Clinical Summary
Clinical Summary: Lemborexant and Daridorexant for the Treatment of Insomnia: An Indirect Comparison Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed
Patients with chronic insomnia often need medication when CBT-I is unavailable or insufficient, but clinicians lack head-to-head data to judge how newer dual orexin receptor antagonists compare in practice. This analysis translates trial results for lemborexant and daridorexant into NNT, NNH, and LHH metrics that are easier to use when weighing likely benefit against common adverse events.
Design
The SUNRISE 1 Phase 3 clinical study was a 1-month, global, randomized, double-blind, placebo- and active comparator–controlled trial
N
There were 1,006 participants randomized (lemborexant 5 mg, 266; lemborexant 10 mg, 269; zolpidem ER, 263; placebo, 208) with a median age of 63 years (range, 55–88 years); 869 participants (86.4%) were women.
Population
eligible participants (women aged ≥ 55 years, men aged ≥ 65 years) met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),21 insomnia disorder criteria characterized by sleep maintenance difficulties (with or without sleep onset difficulties) that were confirmed using sleep diary, sleep history, and polysomnography (PSG)
Duration
The SUNRISE 1 Phase 3 clinical study was a 1-month, global, randomized, double-blind, placebo- and active comparator–controlled trial
Key Findings
- For pooled efficacy data from SUNRISE 1 and SUNRISE 2, NNT values versus placebo at the end of month 1 for pooled lemborexant 5-mg and 10-mg dose groups were < 10 for ISI score < 10, ISI score ≤ 7, ISI score ≥ 6-point decrease from baseline, and sTST > 80-minute increase from baseline; for pooled doses of daridorexant 25 mg and 50 mg, no NNT values versus placebo were < 10.
- Among month 1 objective outcomes in SUNRISE 1, the most robust lemborexant NNT was 5 for ≥ 50% WASO improvement for both 5 mg and 10 mg, and NNT was also 5 for sTST improvement > 80 minutes with lemborexant 10 mg.
- A dose-response signal favored higher-dose lemborexant for subjective sleep time: for sTST outcome, NNT versus placebo was 7 for lemborexant 10 mg and 13 for lemborexant 5 mg, with a NNT for the lemborexant 10-mg group versus 5-mg group of 14 (95% CI, 8–51).
- At month 3, pooled daridorexant 25-mg and 50-mg doses had more favorable tolerability for common sedating adverse events than pooled lemborexant doses: fatigue NNH = 49 versus 29 and somnolence NNH = 85 versus 12.
- For discontinuation due to an AE, pooled daridorexant 25-mg and 50-mg doses had an imputed NNH of 1,000 at month 3, yielding a LHH range of 76.9–100 using statistically significant NNTs of 10–13; pooled lemborexant 5-mg and 10-mg doses had NNH = 52 [NS] at month 3 with a LHH range of 5.2–10.4 using NNTs of 5–10.
Clinical Bottom Line
Lemborexant showed a more favorable efficacy profile than daridorexant on most indirect subjective outcomes, while daridorexant showed a more favorable tolerability profile for somnolence, fatigue, and discontinuation due to an AE. In practice, the choice is a tradeoff between stronger likelihood of benefit with lemborexant and lower likelihood of common sedating harms with daridorexant.
Practice Implications
- If the main goal is maximizing likelihood of sleep benefit on subjective outcomes, lemborexant has the stronger indirect efficacy signal, with pooled month 1 NNT values versus placebo < 10 across all relevant ISI and sTST outcomes.
- If daytime sedation risk is a priority, daridorexant has the more favorable indirect tolerability profile at month 3, with NNH = 85 for somnolence and NNH = 49 for fatigue versus 12 and 29 with pooled lemborexant doses.
- Use lemborexant dose escalation thoughtfully: somnolence showed a dose response at month 1, with NNH 15 for lemborexant 10 mg and 28 for lemborexant 5 mg, consistent with the article’s note that prescribing information recommends starting at 5 mg and increasing based on clinical response and tolerability.
- Interpret cross-drug comparisons cautiously when counseling patients, because SUNRISE 1 enrolled older adults (women aged ≥ 55 years, men aged ≥ 65 years) with ISI score ≥ 13, whereas the daridorexant studies enrolled adults aged ≥ 18 years with ISI score ≥ 15.
