Metabolic adverse events of multitarget kinase inhibitors: a systematic review

Purpose Multitargeted kinase inhibitors (MKIs) are used for the treatment of several cancers. By targeting multiple signaling pathways, MKIs have become cornerstones of the oncologic treatment. Although their use leads to important results in terms of survival, treatment with MKIs can determine important side effects the clinician must be aware of. Among those, arterial hypertension, mucositis and skin lesions are universally reported, while data about metabolic alterations are scarce. In our review, we focused on glucose and lipid alterations in MKI-treated patients. Methods We searched for articles, published between January 2012 and December 2022, evaluating the effects on lipid and glucose metabolism of four MKIs (Cabozantinib, Lenvatinib, Sorafenib, and Vandetanib) in adult patients with cancer. We focused on drugs approved for thyroid malignancies, since a worse metabolic control may potentially impact life expectancy, due to their better overall survival rate. Results As for glucose metabolism, the majority of the studies reported elevation of glucose levels (prevalence: 1–17%) with different grades of severity, including death. As for cholesterol, 12 studies reported worsening or new-onset hypercholesterolemia (prevalence: 4–40%). Finally, 19 studies reported different grades of hypertriglyceridemia (prevalence: 1–86%), sometimes leading to life-threatening events. Conclusions Despite some inherent limitations, our analysis may cast light upon some of the MKIs metabolic disorders that can impact on patients’ health, especially when long-term survival is expected. Future clinical trials should consider routine assessment of glucose and lipid levels, because underdetection and underreporting of alterations can lead to the overlooking of important adverse events.


Introduction
Multitargeted kinase inhibitors (MKI) are increasingly approved and used for multiple solid and hematological malignant neoplasms and target several molecular pathways involved with cellular growth and de-differentiation, such as vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and c-Kit pathways. These drugs are collectively referred to as antiangiogenic drugs, because they also interfere with angiogenesis, to differentiate them from more recent molecules, designed to be selective to specific mutations or pathways [1].
Due to their off-target activities and interactions with multiple kinases, several systemic side effects are commonly reported with these drugs (e.g., arterial hypertension, mucositis, and skin lesions) [2,3].
During randomized clinical trials, not all adverse events were reported. As commonly recognized, data from controlled clinical trials are rarely reproducible in real-life practice, due to their highly controlled setting (optimized to show the effect of the drug), and their carefully selected populations, usually not the same to which the drug is prescribed in clinical practice [4].
Furthermore, drug side effects are heterogeneous by nature, being influenced by age, drug interactions, pharmacokinetics and pharmacodynamics, and developing methods to identify patients at higher risk has proved challenging [5]. Their underdetection and consequent underreporting may thus lead to an underestimate of the impact on patients' health.
For example, some subtle, biochemical side effects of Lenvatinib (adrenal insufficiency [6][7][8], or hypocalcemia) were not specifically reported in the SELECT trial [9], nor in the early real-world reports [10][11][12]. While the metabolic adverse effects of MKIs are known [13,14], data on their severity and prevalence are scarce. In this review, we focused on the alterations of glucose and lipid metabolism in patients treated with some commonly used MKIs (Cabozantinib, Lenvatinib, Sorafenib, and Vandetanib).
We chose to focus on drugs approved for thyroid malignancies. These patients have a better overall survival rate (53.3% 5-year relative survival rate, even in cases with distant metastases, Table 1), and a worse metabolic control may impact life expectancy.

Methods
The study protocol was registered on PROSPERO (registration number CRD42023387091).
The research was carried out using the following wording: (cabozantinib OR lenvatinib OR sorafenib OR vandetanib) AND ("metabolic effects" OR "high glucose" OR "low glucose" OR hyperglycemia OR hypoglycemia OR "glucose alterations" OR dyslipidemia OR hyperlipidemia OR hypercholesterolemia OR cholesterol OR "high cholesterol" OR hypertriglyceridemia OR triglycerides OR "high triglycerides" OR "lipid alterations"). Additional articles were searched analyzing the bibliographic references of the selected articles.
We searched for articles evaluating the effects on glucose and lipid metabolism of four MKIs (Cabozantinib, Lenvatinib, Sorafenib and Vandetanib) in adult patients with cancer.
All types of English-language trials and studies evaluating the effect of Cabozantinib, Lenvatinib, Sorafenib and Vandetanib on glucose or lipid metabolism in adult patients were included in our study.
In vitro studies, studies on animals, no full-text articles, case reports and studies on pediatric population were excluded.
Studies published before January 2012 and studies involving a population of <10 patients were subsequently excluded as well (see Fig. 1).
The initial research in PubMed, EMBASE, Cochrane, Scopus and POPLINE provided 15, 98, 37, 333, and 203 studies respectively. After title and abstract screening, respectively 12, 5, 19, 82, and 3 were selected. Research through the other databases did not provide results consistent with our inclusion criteria. After duplicates were removed, 90 studies were selected for full-text screening and 69 studies met the inclusion criteria. One study was subsequently excluded because of the plausible confounding effect of one molecule (Trebananib).
The research was independently carried out by two investigators (EA and CM), using the same searching strategy. Only one difference in study selection was assessed, and discussed to reach consensus, with the opinion of a third author (MM).
The following data were extracted from each article: type of study, publication year, name of the journal, molecule/s analyzed, recruitment time, population (number of patients), sex, median age, underlying pathology, comorbidities, duration of therapy, daily dose, number of patients undergoing permanent treatment interruption due to adverse events and timing of interruption and effect on glucose, cholesterol and triglyceride metabolism (frequency, timing, grade according to Common Terminology Criteria for Adverse Events [CTCAE]). We chose to report on Table 2 and Fig. 2 only those studies reporting effects on glucose of grade > or = to 3 according to the CTCAE classification.

Metabolic effects of multitargeted kinase inhibitors
Molecularly targeted therapy has become one of the cornerstones of personalized medicine in the oncology field and consists of drugs that specifically interfere with dysregulated signaling pathways in neoplastic cells. Currently, a large spectrum of drugs interfering with cancer cells functions or the tumor microenvironment is being developed. Among those, MKIs target common mechanisms of proliferation, local invasion, metastasis and angiogenesis [15]. Presently, MKIs are widely used for treating several classes of malignant disease, both as a single agent or in combination, and their additional mechanisms of action are still not completely understood [16]. When well tolerated, treatment with a MKI can lead to significant results in terms of overall survival but, occasionally, especially when used in long-term protocol treatments, they can also determine important side effects the clinician must be aware of [3]. Among these effects, glucose and lipids serum levels alterations are not always investigated [17].
As regards cholesterol metabolism, worsening or new onset of high serum cholesterol levels has been reported in only 12 studies (Table 3, Fig. 3). Most studies (7/12) reported CTCAE grade 3 and 4 hypercholesterolemia, while grade 5 was not reported. Sorafenib, Cabozantinib and  Lenvatinib have all been implicated in new onset of different grades of hypercholesterolemia, either when used as a single agent or in combination with other MKIs. Cholesterol metabolism alterations associated with Vandetanib were not described.
Regarding triglycerides metabolism, 19 studies reported on the occurrence of hypertriglyceridemia in patients treated with MKIs. Cabozantinib, Lenvatinib, Sorafenib and Vandetanib adversely affect triglycerides metabolism with different degrees of severity, from mild to life-threatening levels (Fig. 4, Table 4).

Gender
Most of the patients included in the studies were males, which might represent a potential bias, since lipid metabolism is differentially regulated in males and females.

Underreporting
In a minority of papers included in our analysis, toxicities were reported only when graded ≥ 3 according to CTCAE thus leading to important underreporting of mild to moderate adverse events. Furthermore, many studies did not report any glucose or lipid-related AEs, probably due to the lack of planned evaluations in the design of the study.   Table 5 Definitions of "hyperglycemia", "hypoglycemia", "cholesterol, serum-high or hypercholesterolemia" and  Table 6).

Limitations of the review
This systematic review had some limitations. The examined literature reported studies of different designs (randomized clinical trials, prospective studies and retrospective studies) conducted by different research groups in different countries, so potential biases could not be avoided. In many reports, patients were treated with a combination of drugs (MKI plus at least another antineoplastic agent) so that linking the occurrence of specific AEs to a single molecule was not possible (Table 6). Furthermore, some studies evaluated toxicities of severe grades, thus providing only a partial picture of the phenomena described.
Moreover, information about different lipoprotein lipids concentrations (i.e., HDL cholesterol, LDL cholesterol) are lacking in the selected articles, limiting the understanding of the potential atherogenic risk linked to these metabolic disturbances.
In our opinion, clinicians should be familiar with metabolic disorders that MKI-treated patients could develop, including dysglycemia and dyslipidemia. It is important to periodically evaluate glucose and lipid levels in order to recognize and control these adverse events.
In summary, further investigation is necessary for a more comprehensive understanding of the adverse metabolic profile of MKIs. Underdetection and consequent underreporting of potential alterations can lead to the overlooking of important adverse events, especially in the context of MKI-treated patients with a longer overall survival. Future clinical trials should include in their protocol design routine assessment of glucose and lipid profile in order to allow a better understanding of the prevalence of these alterations, identifying subgroups at risk, and possibly paving the way for discovering new molecular mechanisms responsible for these adverse effects.
Author contributions All authors contributed to the study's conception and design. All authors read and approved the final paper.
Funding Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.

Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
Ethics approval This study is a secondary analysis of published data and does not require ethics committee approval.
Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Metabolic AEs of the same class but with different nomenclatures (e.g., "high glucose", "hyperglycemia") were summed up Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.