Therapeutic efficacy and safety of newly approved FDA drug levoketoconazole in cushing syndrome: a systematic review

Abstract

Background:

Cushing syndrome is a severe endocrinopathy due to chronic hypercortisolism with etiology that includes the administration of exogenous glucocorticoids, pituitary adenomas, ectopic ACTH-producing tumors, and adrenal tumors. Expressed as central obesity, hypertension, glucose intolerance, and psychiatric symptoms, it greatly affects the QoL and has a high association with morbidity and mortality.

Aim:

This systematic review summarizes data from clinical trials to compare the effectiveness and safety of a newly approved drug, levoketoconazole, for the treatment of Cushing syndrome.

Methodology:

An extensive search was conducted in PubMed, Google Scholar, and the Cochrane Library for terms related to the effectiveness and safety of levoketoconazole in Cushing syndrome. Selected studies included phase 2 and phase 3 interventional trials enrolling adult patients (≥18 years) with confirmed endogenous Cushing syndrome (ECS). Outcomes of interest included mean urinary free cortisol (mUFC), clinical signs and symptoms, quality of life measures, and adverse events. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias Tool.

Results:

Six interventional studies were included. In the SONICS phase 3 trial, 62% of patients achieved normalization of mUFC at the end of the 6-month maintenance phase, with sustained biochemical and clinical benefits during extended evaluation. During the randomized withdrawal phase of the LOGICS trial, loss of mUFC response occurred in 95.5% of patients switched to placebo compared with 40.5% of patients who continued levoketoconazole treatment (P = 0.0002), demonstrating maintenance of biochemical control with active therapy. Common adverse events included nausea, headache, hypokalemia, and fatigue. Serious drug-related adverse events were uncommon but clinically relevant, including hepatotoxicity, QT prolongation, and adrenal insufficiency.

Conclusion:

Levoketoconazole significantly lowers cortisol levels and alleviates clinical manifestations in patients with Cushing syndrome with reasonable safety. There is a need to perform a periodic checkup of the liver function and adrenal insufficiency. Additional long-term research is needed to strengthen its place in treatment plans.

Introduction

Cushing syndrome is a rare endocrinopathy caused by chronic hypercortisolism due to various causes, including prolonged glucocorticoid therapy, Cushing’s disease due to pituitary adenomas, ectopic ACTH-secreting tumors, and adrenal tumors^[1^]. The common manifestations are central obesity, moon face, hypertension, glucose intolerance, muscle weakness, osteoporosis, and psychological complaints that reduce quality of life and increase morbidity and mortality^[2^]. Levoketoconazole is a newly introduced drug in the American market, an enantiomer of ketoconazole – an antifungal that inhibits enzymes involved in cortisol synthesis – but it also has side effects such as hepatotoxicity. Cortisol acts through the glucocorticoid receptor and, after binding to it, the receptor translocates to the nucleus and modulates the activity of genes affecting metabolism, immune response, and other processes^[3^]. Cushing syndrome occurs when there is prolonged exposure to high levels of cortisol in the body. There is central obesity and facial rounding, which are attributed to changes in adipose tissue distribution, and there are catabolic effects on muscle and bone tissue that lead to muscle weakness and osteoporosis^[4–6^]. Hypertension results from the impact of cortisol on blood vessels, while glucose intolerance is due to cortisol’s impact on glucose metabolism. Also, cortisol affects the central nervous system; therefore, psychiatric disturbances, including depression and cognitive impairment, are evident^[7^].

HIGHLIGHTS

• Levoketoconazole achieved significant normalization of mean urinary free cortisol (mUFC) levels, confirming its potential as an effective medical therapy for endogenous Cushing syndrome.

• The review identifies levoketoconazole as a well-tolerated steroidogenesis inhibitor with manageable adverse effects, such as mild gastrointestinal symptoms and rare hepatotoxicity or adrenal insufficiency.

• Long-term use of levoketoconazole was associated with improvements in blood pressure, glucose metabolism, body weight, and quality of life among treated patients.

Levoketoconazole works by inhibiting some of the enzymes of the steroidogenesis process, leading to decreased cortisol production. In particular, it suppresses the activity of two enzymes, CYP11B1 and CYP17A1, which are involved in the synthesis of cortisol and other steroids from cholesterol. Thus, the drug reduces cortisol concentrations in patients with Cushing syndrome by inhibiting these enzymes^[8^]. The mechanism of action is similar to that of ketoconazole, but levoketoconazole is more selective and therefore expected to have fewer side effects. Preclinical and clinical studies were conducted to determine the efficacy and adverse effects of levoketoconazole. Earlier in vivo experiments confirmed that levoketoconazole effectively reduced cortisol output in animal models with hypercortisolism. These findings laid the groundwork for clinical trials in an effort to compare the effects of the drug in humans^[9^]. Among the clinical trials, there was a multicentre, open-label clinical trial involving patients with endogenous Cushing syndrome. The primary measure used to determine the success of the intervention was the mean urinary free cortisol (mUFC) level, and secondary outcomes were changes in clinical signs, patients’ quality of life, and safety^[9^]. The outcomes of this trial were positive. A high percentage of the patients had their mUFC levels normalized, indicating good control of hypercortisolism. Additionally, clinical parameters including blood pressure, glucose tolerance, and obesity were improved, and patients reported an improved quality of life, which is a general indicator of the medication’s therapeutic value. Most important of all, the rates of adverse events (AEs) were relatively low, and the majority of the reported AEs were mild to moderate in severity^[10^].

Although the drug is related to ketoconazole, it is in the enantiomeric form that provides selectivity and therefore fewer side effects. The side effects described in clinical trials are headache, nausea, vomiting, abdominal pain, and fatigue. Such side effects are usually moderate to severe and often disappear when the dose is reduced or if the patient receives appropriate therapy^[10^]. Another adverse effect related to ketoconazole was hepatotoxicity, which was less frequently reported with levoketoconazole. Patient’s liver function tests were checked periodically during clinical trials, and cases of increased liver enzymes were generally acute and potentially reversible^[11^]. In some cases, hepatotoxic effects were reported, but withdrawal of the drug resulted in the restoration of liver function, which emphasizes the need for monitoring the therapy. As a result of its pharmacology, levoketoconazole can affect the adrenal glands and adrenal insufficiency may be seen, particularly if the treatment is continued for a long time. Corticosteroid replacement therapy should be considered in patients who are at risk of developing adrenal insufficiency and patients should be observed for signs and symptoms of adrenal insufficiency. The drug should, therefore, be prescribed after frequent monitoring of adrenal function has been done^[12–14^].

Levoketoconazole has proven to be a significant advancement toward the treatment of Cushing syndrome. This study shows that the drug has a potent anti-cortisol effect and, at the same time, the drug’s safety profile appears favorable for the management of this complicated condition. It has been established that it can effectively manage cortisol levels and clinical signs. However, it is important to monitor for possible side effects such as hepatotoxicity and adrenal insufficiency, but the risk-benefit analysis of levoketoconazole is promising^[15–17^]. As with any new therapy, there is a need for more research and post-marketing evaluation of the safety profile and effectiveness of levoketoconazole in the long term. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, was developed to provide more selective inhibition of steroidogenic enzymes involved in cortisol synthesis while potentially reducing off-target toxicity. Phase 3 clinical trials have evaluated its biochemical efficacy, clinical benefits, and safety profile in patients with endogenous Cushing syndrome. This systematic review synthesizes available interventional evidence to critically evaluate its therapeutic role.

Rationale

This systematic review is needed because Cushing syndrome (CS) creates many clinical challenges due to the numerous pathogenic effects and the greater morbidity and mortality associated with chronic hypercortisolism. These facts, with regard to surgery and conventional drugs, show that there is a lack of new drugs and therapies. Levoketoconazole, newly approved by the FDA and an enantiomer of ketoconazole, has the potential to become the drug of choice, as it selectively inhibits some of the enzymes involved in cortisol synthesis without many of the side effects associated with ketoconazole. The aim of this article is to present a systematic review of the efficacy and safety of levoketoconazole for clinical treatment and to establish the basis for its application in clinical practice and further studies. This article seeks to gather current data and review it in order to show the drug’s impact on cortisol levels, clinical symptoms, and patient outcomes to provide a comprehensive analysis of its efficacy in the treatment of Cushing syndrome.

Objectives

The aim of this systematic review is to provide an objective evaluation of the efficacy and safety profile of levoketoconazole in the treatment of Cushing syndrome (CS). This entails evaluating the clinical utility of the drug from data obtained from phase III clinical trials and observational studies to assess the ability of the drug to restore cortisol levels and improve patients’ clinical symptoms and overall quality of life. Furthermore, an assessment of the safety of the levoketoconazole intervention will be made in the review; therefore, it will compare side effects such as hepatotoxicity and adrenal insufficiency. It is intended to provide clinical management suggestions for CS treatment, provide evidence for the inclusion of levoketoconazole in therapeutic guidelines, and point to future research avenues to improve CS patient care.

Methodology

The work has been reported in line with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), TITAN, and AMSTAR (assessing the methodological quality of systematic reviews) guidelines.

Inclusion criteria

Only interventional phase 2 and phase 3 clinical trials enrolling adult patients (≥18 years) with confirmed endogenous Cushing syndrome were included. Eligible study designs included open-label, randomized-withdrawal, and double-blind, placebo-controlled trials. Observational studies, pediatric studies, animal studies, case reports, reviews, editorials, and non-clinical comparative studies were excluded. An in-vitro study was included solely to describe mechanistic and pharmacological effects and was not considered in the clinical outcome synthesis.

Exclusion criteria

Exclusion criteria were intended to eliminate studies that would not be useful in the context of the review. Investigations that included children or animals were omitted to focus on the adult human population diagnosed with endogenous Cushing’s syndrome. In addition, studies in which levoketoconazole was not the primary intervention were excluded to limit the review to this therapy. Observational studies, case reports, reviews, editorials, and non-clinical comparative studies were also excluded to focus on clinical trial-level evidence. This approach ensured that the included studies provided sound and clinically valuable information regarding the effectiveness and safety of levoketoconazole in treating Cushing’s syndrome.

Database search

The database search for this systematic review employed PubMed, Google Scholar, and the Cochrane Library to identify papers on the efficacy and safety of levoketoconazole in the treatment of Cushing syndrome. The search terms included multiple synonyms and related terms for efficacy, safety, levoketoconazole, and Cushing syndrome, and the use of these terms resulted in a broader search in PubMed with eight articles, in Google Scholar with 213 articles, and in the Cochrane Library with six articles, which yielded a more comprehensive and relevant body of literature (Table 1).

Table 1.

Database search strategy.

Database	Search terms	Results
PubMed	(“efficacies”[All Fields] OR “efficacious”[All Fields] OR “efficaciously”[All Fields] OR “efficaciousness”[All Fields] OR “efficacy”[All Fields]) AND (“safety”[MeSH Terms] OR “safety”[All Fields] OR “safeties”[All Fields]) AND “Levoketoconazole”[All Fields] AND (“cushing syndrome”[MeSH Terms] OR (“cushing”[All Fields] AND “syndrome”[All Fields]) OR “cushing syndrome”[All Fields])	8
Google scholars	“Safety AND efficacy AND levoketoconazole AND Cushing’s syndrome”	213
Cochrane library	(“safety”):ti,ab,kw AND (“Levoketoconazole”):ti,ab,kw AND (“Cushing syndrome”):ti,ab,kw AND (“efficacy”):ti,ab,kw	6

Screening of studies

The initial step toward screening involved identifying 227 articles in PubMed, Google Scholar, and the Cochrane Library. Of the 115 records identified, 112 were duplicates, and 3 were tagged as ineligible by automated tools; of these, 8 more were screened out for other reasons, making the final total of records to be screened 104. The total number of such materials was 76, and it decreased as most of them were not relevant or contained inadequate information. We then screened the titles of the remaining 28 records and excluded 22 after screening the full text of the articles. Specifically, 6 research papers were included in the final analysis after applying the inclusion and exclusion criteria to all the studies identified in the search.

Outcome measures

The primary end point for this systematic review was the change in mean urinary free cortisol (mUFC) levels in patients with Cushing syndrome treated with levoketoconazole. Secondary endpoints were changes in clinical signs such as blood pressure, glucose metabolism, weight, quality of life, and safety profile, as assessed by the rates of hepatotoxicity, QT interval prolongation, and adrenal insufficiency. Other measures evaluated included patient-reported quality of life using the CushingQoL and depressive symptoms using the Beck Depression Inventory–II (BDI-II).

Data extraction

For this systematic review, data collection required the identification of all relevant information from each study selected for inclusion, using a proforma. Data extracted from the studies included study information, population characteristics, intervention details, primary and secondary outcomes, and findings. Moreover, this approach helped standardize and clarify data collection across all related studies.

Risk of bias assessment

The risk-of-bias assessment was conducted using the Cochrane Collaboration’s tool, focusing on several key domains: the following biases were defined for assessment–random sequence generation (randomization) and allocation concealment; blinding of participants and personnel; blinding of outcome assessors; completeness of outcome data; selective reporting of outcomes; and any other bias. For the purposes of the current review, both published qualitative and quantitative studies were assessed using Cochrane’s risk-of-bias tool; each study was rated as having a low, high, or unclear risk of bias in each domain to provide an overall quality rating of the studies included in the review.

Results

Literature search results

The literature search of the databases PubMed, Google Scholar, and the Cochrane Library resulted in a total of 227 studies. From the original 117 records, a number of records were excluded due to insufficient or insignificant data, and a few were excluded for other reasons. An attempt was made to read the full texts of the remaining 28 records, which resulted in the exclusion of 22 more records. Finally, 6 papers were identified for inclusion in the systematic review (Fig. 1).

Figure 1.

PRISMA flow diagram.

Characteristics of the included studies

Levoketoconazole is a stereoisomer of ketoconazole used as a treatment modality for Cushing’s syndrome, but it has not been tested in clinical trials for this indication until now. Thus, the overarching aim of this trial was to evaluate the efficacy of the antifungal agent levoketoconazole for the treatment of endogenous Cushing’s syndrome. SONICS is a phase 3, multicenter, open-label, nonrandomized single-arm study planned for adult patients with confirmed Cushing’s syndrome and mean 24-hour urine free cortisol (mUFC) equal to or more than 1.5 times the upper limit of normal (ULN), conducted at 60 hospitals as well as other community centers in 19 countries. The patient was gradually built up on the study medication levoketoconazole, starting with 300 mg bid with dosing intervals of 2–21 days until the mUFC normalized or the maximum dose of 600 mg bid was attained and then observed at this dose for 6 months. To assess the comparative effectiveness of treatment, the primary end point used was the proportion of patients with mUFC normalization at the end of the maintenance phase without dose increase during this phase, and other events of special interest included possible liver injury, corrected QT prolongation, and adrenal insufficiency. The trial, registered with ClinicalTrials.gov number NCT01838551, screened 201 patients from 30 July 2014 to 30 June 2017, and 94 patients were enrolled to receive at least one dose of the study medication; of these, 80 (85%) had pituitary Cushing’s syndrome. With regard to the baseline mean mUFC, it reached 671.4 nmol/24 h, i.e., 90 times the upper limit of normal. Out of 77 patients who moved to the maintenance phase, 62 of them (81%) had normal mUFC at the end of the dose titration phase; therefore, a total of 29/94 (31%) of the patients were responders, with a least-squares mean estimate of the proportion of response of 0.30 (95% CI, 0.21–0.40; P = 0.0154 over the null hypothesis of ≤0.20). The common side effects observed in the study included nausea (32%) and headache (28%), and these side effects were deemed severe enough to lead to discontinuation in about 13% of the patients; of them, two had a QT interval (Fridericia corrected) greater than 500 ms, and three patients had signs suggestive of adrenal insufficiency. In this study, alanine aminotransferase elevation of more than three times the upper limit of normal was observed in 11% of patients, but the changes were reversible, and four patients had severe potential adverse drug reactions that were probably or definitely caused by the study drug, including hepatotoxicity, QT-prolongation, and adrenal failure. Concerning the cause of death, the study medication was not related to any of the reported deaths; one patient died from colon carcinoma. In this study, levoketoconazole was administered twice daily, and suppression of urinary free cortisol, indicating its safety and tolerability, was satisfactory, suggesting that levoketoconazole might be a beneficial treatment for Cushing’s syndrome^[18^].

SONICS was a phase 3, multicenter, open-label, single-arm trial evaluating levoketoconazole in adults with endogenous Cushing syndrome and baseline mUFC ≥1.5 × ULN. Patients underwent dose titration (150–600 mg twice daily), followed by a 6-month maintenance phase. At the end of maintenance, 62% of patients achieved mUFC normalization. Common adverse events included nausea (32%) and headache (28%). Serious drug-related adverse events included alanine aminotransferase elevations >3 × ULN (11%), QT prolongation >500 ms (2 patients), and suspected adrenal insufficiency (3 patients)^[19^].

LOGICS was a Phase 3, double-blind, placebo-controlled, randomized-withdrawal study evaluating the maintenance of levoketoconazole efficacy in patients with endogenous Cushing syndrome. During the randomized-withdrawal phase, patients who had achieved biochemical control were assigned either to continue levoketoconazole treatment or to receive placebo. Loss of mUFC response occurred in 95.5% of placebo-treated patients, compared with 40.5% of patients who continued levoketoconazole therapy (P = 0.0002), confirming the sustained biochemical efficacy of active treatment^[20^].

Regarding the personality of CS, it is possible to state that it has several comorbidities, one of which is diabetes. CS clinical management employs the oral ketoconazole stereoisomer levoketoconazole. This umbrella trial was conducted for patients with confirmed CS and mUFC ≥1; thus, SONICS is a phase 3 open-label trial. Six times the upper limit of normal (ULN) was used for the dose-titration phase, the 6-month maintenance phase, and the 6-month extension phase combined. The present subanalysis compared 28 new-onset DM patients and 49 non-DM patients in the maintenance phase with levoketoconazole. In the dose-titration and maintenance phase, safety assessment was conducted for N = 94 patients. Among the 160 DM patients who underwent the maintenance phase, mUFC was normalized in 46 patients (95% CI = 28–66; P = 0.006, compared to a null hypothesis that the proportion would be ≤20%). Similarly, 33 of 164 non-DM patients achieved normalization of mUFC (95% CI = 20–48; P = 0.0209) without an increase in the dosage of umedafop. The primary outcome measure of the SONICS trial showed a mean HbA1c reduction from 6% to 5% in patients with type 2 diabetes on standard liraglutide therapy. At the beginning of the study, 34 patients were screened for TB, and by the end of the study, this number had decreased to 6% of the total number of patients screened. The incidence of the condition reaches 2% in DM patients, with an overall incidence ranging from 5% in the general population to 2.5% to 5%. Studies of the efficacy of umedafop in obesity described a contribution of 3% among non-DM individuals. The levels of fasting blood glucose were significantly raised in the DM patient group compared to normal levels, which had a mean of 5. The level of fasting blood glucose in patients with diabetes mellitus was 4.82 mmol/L (104.9 mg/dL), and for non-DM patients, it was 5.11 mmol/L (92.1 mg/dL). Side effects were more frequent in DM patients: nausea, 62.3%; vomiting, 19%; urinary tract infection, 16%; and only 4% to 7% from the musculoskeletal system, none of which led to the discontinuation of study medication. Levoketoconazole maintained mUFC at normal levels, and it was observed that the study drug was significantly helpful in achieving better glycemic control, especially in the DM participants^[21^]. Table 2 denotes the summary of the studies included.

Table 2.

Summary of the included studies.

Author and year	Study design	Objective/methods, factors, outcome measures	Results	Limitations	Implications
Fleseriu et al, 2019	Phase3, multicenter, open-label, non-randomized, single-arm	Evaluate efficacy and safety of levoketoconazole in patients with CS. Methods: Dose-titration (2-21 weeks, 150-600 mg BID), 6-month maintenance. Primary outcome: mUFC normalization.	62% achieved mUFC normalization. 31% were responders at 6 months. Common AEs: nausea (32%), headache (28%). Serious AEs: liver function, QT prolongation, adrenal insufficiency.	Single-arm design, no control group, small sample size.	Levoketoconazole may be an effective and safe treatment option for CS, but further studies needed.
Fleseriu et al, 2022	Extended evaluation phase of SONICS	Assess long-term safety, tolerability, and benefit/risk of levoketoconazole. Methods: 6-month extension (EE) phase. Outcome measures: mUFC response, clinical signs and symptoms, QoL, depression scores.	55.1% and 40.9% had normalized mUFC at months 9 and 12, respectively. Improvements in glucose, cholesterol, weight, BMI, QoL, and depression maintained. Common AEs: arthralgia, headache, hypokalemia, QT prolongation.	Long-term follow-up limited, observational design, no control group.	Long-term treatment with levoketoconazole shows sustained benefits and acceptable safety profile.
Zacharieva et al, 2021	Phase 3, double-blind, placebo-controlled, randomized-withdrawal (LOGICS)	Investigate levoketoconazole in CS. Methods: Open-label titration-maintenance (14-19 weeks), double-blind randomized-withdrawal (8 weeks), restoration phase (8 weeks). Primary endpoint: loss of mUFC response.	More placebo patients (95.5%) lost mUFC response than levoketoconazole patients (40.9%). mUFC normalization higher in levoketoconazole group (50.0% vs 4.5%).	Short R-W phase duration, potential bias due to open-label titration-maintenance phase.	Confirms levoketoconazole efficacy and safety, supports its use as an important treatment option for CS.
Creemers et al, 2021	In vitro study	Compare levoketoconazole and RK on adrenocortical and pituitary adenoma cells. Methods: HAC15 cells, primary human neoplastic adrenocortical cultures, murine and human corticotroph adenoma cultures incubated with levoketoconazole or RK (0.01–10 µM).	Levoketoconazole more potent in inhibiting cortisol production than RK. Inhibited cell growth and ACTH secretion in AtT20 cells. Reduced cell number in primary human corticotroph pituitary adenoma cultures.	In vitro study, not directly translatable to clinical outcomes, limited sample size of cultures.	Levoketoconazole is a promising pharmacotherapy for CS, showing more potency and potential safety over RK.
Geer et al, 2021	Phase 3, open-label (SONICS)	Evaluate clinical signs, symptoms, and patient-reported outcomes in CS patients. Methods: Dose titration, 6-month maintenance. Secondary endpoints: clinical signs, QoL, depression symptoms.	Significant improvements in acne, hirsutism, peripheral edema, QoL, and depression scores. No significant improvement in composite score of other clinical signs.	Open-label design, lack of control group, potential bias in patient-reported outcomes.	Levoketoconazole treatment improves QoL and specific clinical signs in CS patients.
Pivonello et al, 2021	Phase 3, open-label (SONICS)	Evaluate efficacy in patients with and without DM. Methods: Dose titration, 6-month maintenance. Outcome measures: mUFC normalization, HbA1c, fasting blood glucose, safety.	mUFC normalization in 46% of patients with DM and 33% without DM. Improvements in HbA1c and fasting blood glucose in both groups. Common AEs in DM patients: nausea, vomiting, UTI.	Subanalysis, not initially powered for DM vs non-DM comparisons, open-label design.	Levoketoconazole is effective in normalizing cortisol and improving glycemic control, especially in patients with DM.

Risk-of-bias assessment (Figs 2 and 3)

Figure 2.

Risk of bias summary.

Figure 3.

Risk-of-bias plot.

Overall, the included clinical trials demonstrated a low risk of selection, detection, attrition, and reporting bias. Some concerns regarding performance bias were identified in open-label studies because participants and investigators were aware of treatment allocation, potentially influencing subjective outcomes such as quality of life and depression scores. However, objective biochemical outcomes, including mUFC normalization, were considered less susceptible to bias. The in-vitro study was not assessed using clinical risk-of-bias tools.

Primary outcome

The primary outcome of this systematic review is the comparison of mean urinary free cortisol (mUFC) levels in patients with Cushing syndrome treated with levoketoconazole. This measure is important, as mUFC is used to assess cortisol levels and to evaluate the outcomes of therapies employed in the management of hypercortisolism. Such normalization of these levels indicates that the drug levoketoconazole has the potential to treat the biochemical derangement of Cushing syndrome and, consequently, reduce morbidities associated with the condition and improve patients’ outcomes. This primary outcome is useful in establishing the therapeutic effectiveness of levoketoconazole in normalizing cortisol in affected patients.

Discussion

This systematic review looks at the effectiveness of the recently approved drug, levoketoconazole, in the management of CS. Levoketoconazole has proven to be effective and safe in the management of CS based on the results of phase III trials, namely SONICS and LOGICS. The studies show that levoketoconazole can lower mUFC to within a normal range and alleviate clinical symptoms of CS with reasonable safety^[22^]. Yet, when comparing with other treatments for CS, there are both commonalities and differences. It has been established that mUFC returns to normal in a significant number of patients after taking levoketoconazole. For example, the SONICS trial demonstrated a normalization rate of 62% in patients completing the 6-month maintenance phase. This efficacy is on the same level as other CS treatments such as osilodrostat, which is also a steroidogenesis inhibitor. Osilodrostat also proved to have high efficacy, and clinical trials revealed that the rate of mUFC normalization and the sustained control of hypercortisolism were comparable to those of other drugs. Pasireotide, a somatostatin analog, is another option with a different mechanism of action, directing its effect toward pituitary adenomas. It brought mUFC levels back to normal in about 40% of patients within its Phase 3 trial, but it also introduced a range of serious risks such as hyperglycemia, thus making it unsuitable for diabetic patients. Some of the side effects of levoketoconazole include common adverse effects such as nausea, headache, and hypokalemia, among others. The adverse effects of particular concern are hepatotoxicity and QT prolongation, and patients should be monitored while on the drug. These side effects are mostly mild and can be effectively controlled depending on the patient’s condition and the prescribed dosage.

Like pasireotide, osilodrostat has gastrointestinal and endocrine side effects, but it does not seem to affect glucose metabolism as much as pasireotide does, and therefore it is preferable for patients with diabetes^[23^]. While pasireotide is effective, it is associated with side effects, mostly metabolic, including hyperglycemia, which rules out use of the drug in patients with diabetes. Based on the long-term assessment and outcomes of SONICS, it was evident that levoketoconazole successfully managed Cushing’s syndrome and had a tolerable safety profile over 1 year of treatment. This is useful in a disease such as CS, where long-term patient management is needed. Regarding long-term treatment with osilodrostat, favorable outcomes have also been reported, favorable sustained mUFC control and an acceptable safety profile during long-term treatment. Open-label designs may overestimate improvements in patient-reported outcomes; however, the consistency of objective biochemical endpoints across SONICS and LOGICS supports true pharmacologic efficacy.

The following are the attributes of levoketoconazole that potentially place it as a candidate to manage CS, particularly in patients who are not surgical candidates or those who failed surgery: these include a favorable side-effect profile and the fact that the drug’s efficacy is not compromised when administered chronically, which would make levoketoconazole a good candidate for the chronic management of CS. Similar benefits as above are also provided by osilodrostat, although the choice between this treatment and others depends on certain specific traits of the patient, such as comorbid diabetes, in which case osilodrostat will be preferred over pasireotide due to its minimal impact on glucose metabolism. Among the treatments for CS, levoketoconazole has been deemed one of the more efficient and safer drugs, and it seems to be as efficient as other newer drugs–for instance, osilodrostat–though it appears safer than pasireotide. These comparative findings thus argue that, in the treatment of CS, individual patient factors must come into play, since people are different and will have different needs and states of health. In the future, further follow-up of such patients and more head-to-head trials should be conducted to fine-tune these therapies.

A phase III cross-sectional comparative study of pasireotide – a somatostatin analog – revealed that 40% of patients achieved mUFC normalization at month 7. However, adverse effects such as high blood sugar levels and digestive issues were observed, and therefore supervision is warranted^[24^]. Moreover, a review of mifepristone noted its use in the management of hypercortisolism, especially in patients with cortisol-induced psychosis. Though effective, it is associated with the danger of adrenal insufficiency and requires close monitoring to mitigate these risks^[25^].

By comparing these treatments, one can see variations in terms of effectiveness and side effects. Both levoketoconazole and osilodrostat had excellent outcomes in mUFC, although osilodrostat was slightly better in some parameters. However, as data from the extension study of SONICS show, treatment with levoketoconazole has highly beneficial effects over the first year, which makes it possible to consider it for the long-term management of the disease. Although pasireotide is also effective, it has a relatively higher level of side effects, namely hyperglycemia, which may be an issue in patients with diabetes. On the other hand, levoketoconazole and osilodrostat were mainly associated with tolerable GI and endocrine side effects, which would be suitable for patients with metabolic issues.

The findings presented in this review favor levoketoconazole as a safe and efficacious drug for the treatment of Cushing syndrome. This makes its use more therapeutically beneficial in improving quality of life and managing other coexisting conditions, such as diabetes mellitus (DM). Further research should aim at the long-term consequences of treatment, the use of combined approaches, and different patient subgroups to enhance therapeutic strategies and the outcomes achieved.

Limitations

First of all, it is necessary to note that a significant portion of the identified research papers have an open-label design and, therefore, can be prone to bias related to blinding, which could affect performance and detection biases and, in turn, alter the reported results. Furthermore, some studies are single-arm, including the SONICS trial, which makes it difficult to compare levoketoconazole with placebo or other active treatments, which would be more informative regarding the effectiveness and safety of the drug. The sample sizes in the included studies are relatively small and, therefore, the findings of the studies may not be generalizable to other populations. Moreover, safety data in the long-term are scarce; thus, more studies are needed to validate the long-term effectiveness and safety of levoketoconazole. Another weakness of the review is that it focuses on patient-reported outcomes; although this is useful information, it may be subjective. This review is limited by the restriction to English-language publications and by the database selection, which may introduce publication bias despite adherence to PRISMA methodology. Last but not least, the in vitro studies are informative at the molecular level but cannot replace clinical data regarding the overall efficacy of the drug.

Conclusion

Levoketoconazole represents an effective steroidogenesis inhibitor for the treatment of endogenous Cushing syndrome, demonstrating consistent reductions in cortisol levels, normalization of mean urinary free cortisol levels, and improvements in clinical manifestations and quality of life. Evidence from the SONICS and LOGICS Phase 3 trials supports its role as an important therapeutic option, particularly for patients who are not candidates for surgery or who have persistent disease after surgery. Although the safety profile is generally acceptable, long-term treatment requires careful monitoring of liver function tests, adrenal insufficiency, and QT interval prolongation. Further long-term studies are warranted to better define the durability of its efficacy and long-term safety profile.

Ethical approval

Not applicable.

Consent

Not applicable.

Sources of funding

None.

Author contributions

C.R.S.: Conceptualization, Resources, Software, Validation, Supervision, Writing – original draft preparation, and Writing – review and editing. A.D.: Conceptualization, Resources, Software, Validation, Supervision, Writing – original draft preparation, Writing – review and editing. E.G.: Writing – original draft preparation; Writing – review and editing. V.R.B.: Writing – original draft preparation; Writing – review and editing. H.G.: Writing – original draft preparation; Writing – review and editing. S.S.: Writing – original draft preparation, Writing – review and editing. J.J.: Writing – original draft preparation; writing – review and editing. N.K.: Writing – original draft preparation, Writing – review and editing. O.A.H.: Writing – original draft preparation, Writing – review and editing.

Conflicts of interest disclosure

There is no conflict of interest.

Research registration unique identifying number

(UIN) CRD42024559580.

Guarantor

Not applicable.

Provenance and peer review

Not applicable.

Data availability statement

Data sharing is not applicable, as no new data were created or analyzed in this study.

Acknowledgements

Not applicable.