A real-world analysis of Lomitapide-associated adverse events: Data from FAERS and CVAROD

Abstract

Lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor approved for the treatment of Homozygous Familial Hypercholesterolemia (HoFH), effectively lowers LDL cholesterol but raises safety concerns, particularly regarding hepatic and gastrointestinal adverse events (AEs). We conducted a pharmacovigilance disproportionality analysis using 2 major spontaneous reporting systems: the U.S. FDA Adverse Event Reporting System (FAERS, 2004–2024) and the Canada Vigilance Adverse Reaction Online Database (CVAROD, 2014–2025). All Lomitapide-related reports were extracted and analyzed using 4 statistical algorithms: reporting odds ratio (ROR), proportional reporting ratio, information component (IC), and Empirical Bayes Geometric Mean (EBGM). Signals were assessed at both the system organ class (SOC) and preferred term (PT) levels, with clinical priority scoring applied to rank AEs by relevance and impact. A total of 3665 FAERS and 80 CVAROD reports were analyzed. Gastrointestinal events were most frequent, including diarrhea (n = 1072; LBROR = 7.78), weight loss (n = 832; LBROR = 13.44), and nausea (n = 525; LBROR = 2.87). Hepatic events included elevated liver enzymes (n = 190; LBROR = 11.47) and hepatic steatosis (n = 67; LBROR = 13.01). Metabolic complications such as increased LDL levels (n = 159; LBROR = 85.45) were also observed. Subgroup analyses indicated higher susceptibility in males for diarrhea and weight loss, and in minors for abdominal pain (n = 10; LBROR = 7.53) and vomiting (n = 6; LBROR = 1.96). Novel signals, including renal pain (n = 10; LBROR = 2.33) and intestinal hemorrhage (n = 3; LBROR = 1.98), were identified, previously unreported in clinical trials. Most AEs occurred within the first week of treatment. Lomitapide is associated with clinically significant gastrointestinal, hepatic, and metabolic AEs, with elevated risk in male and pediatric patients. The early onset of reactions and emergence of novel signals highlight the importance of close monitoring, particularly during treatment initiation. Personalized risk mitigation strategies should be implemented to optimize the safety of Lomitapide therapy in HoFH patients.

1. Introduction

Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal dominant inherited disorder, with an estimated prevalence of 1 in 100,000 to 300,000 individuals, particularly affecting high-risk populations.^[1,2] Patients present with markedly elevated low-density lipoprotein cholesterol (LDL-C) from birth, often leading to early onset atherosclerotic cardiovascular disease (ASCVD).^[3] This condition typically results from a severe deficiency or complete absence of functional low-density lipoprotein receptors (LDLR), and in some cases, mutations in APOB or proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9) impair LDL-C clearance.^[4]

Current guidelines, including those of the 2023 National Lipid Association (NLA) and the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS), recommend combination lipid-lowering therapy with statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.^[5] However, these treatments rely on residual LDLR activity, limiting their efficacy in patients with near-complete LDLR loss.^[6] LDL apheresis offers rapid LDL-C reduction but is limited by its high cost and poor adherence.^[7]

Lomitapide, an oral microsomal triglyceride transfer protein (MTP) inhibitor, lowers LDL-C independently of LDLR by inhibiting very low-density lipoprotein (VLDL) and chylomicron assembly.^[8,9] According to both NLA and ESC/EAS guidelines,^[10] Lomitapide has shown > 50% LDL-C reduction with sustained efficacy.^[11] However, safety concerns, especially gastrointestinal intolerance, hepatic enzyme elevation, and fat-soluble vitamin deficiencies – remain significant.^[12]

The existing safety data are mainly derived from small clinical trials. To address this limitation, we conducted a real-world pharmacovigilance study using the U.S. FDA Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Online Database (CVAROD) to identify and characterize Lomitapide-associated adverse event (AE) signals. This analysis includes assessments of AE types, onset times, and demographic risk factors to support personalized risk monitoring.^[13]

2. Methods

This study analyzed real-world AE reports related to Lomitapide from 2 regulatory databases: the FAERS (Q1 2004–Q4 2024) and the CVAROD (Jan 1, 2014–Jan 31, 2025). All reports listing Lomitapide were included for safety signal detection.

Adverse events (AEs) were coded using MedDRA Version 27.0, the most recent stable release at the time of analysis (March 2024, effective May 2024), at both system organ class (SOC) and preferred term (PT) levels. The FAERS data fields included demographics, drug use, AE descriptions, therapy dates, outcomes, indications, and source type. Duplicate reports were removed following FDA guidance. For matching CASE IDs, the record with the latest FDA_DT was kept; if equal, the record with the higher Primary ID was retained. For CVAROD, duplicates were handled according to Health Canada guidance: flagged duplicates were collapsed to the latest follow-up, while unflagged potential duplicates were matched by the Canada Vigilance AER number and, when uncertain, manually reviewed by clinicians to retain the most recent record (Fig. 1).

Figure 1.

Workflow for identification and analysis of Lomitapide-associated AE signals in the FAERS and CVAROD databases. (A) Data extraction and preprocessing workflow for the FAERS database. (B) Corresponding workflow for the CVAROD database. AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, FAERS = FDA adverse event reporting system, PS = primary suspect.

Four standard disproportionality algorithms were applied to detect potential safety signals: reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and Empirical Bayesian Geometric Mean (EBGM). A signal was considered positive if it met the predefined thresholds: lower bound of the 95% CI of the ROR (LBROR) > 1 with N ≥ 3; PRR ≥ 2 with χ² ≥ 4 and N ≥ 3; IC025 > 0; or EBGM05 > 2. The detailed equations remain available in Table S1 (Supplemental Digital Content, https://links.lww.com/MD/Q601). Cross-method validation was required to improve robustness. To minimize false positive signals, we conducted signal refinement following recommended pharmacovigilance practices.^[14,15] This included the removal of non-AE terms (e.g., administrative or indication-related preferred terms [PTs]), consolidation of clinically synonymous PTs, and a sensitivity analysis restricted to reports listing Lomitapide as the sole suspect drug. P-values for PT-level disproportionality tests were adjusted for multiple comparisons using the Bonferroni method, in which each raw P-value was multiplied by the total number of PTs tested, and adjusted values < .05 were considered statistically significant.

This analysis included 4 components. First, the overall signal detection was conducted at both the SOC and PT levels to identify frequently reported or high-risk AEs. Second, all identified PT signals were compared with the most recent version of the Lomitapide label (revision: 01/2024) to determine whether they represented novel or unlabeled events. Third, onset time was evaluated as the interval between the initiation of Lomitapide (START_DT) and AE occurrence (EVENT_DT), with the median and interquartile range (IQR) reported. Finally, subgroup analyses were performed according to gender and age to explore demographic variations and identify potentially high-risk populations.

All the data processing, statistical analyses, and visualizations were performed using R software (version 4.3.3), with additional manual review and the quality assurance conducted using Microsoft Excel 2019 (Microsoft Corporation, Redmond). Disproportionality measures (ROR, PRR, IC, EBGM) quantify relative reporting rather than incidence or risk; they cannot infer causality. All results are therefore hypothesis-generating and require triangulation with external data sources. This study adheres to the READUS-PV checklist for reporting disproportionality analyses.

3. Results

3.1. General overview

The baseline characteristics of Lomitapide-associated AE reports are summarized in Table 1. In FAERS (n = 3665), reports were predominantly from female patients (48.9%), while in CVAROD (n = 80), males constituted the majority (67.5%). Most cases in both databases involved adults aged 18 to 65 years (35.0% in FAERS; 72.5% in CVAROD), but missing age data were common in FAERS (45.8%). Regarding body weight, nearly half of FAERS reports involved patients weighing 50 to 100 kg (45.9%), whereas in CVAROD, weight information was mostly missing (85%).

Table 1.

Baseline characteristics of AE reports involving Lomitapide in FAERS and CVAROD.

Characteristics	FAERS		CVAROD
	Number, n	Proportion, %	Number, n	Proportion, %
Number of Events	3665		80
Gender
Female	1794	48.9	13	16.3
Male	932	25.4	54	67.5
Unkonwn	939	25.6	13	16.3
Age
<18	34	0.9	—	—
18–65	1284	35.0	58	72.5
>65	670	18.3	1	1.3
Unkonwn	1677	45.8	21	26.3
Weight
<50	75	2.0	—	—
50–100	1681	45.9	11	13.7
>100	359	9.8	1	1.3
Unknown	1550	42.3	68	85
Reported countries (top 5)
US	3364	91.8
UK	68	1.9
CA	35	1.0	80	100
IT	31	0.8
JP	28	0.8
Reporting person
Physician	1109	30.3	6	7.5
Consumer	1048	28.6	9	11.3
Other health-professional	1001	27.3	52	65.0
Pharmacist	204	5.6	4	5.0
Healthcare practitioner	193	5.3	—	—
Missing	107	2.9	8	10.0
Registered nurse	2	0.1	1	1.3
Lawyer	1	0.0	—	—
Outcomes
Total	3665	100	80	100
Missing	2499	68.2
Other Serious	787	21.5
Hospitalization	308	8.4
Death	55	1.5
Life-Threatening	10	0.3
Disability	6	0.2
Unknown			41	51.3
Fatal			15	18.8
Recovered/resolved			11	13.8
Not recovered/not resolved			8	10
Recovering/resolving			5	6.3
Indications (top 5)
Type IIA hyperlipidemia	3269	89.2
Product used for unknown indication	213	5.8
Hypercholesterolaemia	55	1.5
Hyperlipidaemia	30	0.8
Blood cholesterol increased	18	0.5

FAERS data from Q1 2004 to Q4 2024; CVAROD data from Jan 1, 2014, to Jan 31, 2025.

AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, FAERS = FDA adverse event reporting system.

Notable differences were also observed in the reporting source: in FAERS, physicians, consumers, and other healthcare professionals each accounted for roughly one-third of reports, whereas in CVAROD, two-thirds (65.0%) originated from other healthcare professionals.

Clinical outcomes further underscored the potential severity of Lomitapide-related AEs. In FAERS, 21.5% of reports were classified as “other serious events” and 8.4% involved hospitalization, while in CVAROD, 18.8% of cases were fatal and 13.8% were reported as recovered or resolved.

Geographically, FAERS reports were overwhelmingly from the United States (91.8%), while CVAROD represented exclusively Canadian reports. Across databases, the most frequent indication was type IIA hyperlipidemia.

In FAERS, the median onset time for Lomitapide-associated AEs was 97.00 days (IQR: 16.00–461.50). Hepatobiliary disorders appeared later (median 135.50 days, IQR: 51.00–550.75), whereas gastrointestinal disorders occurred earlier (median 34.50 days, IQR: 5.00–219.00). In CVAROD, onset data were less consistently available due to reporting characteristics. Temporal patterns are shown in Figure 2, with FAERS reports peaking in 2015 and then declining, while CVAROD reports increased after 2021. The distribution further indicated an early cluster within the first treatment week and a secondary rise after prolonged exposure (>360 days).

Figure 2.

Temporal patterns of Lomitapide-associated AE signals reporting based on FAERS and CVAROD data. (A) Number of AE reports involving Lomitapide recorded in the FAERS database from 2013 to 2024. (B) Corresponding report counts in the CVAROD database from 2015 to 2024. (C) Distribution of AE onset time in the FAERS database, defined as the interval between Lomitapide initiation and the reported AE occurrence. AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, FAERS = FDA adverse event reporting system.

3.2. Results at the SOC level

Lomitapide-related AE categories that met the positive signal threshold in at least 1 of the 4 algorithms are summarized in Table 2, and the complete list is provided in Table S2 (Supplemental Digital Content, https://links.lww.com/MD/Q601).

Table 2.

Disproportionality signals of AEs at the SOC level in the FAERS and the CVAROD database.

SOC	n	ROR (95% Cl)	PRR (χ2)	EBGM (EBGM05)	IC (IC025)
FAERS
Gastrointestinal disorders	3713	4.15 (3.99–4.31)	3.26 (6372.84)	3.26 (3.16)	1.71 (1.65)
Surgical and medical procedures	1086	6.45 (6.06–6.86)	6 (4583.33)	5.99 (5.69)	2.58 (2.49)
Investigations	2463	3.44 (3.3–3.6)	2.99 (3472.44)	2.99 (2.88)	1.58 (1.52)
Social circumstances	103	1.78 (1.47–2.16)	1.78 (35.15)	1.78 (1.51)	0.83 (0.55)
Hepatobiliary disorders	173	1.43 (1.23–1.66)	1.42 (21.64)	1.42 (1.25)	0.51 (0.28)
CVAROD
Gastrointestinal disorders	70	2.23 (1.72–2.9)	1.99 (38.12)	1.99 (1.53)	0.99 (−0.68)
Investigations	45	1.71 (1.25–2.34)	1.62 (11.54)	1.62 (1.18)	0.69 (−0.98)
Surgical and medical procedures	25	6.22 (4.14–9.34)	5.85 (101.69)	5.85 (3.89)	2.55 (0.87)
Cardiac disorders	38	6.57 (4.69–9.2)	5.97 (160.07)	5.97 (4.26)	2.58 (0.9)
Congenital, familial and genetic disorders	15	36.28 (21.62–60.9)	34.79 (491.39)	34.69 (20.67)	5.12 (3.44)
Hepatobiliary disorders	7	3.25 (1.54–6.87)	3.21 (10.69)	3.21 (1.52)	1.68 (0.01)

This table includes SOC-level AE categories that met the positive signal threshold in at least 1 of the 4 algorithms: ROR, PRR, IC, or EBGM.

AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, EBGM = empirical Bayesian geometric mean, FAERS = FDA adverse event reporting system, IC = information component, PRR = proportional reporting ratio, ROR = reporting odds ratio, SOC = system organ class based on MedDRA version 27.0.

In FAERS, Gastrointestinal Disorders showed the strongest disproportionality (n = 3713; LBROR = 3.99; EBGM = 3.26; IC025 = 1.65). Significant signals were also observed for Surgical and Medical Procedures (n = 1086; LBROR = 6.06; EBGM = 5.99; IC025 = 2.49) and Investigations (n = 2463; LBROR = 3.30; EBGM = 2.99; IC025 = 1.52). By contrast, weaker associations were noted for Social Circumstances (n = 103; LBROR = 1.47; EBGM = 1.78; IC025 = 0.55) and Hepatobiliary Disorders (n = 173; LBROR = 1.23; EBGM = 1.42; IC025 = 0.28).

In CVAROD, Gastrointestinal Disorders also showed notable disproportionality (n = 70; LBROR = 1.72; EBGM = 1.99; IC025 = –0.68). Stronger signals were seen for Surgical and Medical Procedures (n = 25; LBROR = 4.14; EBGM = 5.85; IC025 = 0.87) and Cardiac Disorders (n = 38; LBROR = 4.69; EBGM = 5.97; IC025 = 0.90). Particularly robust disproportionality was noted for Congenital, Familial, and Genetic Disorders (n = 15; LBROR = 21.62; EBGM = 34.69; IC025 = 3.44). Weaker associations included Investigations (n = 45; LBROR = 1.25; EBGM = 1.62; IC025 = –0.98) and Hepatobiliary Disorders (n = 7; LBROR = 1.54; EBGM = 3.21; IC025 = 0.01).

3.3. Results at the PT level

After analyzing all PTs related to Lomitapide, we manually removed those clearly unrelated to the drug or its associated disease. Table 3 presents the top 15 most frequent PTs that met the positive signal threshold in all 4 algorithms (ROR, PRR, IC, and EBGM) for both the FAERS and CVAROD databases; the complete list is in Tables S3 and S4 (Supplemental Digital Content, https://links.lww.com/MD/Q601). Figure S1 (Supplemental Digital Content, https://links.lww.com/MD/Q602) displays a Venn diagram of PT overlaps, Figure 3 shows a forest plot of the top 30 PTs by frequency and ROR, and Figure S2 (Supplemental Digital Content, https://links.lww.com/MD/Q602) presents the distribution of leading PTs and their SOCs. Forest plot of the top 30 most frequently reported PTs in the FAERS database that met the positive signal threshold across all 4 disproportionality algorithms: ROR, PRR, IC, and EBGM. Corresponding analysis for PTs in the CVAROD database. Subgroup analysis comparing female and male patients. Subgroup analysis comparing minors (<18 years) and adults.

Table 3.

Disproportionality signals of AEs at the PT level in the FAERS and the CVAROD database.

PT	n	ROR (95% Cl)	PRR (χ2)	EBGM (EBGM05)	IC (IC025)
FAERS
Diarrhoea	1072	8.28 (7.78–8.82)	7.69 (6296.44)	7.68 (7.29)	2.94 (2.85)
Weight decreased	832	14.42 (13.44–15.47)	13.57 (9702.19)	13.53 (12.76)	3.76 (3.65)
Therapy cessation	806	78.68 (73.22–84.54)	73.94 (57,015.79)	72.65 (68.41)	6.18 (6.08)
Nausea	525	3.13 (2.87–3.42)	3.05 (731.68)	3.05 (2.83)	1.61 (1.48)
Abdominal pain upper	267	6.1 (5.4–6.88)	5.99 (1112.93)	5.99 (5.41)	2.58 (2.4)
Abdominal discomfort	234	6.55 (5.75–7.45)	6.45 (1078.36)	6.44 (5.78)	2.69 (2.5)
Flatulence	232	19.34 (16.98–22.02)	19.02 (3945.18)	18.93 (16.98)	4.24 (4.05)
Hepatic enzyme increased	190	13.24 (11.47–15.28)	13.06 (2111.79)	13.02 (11.55)	3.7 (3.49)
Alanine aminotransferase increased	162	11.93 (10.21–13.93)	11.8 (1597.66)	11.76 (10.33)	3.56 (3.33)
Constipation	162	3.56 (3.05–4.15)	3.52 (293.75)	3.52 (3.09)	1.82 (1.59)
Abdominal pain	161	3.19 (2.73–3.73)	3.17 (239.37)	3.16 (2.78)	1.66 (1.43)
Low density lipoprotein increased	159	100.1 (85.45–117.27)	98.91 (15,049.69)	96.61 (84.63)	6.59 (6.36)
Blood cholesterol increased	152	15.1 (12.87–17.72)	14.94 (1971.12)	14.89 (13.02)	3.9 (3.66)
Product used for unknown indication	144	619.58 (519.62–738.78)	612.85 (76,531.82)	533.33 (460.32)	9.06 (8.8)
Gastrointestinal disorder	133	7.43 (6.27–8.82)	7.37 (731.96)	7.36 (6.38)	2.88 (2.63)
CVAROD
Therapy cessation	18	180.61 (112.05–291.13)	171.45 (3008.4)	169.06 (104.88)	7.4 (5.73)
Diarrhoea	15	4.04 (2.41–6.77)	3.91 (32.8)	3.91 (2.33)	1.97 (0.29)
Myocardial infarction	15	21.62 (12.88–36.27)	20.74 (281.93)	20.71 (12.34)	4.37 (2.7)
Type IIA hyperlipidemia	15	31,484.9 (12,143.02–81,635.32)	30,147.06 (129,193.76)	8614.16 (3322.29)	13.07 (11.29)
Disease progression	15	32.6 (19.42–54.71)	31.26 (438.79)	31.18 (18.58)	4.96 (3.29)
Cerebrovascular accident	13	21.75 (12.5–37.87)	20.99 (247.48)	20.95 (12.04)	4.39 (2.72)
Flatulence	8	22.99 (11.4–46.36)	22.49 (164.11)	22.45 (11.13)	4.49 (2.81)
Product dose omission issue	7	7.87 (3.72–16.63)	7.73 (41.1)	7.73 (3.66)	2.95 (1.28)
Hepatic enzyme increased	7	13.49 (6.38–28.51)	13.24 (79.23)	13.23 (6.26)	3.73 (2.05)
Abdominal distension	7	9.66 (4.57–20.41)	9.49 (53.21)	9.48 (4.48)	3.24 (1.57)
Abdominal pain upper	6	5.28 (2.35–11.83)	5.2 (20.43)	5.2 (2.32)	2.38 (0.71)
Treatment noncompliance	6	31.79 (14.17–71.33)	31.27 (175.44)	31.19 (13.9)	4.96 (3.29)
Alanine aminotransferase increased	6	16.09 (7.17–36.07)	15.83 (83.33)	15.81 (7.05)	3.98 (2.31)
Dyspnoea	5	1.23 (0.51–2.98)	1.23 (0.22)	1.23 (0.51)	0.3 (−1.37)
Palpitations	5	6.63 (2.74–16.04)	6.55 (23.56)	6.55 (2.71)	2.71 (1.04)

This table includes top 15 PT-level AEs that met all positive signal threshold in the 4 algorithms: ROR, PRR, IC, and EBGM.

AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, EBGM = empirical Bayesian geometric mean, FAERS = FDA adverse event reporting system, IC = information component, PRR = proportional reporting ratio, PT = preferred term based on MedDRA version 27.0, ROR = reporting odds ratio,

Figure 3.

Forest plots of Lomitapide-associated AE signals (top PT-level, and subgroup analyses by gender and age). (A) Forest plot of the top 30 most frequently reported PTs in the FAERS database that met the positive signal threshold across all 4 disproportionality algorithms: ROR, PRR, IC, and EBGM. (B) Corresponding analysis for PTs in the CVAROD database. (C) Subgroup analysis comparing female and male patients. (D) Subgroup analysis comparing minors (<18 yr) and adults. AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, EBGM = empirical Bayesian geometric mean, FAERS = FDA adverse event reporting system, IC = information component, PRR = proportional reporting ratio, PT = preferred term, ROR = reporting odds ratio.

3.3.1. PTs in FAERS

In FAERS, the most frequent PTs with positive signals were diarrhea (n = 1072; LBROR = 7.78; EBGM = 7.68; IC025 = 2.85), weight decrease (n = 832; LBROR = 13.44; EBGM = 13.53; IC025 = 3.65), nausea (n = 525; LBROR = 2.87; EBGM = 3.05; IC025 = 1.48), abdominal pain upper (n = 267; LBROR = 5.40; EBGM = 5.99; IC025 = 2.40), and abdominal discomfort (n = 234; LBROR = 5.75; EBGM = 6.44; IC025 = 2.50), all of which were consistent with the known gastrointestinal side effects of Lomitapide. Other common gastrointestinal PTs included flatulence (n = 232; LBROR = 16.98; EBGM = 18.93; IC025 = 4.05), constipation (n = 162; LBROR = 3.05; EBGM = 3.52; IC025 = 1.59), and abdominal pain (n = 161; LBROR = 2.73; EBGM = 3.16; IC025 = 1.43).

Immune-related AEs such as influenza (n = 78; LBROR = 2.70; EBGM = 3.36; IC025 = 1.42) and gastroenteritis virus (n = 47; LBROR = 9.12; EBGM = 12.08; IC025 = 3.18) were also observed, as well as hepatic-related AEs such as hepatic steatosis (n = 67; LBROR = 13.01; EBGM = 16.40; IC025 = 3.68), hepatic enzyme increase (n = 190; LBROR = 11.47; EBGM = 13.02; IC025 = 3.49), and aspartate aminotransferase increase (n = 129; LBROR = 9.19; EBGM = 10.81; IC025 = 3.18), prompting potential liver toxicity.

Among the PTs not listed in the prescription information but showing significant disproportionality, notable findings included treatment noncompliance (n = 53; LBROR = 3.56; EBGM = 4.64; IC025 = 1.82), steatorrhea (n = 4; LBROR = 2.52; EBGM = 6.71; IC025 = 1.45), large intestinal hemorrhage (n = 3; LBROR = 1.98; EBGM = 6.15; IC025 = 1.18), hepatomegaly (n = 10; LBROR = 2.39; EBGM = 4.44; IC025 = 1.28), hepatic pain (n = 6; LBROR = 2.85; EBGM = 6.35; IC025 = 1.57), hepatic fibrosis (n = 6; LBROR = 3.71; EBGM = 8.25; IC025 = 1.95), increased VLDL (n = 9; LBROR = 103.94; EBGM = 193.37; IC025 = 6.66), and xanthoma (n = 11; LBROR = 141.10; EBGM = 244.00; IC025 = 7.07), indicating possible concerns for hepatic and lipid metabolism abnormalities.

3.3.2. PTs in CVAROD

The most frequent PTs consistent with prescription information were diarrhea (n = 15; LBROR = 2.41; EBGM = 3.91; IC025 = 0.29), flatulence (n = 8; LBROR = 11.40; EBGM = 22.45; IC025 = 2.81), abdominal distension (n = 7; LBROR = 4.57; EBGM = 9.48; IC025 = 1.57), and abdominal pain upper (n = 6; LBROR = 2.35; EBGM = 5.20; IC025 = 0.71), confirming the gastrointestinal AE profile observed in FAERS. Liver-related AEs, hepatic steatosis (n = 3; LBROR = 9.04; EBGM = 27.89; IC025 = 3.13), increased hepatic enzyme levels (n = 7; LBROR = 6.38; EBGM = 13.23; IC025 = 2.05), and increased alanine aminotransferase levels (n = 6; LBROR = 7.17; EBGM = 15.81; IC025 = 2.31), were also reported, indicating potential hepatic toxicity.

Notably, cardiovascular PTs, such as palpitations (n = 5; LBROR = 2.74; EBGM = 6.55; IC025 = 1.04), atrial fibrillation (n = 4; LBROR = 4.31; EBGM = 11.43; IC025 = 1.84), and angina pectoris (n = 3; LBROR = 5.11; EBGM = 15.79; IC025 = 2.31), suggest possible cardiovascular risks. Newly identified PTs included decreased blood iron levels (n = 3; LBROR = 6.97; EBGM = 21.51; IC025 = 2.75), epistaxis (n = 4; LBROR = 4.01; EBGM = 10.63; IC025 = 1.74), and pleural effusion (n = 3; LBROR = 3.96; EBGM = 12.24; IC025 = 1.94), indicating possible hematological and pulmonary complications.

3.3.3. Clinical priority

In addition to analyzing the frequency and ROR values of PTs in the FAERS and CVAROD databases, we conducted clinical priority scoring, as detailed in Table S5 (Supplemental Digital Content, https://links.lww.com/MD/Q601). Table 4 presents the PTs that met the positive signal criteria for all 4 algorithms and received a clinical priority score of moderate or higher.

Table 4.

PT-level AE signals for Lomitapide with moderate clinical priority and full algorithmic signal positivity in the FAERS and the CVAROD database.

PT	n	Reporting rate, %	Positive signals	Reported case fatality rate, %	Clinical relevance	Total	Priority
FAERS
Diarrhoea	1072	8.82	4	0.28	0	3	Moderate
Weight decreased	832	6.72	4	0.12	0	3	Moderate
Therapy cessation	806	6.49	4	0.5	0	3	Moderate
Nausea	525	4.14	4	0.19	0	3	Moderate
Abdominal pain upper	267	2.06	4	0	0	3	Moderate
Abdominal discomfort	234	1.80	4	0.43	0	3	Moderate
Flatulence	232	1.79	4	0.86	0	3	Moderate
Hepatic enzyme increased	190	1.46	4	0	0	3	Moderate
Alanine aminotransferase increased	162	1.24	4	1.23	0	3	Moderate
Constipation	162	1.24	4	0.62	0	3	Moderate
Abdominal pain	161	1.23	4	0.62	0	3	Moderate
Low density lipoprotein increased	159	1.22	4	0.63	0	3	Moderate
Blood cholesterol increased	152	1.16	4	0	0	3	Moderate
Product used for unknown indication	144	1.10	4	0	0	3	Moderate
Gastrointestinal disorder	133	1.02	4	0	0	3	Moderate
Angina pectoris	37	0.28	4	2.7	1	3	Moderate
Coronary artery occlusion	15	0.11	4	6.67	1	3	Moderate
Angina unstable	10	0.08	4	20	1	3	Moderate
Carotid artery stenosis	9	0.07	4	11.11	1	3	Moderate
Carotid artery occlusion	8	0.06	4	0	1	3	Moderate
Carotid artery disease	8	0.06	4	0	1	3	Moderate
Hepatic fibrosis	6	0.05	4	0	1	3	Moderate
Aortic stenosis	5	0.04	4	0	1	3	Moderate
Aortic valve replacement	4	0.03	4	25	0	3	Moderate
Blood triglycerides decreased	3	0.02	4	33.33	0	3	Moderate
Vascular stent stenosis	3	0.02	4	0	1	3	Moderate
Large intestinal hemorrhage	3	0.02	4	33.33	1	4	Moderate
Type IIA hyperlipidemia	3	0.02	4	100	0	4	Moderate
Pancreatitis relapsing	3	0.02	4	0	1	3	Moderate
Carotid arteriosclerosis	3	0.02	4	0	1	3	Moderate
CVAROD
Therapy cessation	18	5.37	4	0	0	3	Moderate
Diarrhoea	15	4.44	4	0	0	3	Moderate
Myocardial infarction	15	4.44	4	6.67	1	4	Moderate
Type IIA hyperlipidemia	15	4.44	4	6.67	0	3	Moderate
Disease progression	15	4.44	4	6.67	0	3	Moderate
Cerebrovascular accident	13	3.82	4	0	1	4	Moderate
Flatulence	8	2.32	4	0	0	3	Moderate
Product dose omission issue	7	2.02	4	0	0	3	Moderate
Hepatic enzyme increased	7	2.02	4	0	0	3	Moderate
Abdominal distension	7	2.02	4	0	0	3	Moderate
Abdominal pain upper	6	1.73	4	0	0	3	Moderate
Treatment noncompliance	6	1.73	4	0	0	3	Moderate
Alanine aminotransferase increased	6	1.73	4	0	0	3	`Moderate
Palpitations	5	1.44	4	0	0	3	Moderate
International normalized ratio increased	5	1.44	4	0	0	3	Moderate
Gastrointestinal disorder	5	1.44	4	0	0	3	Moderate
Epistaxis	4	1.15	4	0	0	3	Moderate
Atrial fibrillation	4	1.15	4	0	1	4	Moderate
Angina pectoris	3	0.86	4	0	1	3	Moderate
Carotid artery stenosis	3	0.86	4	33.33	1	4	Moderate

This table lists PTs that met the positive signal criteria in all 4 disproportionality algorithms (ROR, PRR, IC, EBGM) and were classified as having moderate clinical priority based on a composite scoring system (see Table S5, Supplemental Digital Content, https://links.lww.com/MD/Q601).

AEs = adverse events, CVAROD = Canada Vigilance Adverse Reaction Online Database, EBGM = empirical Bayesian geometric mean, FAERS = FDA adverse event reporting system, IC = information component, PRR = proportional reporting ratio, PT = preferred term, ROR = reporting odds ratio.

3.4. Subgroup analysis (FAERS)

Subgroup analyses were conducted to explore potential differences in AE reporting across various demographic groups, including age and gender (Tables S6 and S7, Supplemental Digital Content, https://links.lww.com/MD/Q601). The findings of these analyses are shown in the forest plots presented in Figure 3.

3.4.1. Age subgroup analysis

Diarrhea was more frequent and had a higher ROR in minors (n = 10; LBROR = 7.53; EBGM = 13.19; IC025 = 2.81) than in adults (n = 614; LBROR = 7.70; EBGM = 7.71; IC025 = 2.83), may be associated with greater sensitivity in younger patients. Minors also showed higher RORs for upper abdominal pain (n = 6; LBROR = 7.39; EBGM = 15.94; IC025 = 2.87 vs adults n = 152; LBROR = 5.24; EBGM = 6.03; IC025 = 2.36) and vomiting (n = 6; LBROR = 1.96; EBGM = 4.26; IC025 = 0.97 vs adults n = 327; LBROR = 3.05; EBGM = 3.29; IC025 = 1.56). Notably, minors exhibited a markedly elevated ROR for low-density lipoprotein (n = 4; LBROR = 279.32; EBGM = 716.46; IC025 = 8.14) compared to adults (n = 74; LBROR = 66.81; EBGM = 81.84; IC025 = 6.02), highlighting the potential metabolic risks in pediatric patients.

3.4.2. Gender subgroup analysis

In FAERS, diarrhea was common in both males (n = 265; LBROR = 8.66; EBGM = 9.00; IC025 = 2.98) and females (n = 499; LBROR = 7.02; EBGM = 7.16; IC025 = 2.71), with males exhibiting a higher risk. Similarly, decreased weight was more frequently reported in males (n = 235; LBROR = 14.82; EBGM = 15.60; IC025 = 3.77) than females (n = 362; LBROR = 12.20; EBGM = 12.81; IC025 = 3.52). In contrast, abdominal pain (males: n = 34; LBROR = 2.43; EBGM = 3.38; IC025 = 1.27; females: n = 67; LBROR = 2.00; EBGM = 2.52; IC025 = 0.98) and abdominal distension (males: n = 31; LBROR = 5.14; EBGM = 7.26; IC025 = 2.35; females: n = 58; LBROR = 3.77; EBGM = 4.85; IC025 = 1.90) showed comparable frequencies and ROR values, could be linked to that gender had a limited impact on these symptoms.

Females had higher reports and RORs for therapy cessation (females, n = 349; LBROR = 62.04; EBGM = 64.53; IC025 = 5.85 vs males, 142; LBROR = 50.85; EBGM = 56.81; IC025 = 5.58), indicating a greater likelihood of discontinuing treatment due to AEs. Liver-related events were reported more frequently by females; in particular, hepatic enzyme increased (females: n = 86; LBROR = 9.57; EBGM = 11.67; IC025 = 3.23 vs males: n = 41; LBROR = 10.78; EBGM = 14.45; IC025 = 3.40) and aspartate aminotransferase increased (females: n = 49; LBROR = 7.39; EBGM = 9.70; IC025 = 2.87 vs males: n = 27; LBROR = 5.84; EBGM = 8.46; IC025 = 2.53), although ROR values were similar (see Table S7, Supplemental Digital Content, https://links.lww.com/MD/Q601).

4. Discussion

Lomitapide, an LDLR-independent MTP inhibitor, offers an oral alternative for HoFH patients unresponsive to standard therapies.^[16–18] By inhibiting apoB-containing lipoprotein secretion, it effectively reduces VLDL and LDL-C levels.^[19,20] It is recommended by both NLA and ESCs/EASs as adjunctive therapy in resistant cases.^[21] However, its growing use has raised concerns over long-term safety, especially hepatotoxicity and gastrointestinal intolerance,^[22] with current evidence largely based on small trials and lacking real-world validation.^[23]

This is the first real-world pharmacovigilance study of Lomitapide using both FAERS and CVAROD, enhancing signal robustness and generalizability. We applied 4 disproportionality methods (ROR, PRR, IC, and EBGM) for cross validation. Subgroup analyses by gender and age, along with a first-time time-to-onset evaluation, support early clinical monitoring strategies and dynamic risk management.

This study uses disproportionality analyses of spontaneous reporting systems (FAERS, CVAROD) to identify reporting signals. By design, these methods are hypothesis-generating and do not establish causality. Estimates reflect reporting disproportionality, which can be influenced by under-/over-reporting, notoriety bias, co-medications, indication, and data quality. Hence, our findings should be interpreted as signals that warrant verification with complementary epidemiologic designs, not as causal risk estimates.

4.1. Previously unreported signals identified in real-world data

This study identified several important AE signals not previously documented in the prescribing information or postmarketing literature for Lomitapide, thereby expanding the real-world safety profile of the drug and offering clinically relevant insights.^[24] Notably, renal pain (n = 10; LBROR = 2.33) emerged in the FAERS database, indicating potential renal involvement requiring close monitoring in vulnerable patients.^[25] Additionally, metabolic-related events such as xanthoma (n = 11; LBROR = 141.10) and yellow skin (n = 5; LBROR = 2.00) may reflect disruptions in lipid trafficking or hepatic-biliary processes, underscoring the need for mechanistic investigation. New bleeding-related signals, including large intestinal hemorrhage (n = 3; LBROR = 1.98, FAERS) and epistaxis (n = 4; LBROR = 4.01, CVAROD), prompt a potential hemostatic imbalance, possibly exacerbated by concomitant anticoagulants. Collectively, these previously unreported events may inform future hypothesis-driven studies and guide targeted risk monitoring in vulnerable subpopulations.

These novel signals should be interpreted in the context of established safety evidence. Clinical trials and registry data consistently identified gastrointestinal and hepatic events as the dominant risks of Lomitapide, which aligns with our strongest disproportionality findings. By contrast, the newly observed signals in this analysis (e.g., bleeding, renal, metabolic) have not been systematically described in controlled studies, indicating they may emerge more readily in real-world practice under heterogeneous patient conditions and concomitant therapies. This contrast underscores the hypothesis-generating value of pharmacovigilance studies and highlights the need for validation in longitudinal datasets.

4.2. Potential progressive hepatic injury associated with Lomitapide

Although the 72-week trial cited in the labeling reported reversible hepatic steatosis without progression to fibrosis, our findings raise concerns regarding potential long-term hepatic AEs. We detected signals for hepatic steatosis (n = 67; LBROR = 13.01), hepatic pain (n = 6; LBROR = 2.85), hepatomegaly (n = 10; LBROR = 2.39), and hepatic fibrosis (n = 6; LBROR = 3.71). Despite the small number of reports, the signal strength and clinical implications highlight possible progressive liver injury with prolonged exposure.^[26] Mechanistically, Lomitapide inhibits MTP in the endoplasmic reticulum of hepatocytes and enterocytes, impairing apoB-lipoprotein secretion, which promotes lipid accumulation and endoplasmic reticulum stress.^[27,28] While mid-term trials showed no irreversible damage, real-world data call for caution when interpreting long-term hepatic safety.

Future studies should further investigate whether extended treatment durations may be associated with cumulative fibrotic progression and explore the reversibility of such damage. These insights are critical for developing personalized safety monitoring strategies and optimizing long-term therapeutic management.^[13]

4.3. Individualized dose adjustment recommendations for Lomitapide

Lomitapide was initiated at 5 mg/day and titrated to a maximum of 60 mg/day per current labeling.^[29] However, our analysis revealed significant inter-individual variability in the lipid response following Lomitapide treatment, reflecting that a fixed-dose escalation strategy may not be suitable for all patients. In the FAERS database, we identified multiple lipid-related AE signals in opposing directions, including “LDL increased” (n = 159; LBROR = 85.45), “LDL decreased” (n = 5; LBROR = 6.78), and “LDL abnormal” (n = 12; LBROR = 55.25); “blood cholesterol increased” (n = 152; LBROR = 12.87), “blood cholesterol decreased” (n = 4, LBROR = 3.66), and “blood cholesterol abnormal” (n = 5; LBROR = 2.05); “HDL increased” (n = 4; LBROR = 6.95) and “HDL decreased” (n = 31; LBROR = 29.21); as well as “triglycerides increased” (n = 38; LBROR = 7.02) and “triglycerides decreased” (n = 3; LBROR = 12.74).

The variability in signal patterns underscores that some patients may be over treated, whereas others remain under treated. Given stable liver enzymes, dose adjustments should be individualized based on lipid profiles. Real-time monitoring enables timely modifications to optimize efficacy and minimize AEs.

4.4. Bleeding-related AEs and clinical implications for anticoagulant co-administration

Although bleeding is not listed in Lomitapide’s prescription information, our analysis identified potential associations with hemorrhagic AEs. In FAERS, large intestinal hemorrhage (n = 3; LBROR = 1.98) was statistically significant, while epistaxis (n = 4; LBROR = 4.01) was notable in CVAROD. The former was also classified as a moderate clinical priority, reinforcing its relevance in clinical practice. These signals indicate that Lomitapide may increase the bleeding risk under certain clinical conditions. Patients with HoFH, due to elevated LDL-C and ASCVD risk, frequently require anticoagulation, particularly with Warfarin.^[29] Lomitapide is known to elevate warfarin plasma concentrations, necessitating the close monitoring of coagulation parameters. This interaction may potentiate Warfarin’s intrinsic bleeding risk, yet it remains under-recognized in routine care.

Given these findings, caution is advised when Lomitapide is co-administered with anticoagulants. Clinicians should monitor for signs of bleeding, especially gastrointestinal and nasal, and regularly assess the coagulation status. In particular, INR monitoring is recommended at baseline, weekly during initiation or dose adjustments, and periodically (e.g., each 1–3 months) once stable. Dose adjustments of Lomitapide or the anticoagulant may be necessary to reduce the bleeding risk and ensure safe co-therapy.

Furthermore, the higher RORs observed in minors for several PTs highlight the need for more cautious use in pediatric patients. Initiation and titration should be conservative, accompanied by closer monitoring. More frequent liver enzyme assessments during titration, reinforcement of dietary counseling, and attention to fat-soluble vitamin supplementation are advisable. These recommendations should be interpreted with caution, given the limited pediatric sample size and the hypothesis-generating nature of disproportionality analyses.

4.5. Early onset gastrointestinal AEs and adherence management

Our analysis revealed that most GI AEs related to Lomitapide occurred within the first 2 weeks of treatment, peaking at initiation. This early onset may stem from poor adherence to the recommended low-fat diet (<20% of the total caloric intake), which can exacerbate lipid malabsorption due to MTP inhibition.^[30] In real-world settings, suboptimal dietary compliance is likely to contribute to the high incidence of GI intolerance.

The prominent symptoms included diarrhea (n = 1072; LBROR = 7.78), nausea (n = 525; LBROR = 2.87), upper abdominal pain (n = 267; LBROR = 5.40), abdominal discomfort (n = 234; LBROR = 5.75), flatulence (n = 232; LBROR = 16.98), and constipation (n = 162; LBROR = 3.05). Literature reports GI AE rates as high as 93%, with diarrhea and nausea being the most common. These symptoms significantly impair the quality of life and are a major cause of early treatment discontinuation.

To mitigate GI AEs, patient education regarding strict dietary fat restriction is essential. Integration of structured dietary counseling protocols – ideally involving dietitians at treatment initiation and follow-up visits – may help reinforce adherence, minimize GI intolerance, and improve long-term treatment persistence. Early dietary supervision, coupled with gradual dose titration, may improve tolerance and adherence, thereby reduce premature discontinuation and optimizing treatment outcomes.

4.6. Limitations

Despite strengthened signal detection through multi-database integration and cross-validation, this study has limitations. Disproportionality methods (ROR, PRR, IC, EBGM) are frequency-based and cannot infer causality, and are vulnerable to reporting bias, under-reporting, and duplication. The CVAROD dataset included relatively few reports, which may weaken signal stability. Both FAERS and CVAROD are spontaneous reporting systems subject to inconsistencies, subjective severity ratings, and variable reporting quality. Moreover, the absence of reliable exposure duration, dosing, and precise event timing may lead to misclassification.

Future work should apply leave-one-out sensitivity analyses to assess robustness in small datasets like CVAROD. Complementary designs – such as active-comparator cohorts, self-controlled case series, and negative-control outcomes – are also needed to validate these signals. Larger prospective studies and real-world data will be essential to confirm findings and clarify potential causal associations.

5. Conclusion

This study, based on the analysis of the FAERS and CVAROD databases, identified several common AEs associated with the clinical use of Lomitapide, including gastrointestinal symptoms, hepatic toxicity, and lipid metabolism abnormalities. Diarrhea and weight decrease were the most commonly reported AEs, with high occurrence rates observed across different gender and age groups. Additionally, hepatic-related AEs such as increased hepatic enzyme levels warrant particular attention. Furthermore, Lomitapide appears to affect lipid metabolism, particularly with changes in LDL, suggesting the need to monitor the metabolic status during treatment.

Acknowledgments

The authors would like to acknowledge the use of data from the FDA Adverse Event Reporting System (FAERS), provided by the FDA, and the Canada Vigilance Adverse Reaction Online Database (CVAROD), provided by Health Canada.

Author contributions

Conceptualization: Shangze Li.

Data curation: Yijia Liu, Hui Wang.

Formal analysis: Qiaoyan Chen.

Funding acquisition: Yijia Liu.

Investigation: Qiaoyan Chen, Shangze Li, Hui Wang.

Methodology: Yijia Liu.

Project administration: Zhiwen Zheng.

Resources: Zhiwen Zheng.

Software: Zhiwen Zheng, Qiaoyan Chen, Shangze Li, Hui Wang.

Supervision: Qiaoyan Chen.

Visualization: Xurong Liu, Qiaoyan Chen, Hui Wang.

Writing – original draft: Xurong Liu, Zhiwen Zheng, Shangze Li.

Writing – review & editing: Xurong Liu, Zhiwen Zheng, Qiaoyan Chen, Yijia Liu.