What is the available comparative evidence between lubiprostone and linaclotide?

Comment by InpharmD Researcher

There is a paucity of direct head-to-head comparisons on efficacy and safety of lubiprostone versus linaclotide. Several meta-analyses have reported similar efficacy between lubiprostone and linaclotide for changes in spontaneous bowel movements (SBM) and weekly complete spontaneous bowel movements (CSBM) via indirect comparisons; however, one found higher doses of linaclotide to be better than lubiprostone. One study suggests that linaclotide may confer greater efficacy with reduction of abdominal bloating, although no significant difference was found between treatment arms.
Background

A 2024 systematic review and meta-analysis (N= 24 studies) indirectly compared efficacy and safety of lubiprostone, linaclotide, and elobixibat (not FDA-approved, but available internationally) for chronic constipation. Impact of treatments on spontaneous bowel (SBM) movements was assessed as the primary outcome, including SBM frequency, change from baseline in SBM frequency, SBM in ≤ 24 h, the response rate, and the time to first SBM. A meta-analysis was conducted for each agent. Two studies were included for lubiprostone, finding a significantly higher pooled effect estimate for mean change from baseline in SBM frequency (mean difference [MD] 3.64; 95% CI 0.83 to 6.46, p= 0.0111) when compared to placebo. For linaclotide, 3 studies were included evaluating 500 mcg (2 studies) and 145 mcg (1 study) doses. Linaclotide 500 mcg was associated with significantly improved change in SBM frequency (MD 2.24; 95% CI 1.65 to 2.83, p< 0.0001) when compared to placebo. Similar results were found for the 145 mcg dose (MD 2.40; 95% CI 1.53 to 3.27), p< 0.0001). Number needed to treat (NNT) for the full responder rate at week 1 was 5 (≥ 3 SBM per week) for lubiprostone 24 mcg BID compared to 5 for linaclotide 500 mcg. The number needed to harm (NNH) for diarrhea was 14 (95% CI 10 to 23) for lubiprostone, 12 (95% CI 8 to 26) for linaclotide 500 mcg, and 8 (95% CI 7 to 11) for linaclotide 145 mg. For nausea, NNH was higher for linaclotide 145 mg (46; 95% CI -69 to 17) compared to lubiprostone (5; 95% CI 4 to 6). Finally, for abdominal pain NNH was higher for linaclotide 145 mcg (70; 95% CI -171 to 29) compared to lubiprostone (47; 95% CI -209 to 21). Ultimately, both lubiprostone and linaclotide were both associated with significantly increased SBM frequency compared to placebo, but the authors concluded no major differences in efficacy between either of these two drugs. [1]

A 2020 Bayesian network meta-analysis compares linaclotide 500 μg to other oral chronic constipation treatments, including over-the-counter agents, at various dosages. A total of 54 trials were included with 47 treatments, comprised of 16 drugs altogether. Of the trials included, 9 studies (N= 1,674 patients) examined use of lubiprostone versus placebo. In comparison to linaclotide, lubiprostone 16 mcg was found to be less efficacious when looking at change in weekly SBMs (mean difference [MD] -2.090; 95% credible interval [CrI] -3.226 to -0.968). Linaclotide was also found to be more effective than lubiprostine 32 mcg and 48 mcg in point estimate terms, although this was non-significant. Notably, a majority of published trials were placebo-controlled, limiting the applicability of findings due to the lack of head-to-head comparisons. Of note, treatments were compared against 500 mcg of linaclotide, which is a higher dose than the 290 mcg dose approved for chronic constipation in the US. [2]

A 2021 systematic review and meta-analysis (N= 13 studies; 10,091 patients) was conducted to investigate efficacy of linaclotide, lubiprostone and other medications for treatment of bloating in irritable bowel syndrome with constipation (IBS-C). While the included trials utilized varying primary outcomes, all trials evaluated a similar endpoint for abdominal bloating, defined by ≥ 30% decrease in abdominal bloating score for 6 out of 12 weeks. All studied drugs were found to be significantly more effective than placebo. While indirect comparisons revealed no significant differences between individual drugs, linaclotide 290 mcg was concluded to have a 97% probability (indicated by P-score = 0.97) of being the most efficacious treatment (risk ratio [RR] 0.78; 95% CI 0.74 to 0.83; NNT 7, followed by lubiprostone 8 mcg (RR 0.85; 95% CI 0.76 to 0.95; NNT 8; P-score = 0.54). [3]

A 2021 systematic review and network meta-analysis (N= 6 randomized controlled trials [RCTs]; 1,460 patients) compared the efficacy of linaclotide, elobixibat, lubiprostone, and lactulose for the treatment of chronic idiopathic constipation (CIC). Due to the lack of direct comparisons, SBMs within 1 week were indirectly compared as an endpoint. Dosages utilized for linaclotide ranged up to 500 mcg, while doses of lubiprostone ranged up to 48 mcg. Overall, all dosage forms showed a higher increase in SMBs than placebo, although most of them lacked significance. Similarly, there was a lack of significant between-groups difference when comparing the medications to one another for change in weekly SBMs, patients with SBM within 24 hours, time to first SBM, and changes in weekly complete spontaneous bowel movements (CSBM). When ranking the intervention arms, lubiprostone 48 mcg was first for proportion of patients with SBM within 24 hours, while linaclotide 0.5 mg was among the medications ranked last. [4]

A 2020 model-based meta-analysis sought to determine the efficacy and safety of agents in the treatment of chronic constipation, including a total of 20 studies consisting of 9,998 participants. Four studies focused on lubiprostone (n= 395), while 4 focused on linaclotide (n= 1,431). Changes in SBM frequency were estimated to be similar between linaclotide (Emax 2.4; 95% CI 2.0 to 2.8) and lubiprostone (Emax 2.2; 95% CI 1.9 to 2.5), with comparable predicted frequency change relative to placebo between agents. Changes in CSBM (Emax 1.5; 95% CI 1.2 to 1.7) and predicted frequency change (rate of loss of efficacy -0.019; 95% CI -0.031 to -0.007) were solely reported for linaclotide. Of note, some trials only had a duration of treatment up to 4 weeks, and results were extracted from a model, which should be interpreted with caution. [5]

A 2011 systematic review and meta-analysis of randomized controlled trials assessed the efficacy of laxatives, including lubiprostone and linaclotide, for CIC. A total of 21 placebo-controlled RCTs with a minimum duration of therapy of 1 week were included. Results showed lubiprostone (3 RCTs, N= 610; RR 0.67, 95% CI 0.56 to 0.80) and linaclotide (3 trials, N= 1582; RR 0.84, 95% CI 0.80 to 0.87) were both superior to placebo in terms of risk of therapy failure. In the response to therapy with lubiprostone, 45.1% failed to respond to therapy compared to 66.9% from the placebo group; linaclotide had 79.0% fail to respond compared to 94.9% of placebo patients. Adverse events of diarrhea and nausea were higher with lubiprostone, while the most common adverse event with linaclotide was diarrhea. This analysis showed that lubiprostone and linaclotide were more effective than placebo for the treatment of CIC. [6]

References:

[1] Rao SS, Manabe N, Karasawa Y, et al. Comparative profiles of lubiprostone, linaclotide, and elobixibat for chronic constipation: a systematic literature review with meta-analysis and number needed to treat/harm. BMC Gastroenterol. 2024;24(1):12. Published 2024 Jan 2. doi:10.1186/s12876-023-03104-8
[2] Okumura H, Tang W, Iwasaki K, Shoji S, Odaka T, Nakajima A. Comparative efficacy of linaclotide versus other oral constipation treatments in chronic constipation: a network meta-analysis. SN Compr Clin Med. 2020;2(10):1831-1847.
[3] Nelson AD, Black CJ, Houghton LA, Lugo-Fagundo NS, Lacy BE, Ford AC. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2021;54(2):98-108. doi:10.1111/apt.16437
[4] Nakajima A, Shoji A, Kokubo K, Igarashi A. A Systematic Review and Network Meta-Analysis on the Efficacy of Medications in the Treatment of Chronic Idiopathic Constipation in Japan. Gastroenterol Res Pract. 2021;2021:5534687. Published 2021 Nov 30. doi:10.1155/2021/5534687
[5] Zhang Y, Yin F, Xu L, et al. Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines. J Clin Gastroenterol. 2020;54(10):e93-e102. doi:10.1097/MCG.0000000000001303
[6] Ford AC, Suares NC. Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis. Gut. 2011;60(2):209-218. doi:10.1136/gut.2010.22713

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the available comparative evidence between lubiprostone and linaclotide?

Please see Table 1 for your response.


 

Evaluating When and Why Patients Discontinue Chronic Therapy for Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation

Design

Retrospective, observational, cohort study

 N= 1,612

Objective

To evaluate the duration of therapy until discontinuation, reasons for medication discontinuation, and clinical factors leading to discontinuation for approved pharmacotherapies for IBS-C and CIC in clinical practice

Study Groups

Lubiprostone (n= 679)

Linaclotide (n= 933)

Inclusion Criteria

Age >18 years, new initiation of linaclotide or lubiprostone therapy, at least 1 documented outpatient office visit after medication initiation

Exclusion Criteria

Patients who were prescribed lubiprostone before linaclotide was available, previous use of either lubiprostone, linactolide, or enrollment in an irritable bowel sydrome-constipation (IBS-C) clinical trial, patients that received plecanatide

Methods

Patients taking lubiprostone or linaclotide were identified using the Michigan Medicine Electronic Medical Record Search Engine information retrieval system.

Duration of therapy until discontinuation was determined at 3, 6, and 12 months after initiation of therapy. Reasons for discontinuation were categorized as due to intolerance, perceived lack or loss of efficay, financial cost of prescription refills, or sufficient improvement in the underlying IBS-C/CIC no longer requiring drug therapy.

Duration

December 2012 to November 2016

Outcome Measures

Reason for discontinuation within 3 months or between 3 and 12 months (no longer neeeded, insufficient efficacy, insurance noncoverage, or adverse effects

Baseline Characteristics

 

Lubiprostone (n= 679)

Linaclotide (n= 933)

Age, years

48.6 ± 17.8 49.9 ± 16.4

Female

586/679 (86.3%)

760/933 (81.5%)

Diagnosed with IBS-C

492/679 (72.5%)  225/933 (24.1%) 

Managed by gastroenterology

599/679 (88.2%)  821/933 (88%) 

Abbreviations: CIC, chronic idiopathic constipation; IBS-C, constipation-predominant irritable bowel syndrome.

Results

Endpoint

Lubiprostone (n= 679)

Linaclotide (n= 933)

No longer needed

Discontinuation within 3 mo of initiating

Discontinuation between 3–12 mo of initiating

 

0%

0%

 

3.1%

1.0%

Insufficient efficacy

Discontinuation within 3 mo of initiating

Discontinuation between 3–12 mo of initiating

 

16.6%

39.6%

 

25%

23.7% 

Insurance noncoverage 

Discontinuation within 3 mo of initiating

Discontinuation between 3–12 mo of initiating

 

42.7%

17.9% 

 

8.6%

9.3% 

Adverse events

Discontinuation within 3 mo of initiating

Discontinuation between 3–12 mo of initiating

 

26.1%

17.9% 

 

57%

50.5% 

The overall rates of discontinuation on lubiprostone therapy were 23.6% (95% CI, 20.5–27.0) at 3 months, 33.8% (95% CI, 30.4–37.6) at 6 months, and 45.7% (95% CI, 41.8–49.7) at 12 months.

For linaclotide, the rates of discontinuation were 14.7% (95% CI, 12.5–17.2) at 3 months, 22.2% (95% CI, 19.5–25.2) at 6 months, and 28.9% (95% CI, 25.7–32.3) at 12 months.

Adverse Events

Diarrhea, nausea, abdominal pain, abdominal bloating or discomfort

Study Author Conclusions

Individuals appear more likely to discontinue lubiprostone than linaclotide overall, but more likely to discontinue linaclotide compared with lubiprostone due to intolerance (mostly diarrhea). Most discontinuations due to intolerance occur in the first 3 months. These results may be useful in individualized treatment selection and enhancing patient knowledge regarding long-term outcomes.

InpharmD Researcher Critique

This study did not evaluate the efficacy of these medications directly. The authors censored the length of treatment in patients who left the center and did not count them as discontinuations, which can negatively impact the validity of the data given this study was aimed at gathering reasons for discontinuation of therapy. In addition, this study does not take into account the severity of IBS-C/CIC in this patient population, which may account for the variation in results, specifically regarding adverse effects, as some patients may have been initiated on higher doses resulting in possible earlier discontinuation due to side effects.



References:

Shah ED, Suresh S, Jou J, Chey WD, Stidham RW. Evaluating When and Why Patients Discontinue Chronic Therapy for Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation. Am J Gastroenterol. 2020;115(4):596-602. doi:10.14309/ajg.0000000000000530