What are the concerns and considerations for tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) discontinuation rates due to potential side effects?

Tirzepatide Discontinuation Rates Due to Side Effects

Gastrointestinal side effects are the primary reason for tirzepatide discontinuation, with rates increasing in a dose-dependent manner reaching approximately 10% at the highest dose (15 mg). 1

Common Side Effects Leading to Discontinuation

• Gastrointestinal (GI) adverse events are the most frequently reported side effects of tirzepatide, occurring in 39% (5 mg), 46% (10 mg), and 49% (15 mg) of patients 1
• Nausea and diarrhea are the most common GI side effects across all tirzepatide doses 1
• Drug discontinuation rates due to adverse events increase with dose: highest at 15 mg (10%), with lower rates at 5 mg and 10 mg 1
• Discontinuation rates for tirzepatide 10 mg (RR=1.75,95% CI [1.16-2.63]) and 15 mg (RR=2.03,95% CI [1.37-3.01]) are significantly higher compared to control groups 2

Specific Adverse Events of Concern

Gastrointestinal Effects

• In placebo-controlled trials, severe gastrointestinal adverse reactions occurred more frequently with tirzepatide (5 mg: 1.3%, 10 mg: 0.4%, 15 mg: 1.2%) than placebo (0.9%) 3
• Tirzepatide is not recommended in patients with severe gastrointestinal disease, including severe gastroparesis 3

Hypoglycemia

• Risk of hypoglycemia is significantly higher with tirzepatide 15 mg (pooled RR=3.83,95% CI [1.19-12.30]) 2
• Mild hypoglycemia (blood glucose <70 mg/dL) occurs in up to 22.6% of patients taking tirzepatide 10 mg 1
• Hypoglycemia risk increases when tirzepatide is combined with insulin secretagogues or insulin 3

Serious Adverse Events

• Rates of serious adverse events are extremely low across all doses of tirzepatide (≤1%) 1:
  • Fatal adverse events
  • Severe hypoglycemia
  • Acute pancreatitis
  • Cholelithiasis and cholecystitis

Weight Regain After Discontinuation

• Sudden discontinuation of tirzepatide results in regain of one-half to two-thirds of the weight loss within 1 year 4
• This significant weight regain highlights the importance of considering long-term treatment strategies 4

Monitoring and Management Recommendations

• Assess effectiveness and safety at least monthly for the first 3 months and quarterly thereafter 4
• Early responders (>5% weight loss after 3 months) typically have better long-term outcomes 4
• For modest early weight loss (<5% after 3 months), evaluate benefits in context of glycemic response, treatment tolerance, and overall burden 4
• Consider shared decision-making for long-term management approaches, including continuing on lowest effective dose, using intermittent therapy, or stopping with close monitoring 4

Special Considerations

• Monitor renal function when initiating or escalating doses in patients with renal impairment who report severe GI adverse reactions 3
• Patients with a history of diabetic retinopathy should be monitored for progression, as rapid improvement in glucose control can temporarily worsen retinopathy 3
• Rare but serious hypersensitivity reactions (anaphylaxis, angioedema) have been reported 3
• Tirzepatide delays gastric emptying, which may increase risk of pulmonary aspiration during general anesthesia 3

Comparative Discontinuation Rates

• Tirzepatide discontinuation rates are higher than those observed with some other diabetes medications 4
• However, when comparing overall adverse event rates in clinical trials, the absolute difference between intervention and placebo groups for most individual adverse events is typically less than 5% 4

By understanding these discontinuation patterns and implementing appropriate monitoring strategies, clinicians can optimize tirzepatide therapy while minimizing adverse effects that might lead to treatment discontinuation.