What is the incidence of foot drop with tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist)?

Incidence of Foot Drop with Tirzepatide

Foot drop is a rare but documented adverse effect associated with tirzepatide-induced rapid weight loss, with case reports showing development within 6-8 months of therapy initiation.

Mechanism of Foot Drop with Tirzepatide

• Foot drop associated with tirzepatide appears to be a consequence of rapid weight loss rather than a direct medication effect, a phenomenon sometimes called "slimmer's paralysis" 1
• The condition involves peroneal nerve neuropathy that can develop bilaterally after significant and rapid weight reduction 1
• Tirzepatide's potent weight loss effects (up to 20.9% at the 15mg dose) may contribute to this risk through rapid fat loss around nerve structures 2, 3

Incidence and Risk Factors

• While the exact incidence rate is not precisely documented in large clinical trials, foot drop appears to be a rare adverse event 1
• Risk factors include:
  • Rate of weight loss (faster loss increases risk) 1
  • Magnitude of weight loss (greater total loss increases risk) 1
  • Pre-existing conditions affecting peripheral nerves 4
  • Duration of therapy (cases reported at 6-8 months of treatment) 1

Clinical Presentation and Diagnosis

• Patients typically present with:
  • Inability to dorsiflex the foot (lift the foot upward) 4
  • Foot dragging during walking 4
  • Bilateral involvement in tirzepatide-associated cases 1
• Diagnosis requires:
  • Neurological examination focusing on L5 nerve root and common peroneal nerve function 4
  • Electromyography (EMG) and nerve conduction studies to confirm peroneal neuropathy 4

Management and Prevention

• For patients on tirzepatide:
  • Monitor for early symptoms of numbness or weakness in the foot/ankle 1
  • Consider slowing the rate of weight loss if neurological symptoms develop 1
  • Implement regular follow-up during periods of rapid weight loss 2, 3
• Treatment options for established foot drop:
  • Ankle-foot orthosis to improve gait 4
  • Physical therapy to maintain muscle strength 4
  • In severe cases, surgical decompression of the peroneal nerve may be considered 4

Comparison with Other GLP-1/GIP Medications

• Similar adverse effects may occur with other weight loss medications that cause rapid weight reduction 2
• Tirzepatide's dual GIP/GLP-1 receptor agonism leads to greater weight loss than single-receptor GLP-1 agonists like semaglutide (20.9% vs 14.9%), potentially increasing this risk 2, 5
• Common adverse events with tirzepatide are primarily gastrointestinal (39-49% depending on dose), with foot drop not listed among the frequently reported adverse effects 6

Clinical Implications

• Healthcare providers should:
  • Counsel patients about this potential complication of rapid weight loss 1
  • Consider more gradual dose titration in patients at higher risk for neuropathy 2, 3
  • Monitor patients closely during the first 6-12 months of therapy when weight loss is most rapid 1
  • Implement early intervention if symptoms of nerve compression develop 4, 1

Research Gaps

• Current evidence is limited to case reports rather than large-scale epidemiological data 1
• More research is needed to determine the true incidence and risk factors for this complication 1
• Long-term follow-up studies should assess whether risk changes with extended treatment duration 2