different anatomical sites (abdomen, thighs, upper arms, buttocks) 1
• Within each site, move the injection point at least 1 cm from the previous injection 1
• Use injection site map handouts or rotation apps to track injection locations 1
• Avoid injecting cold medication directly from refrigerator 1

Monitor for resolution: Document lipohypertrophy sites with photographs to track improvement over time; nodules typically resolve gradually when the area is rested from injections 1.

Critical Clinical Pitfalls to Avoid

• Do not assume these are benign lipomas requiring dermatology referral without first confirming injection-site correlation—this delays appropriate management and allows continued problematic injection technique 1
• Do not continue injecting into affected areas even if they seem "healed"—subclinical lipodystrophy can persist and affect medication absorption 1
• Do not dismiss patient education on injection technique as the primary intervention—proper rotation is essential to prevent recurrence and ensure therapeutic efficacy 1

When Dermatology Referral IS Indicated

Refer to dermatology only if:

• Nodules persist or enlarge despite 3-6 months of site avoidance 1
• Nodules develop in areas that are NOT injection sites 2
• Patient develops pain in the nodules (consider Dercum's disease or other pathology) 3
• Skin changes suggest infection, inflammation, or other dermatologic pathology 1

The patient's request for dermatology referral to determine "what is causing this" should be redirected to proper injection-technique education and monitoring, as this is almost certainly iatrogenic lipohypertrophy from inadequate site rotation, not a spontaneous dermatologic condition requiring specialist evaluation.