When is it appropriate to give liothyronine (T3) and levothyroxine (T4) together?

When to Give Liothyronine and Levothyroxine Together

Combination therapy with levothyroxine plus liothyronine should be considered only as a trial for hypothyroid patients who remain persistently symptomatic despite adequate levothyroxine monotherapy with normalized TSH levels, after ruling out other causes of their symptoms. 1

Standard Treatment Remains Levothyroxine Monotherapy

Levothyroxine alone should remain the first-line treatment for all newly diagnosed hypothyroid patients. 2, 1 The evidence supporting combination therapy is limited, with most clinical trials showing no clear advantage over levothyroxine monotherapy for objective outcomes. 2, 3 While some studies showed patient preference for combination therapy, this preference was not explained by measurable improvements in psychological or psychometric testing. 2, 3

Criteria for Considering Combination Therapy

You should only consider adding liothyronine to levothyroxine when ALL of the following criteria are met:

• The patient has persistent hypothyroid symptoms (fatigue, weight gain, cognitive difficulties, mood disturbances) despite adequate levothyroxine therapy 1
• TSH is normalized within the reference range (0.5-4.5 mIU/L) on current levothyroxine dose 4
• Other causes of symptoms have been excluded (depression, anemia, sleep disorders, other medical conditions) 1
• The patient has been on a stable levothyroxine dose for at least 6-8 weeks 4
• The patient understands this is a trial therapy with uncertain benefit 1

Practical Dosing Protocol for Combination Therapy

When initiating combination therapy, use this specific approach:

• Reduce the current levothyroxine dose by 25 mcg/day 1
• Add liothyronine 2.5-7.5 mcg once or twice daily 1
• Start with the lower end of the liothyronine range (2.5-5 mcg) to minimize risk of transient hypertriiodothyroninemia 1
• Recheck TSH and free T4 (and consider free T3) after 6-8 weeks 4
• Target TSH should remain within the reference range (0.5-4.5 mIU/L) 4

Important Safety Considerations

The addition of liothyronine carries potential risks that must be weighed against uncertain benefits. Transient episodes of elevated T3 with these doses are unlikely to exceed the reference range but warrant monitoring. 1 Overreplacement indicated by TSH <0.1 mIU/L significantly increases risk of atrial fibrillation and bone loss, particularly in elderly patients. 4 Patients with cardiac disease, atrial fibrillation, or osteoporosis require especially cautious monitoring. 4

Evidence Quality and Long-Term Safety

An observational study following approximately 400 patients for a mean of 9 years on combination therapy showed no increased mortality or morbidity risk from cardiovascular disease, atrial fibrillation, or fractures compared to levothyroxine monotherapy after adjusting for age. 1 However, trials have been generally short-term and underpowered, with significant shortcomings in study design. 5 Most controlled trials comparing levothyroxine alone versus combination therapy have failed to demonstrate clear objective benefits. 2, 3

When NOT to Use Combination Therapy

Never initiate combination therapy in these situations:

• Newly diagnosed hypothyroidism—always start with levothyroxine monotherapy 1
• TSH not yet normalized on current levothyroxine dose 4
• Symptoms present for less than 3-4 months on adequate levothyroxine replacement 6
• Other medical causes of symptoms not yet excluded 1
• Patients with recent cardiac events or uncontrolled atrial fibrillation without cardiology consultation 4

Monitoring During Combination Therapy

After initiating combination therapy, monitor TSH and free T4 every 6-8 weeks during dose titration. 4 Free T3 levels can help interpret ongoing abnormal TSH levels, as TSH may take longer to normalize. 7 Once stable, repeat testing every 6-12 months or with symptom changes. 7 Development of low TSH on therapy suggests overtreatment and requires dose reduction. 6

Alternative: Desiccated Thyroid Extract

Desiccated thyroid extract (DTE) provides combination therapy with an LT4:LT3 ratio of approximately 4:1, with mean daily doses containing approximately 11 mcg T3. 1 However, DTE remains outside formal FDA oversight, and consistency of T4 and T3 content is monitored only by manufacturers, making it a less reliable option. 1

Critical Pitfalls to Avoid

Do not add liothyronine simply because a patient requests it without meeting the criteria above—patient preference alone is insufficient justification given the lack of objective benefit in most trials. 2, 3 Avoid excessive liothyronine doses that could cause TSH suppression below 0.1 mIU/L, which significantly increases complications. 4 Never start combination therapy before confirming adequate levothyroxine monotherapy has been tried for sufficient duration with normalized TSH. 1