A meta-analysis of the risk of adverse cardiovascular events in patients with cancer treated with inhibitors of the PI3K/AKT/mTOR signaling pathway

doi:10.21203/rs.3.rs-4675510/v1

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A meta-analysis of the risk of adverse cardiovascular events in patients with cancer treated with inhibitors of the PI3K/AKT/mTOR signaling pathway

https://doi.org/10.21203/rs.3.rs-4675510/v1

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Background: With the increasing of PI3K/AKT/mTOR (PAM) inhibitors in cancer therapy, there is a growing need to understand the incidence of cardiovascular events (CVAEs) associated with PAM inhibitors.

Methods: A systematic search of all randomized clinical trials (RCTs) containing at least one PAM group in electronic databases such as PubMed, ClinicalTrials.gov registry, Embase, Medline, Cochrane Library, and major conferences was performed to extract available CVAEs. The cut-off date was January 31, 2024. Study heterogeneity was assessed using the I² statistic. The risk of CVAEs associated with PAM inhibitors was calculated using Peto OR.

Main outcomes and measures:

The primary outcome was the incidence (95% CI) of PAM inhibitors cardiovascular adverse events in the total population and subgroups. The secondary outcome was the pooled risk of different CVAEs associated with PAM inhibitor exposure in the RCTs.

Results:

33 unique RCTs (n=12,351) were included. The incidence of PAM inhibitors CVAEs of any grade in the intervention group was 48.2%, yielding a combined OR of 2.52 (95% CI, 1.82 - 3.49). The incidence of severe adverse cardiovascular events (≥ grade 3) in the intervention group was estimated at 7.1%, yielding a combined Peto OR of 1.41 (95% CI,1.04 - 1.93). PAM inhibitors were associated with an increased risk of 5 CVAEs including peripheral edema, lymphoedema, hypercholesterolemia, hypertriglyceridaemia and hyperlipidemia, with higher risks for hypercholesterolemia (Peto OR:3.27,95% CI:2.61-4.11, P<0.01; I² = 55.5%，P=0.06) and hyperlipidemia (Peto OR:3.53. 95%CI:1.70-7.32, P<0.01; I² = 19.3%，P=0.29).

Conclusion:

This study identified an overall incidence of PAM inhibitors CVAEs and the increased risks associated with PAM inhibitor for five specific CVAEs, not confined to hypercholesterolemia and peripheral edema.

PI3K

AKT

mTOR inhibitors

adverse events

The phosphatidylinositol-3-kinase (PI 3 K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway (PAM signaling pathway) is key in the regulation of diverse cellular processes including growth, proliferation, adhesion, survival, and motility^[1]. With indications spanning multiple tumour types. PI3K is stimulated by activated tyrosine kinases, phosphorylates PIP2 to PIP3 (second messenger) at the plasma membrane, binds and recruits a variety of proteins, and thus activates the downstream AKT and mTOR signaling pathways^[2].The PI3K pathway is implicated in almost half of all malignant diseases and is among the most frequently activated pathways in human cancers^[3]. So PAM pathway inhibitors are one of the important approaches for tumor therapy.

There are currently 7 approved PAM inhibitors: (1) Idelalisib, a PI3K-δ inhibitor approved for treating relapsed chronic lymphocytic leukemia (CLL), follicular non-Hodgkin lymphoma (FL), and small lymphocytic lymphoma (SLL)^[4]; (2) Alpelisib, a PI3K-α inhibitor used in combination with fulvestrant for men and postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative, PIK3CA-mutated,advancedormetastatic breast cancer^[5]; (3) Copanlisib, a PI3Kpan-p110 inhibitor for relapsed FL^[6]; (4) Duvelisib, a dual PI3K-γ andPI3K-δ inhibitor for refractory or relapsed FL, CLL, and SLL^[7]; (5) Capivasertib, a AKT inhibitor for the treatment of HR+/HER2- advanced or metastatic breast cancer^[8];(6) Everolimus, an oral selective inhibitor of mTOR for the treatment of ER-positive / HER - negative breast cancer^[9]. It has demonstrated promising results in several clinical studies in cancer. (7) Temsirolimus, an inhibitor of the mTOR for the treatment of advanced renal cell carcinoma^[10].

In clinical trials, hypertension, heart failure, and circulatory issues were common with PI3K inhibitors; hypercholesterolemia was prevalent with mTOR inhibitors. Despite the commonly reported CVAEs linked to PAM inhibitors, previous meta-analyses of RCTs in this area have primarily emphasized oncological endpoints over adverse events, including CVAEs.

This study used a systematic review and safety meta-analysis aims to synthesize evidence pertaining to the CVAEs associated with the use of PAM inhibitors in the treatment of cancer.

Data sources, search strategy, and data extraction

We used a comprehensive approach to capture all available CVAE cases, starting with a careful examination of the headings based on predetermined inclusion and exclusion criteria^[11], followed by the full text of the qualifying studies, and resolving discrepancies through discussion with the senior investigator (JZ), from study entry to January 31, 2024, for all CVAEs using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0^[12]. All CVAEs categorized according to the Common Terminology for adverse events in ClinicalTrials.gov were extracted. If CVAEs were not reported on ClinicalTrials.gov, all reported CVAEs were extracted from published randomized controlled trials (RCTs), excluding case reports or case series, case-control studies, observational studies, single-group studies, and nonrandomized trials. Finally, for RCTs for which we did not have an available CVAEs on ClinicalTrials.gov or did not have an available CVAEs in the publication, the corresponding author or sponsor of the study was contacted via e-mail to provide the requested information.

A literature search was performed in PubMed, Embase, Web of Science, the Cochrane Library and major conferences over the past 3 years for RCTs related to marketed PAM inhibitors. The keywords included “PI3K/AKT/mTOR”, “alpelisib”, “idelalisib”, “duvelisib”, “copanlisib”, “capivasertib”, “everolimus”, “temsirolimus”, “adverse events”. No search filters related to age, language or year of publication were used at this stage. And literature duplicates were removed using Endnote software. Available RCTs were retained for final analysis. Inclusion criteria included phase 2 and phase 3 randomized controlled trials of PAM inhibitors in cancer treatment reporting CVAEs. CVAEs of interest were hypertension, hypotension, palpitations, myocardial infarction, heart failure, congestive heart failure, venous thrombosis (VTE), Pericardial effusion, ardiac respiratory arrest, atrial fibrillation, atrial flutter, pulmonary embolism, chest pain, embolism, phlebitis, tachyarrhythmia, acute coronary syndrome, tachycardia, angina pectoris, hot flushes, peripheral edema, lymphedema, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia.

Outcomes

The primary outcome was incidence of PAM inhibitors CVAEs (with 95% CIs). The secondary outcome was the summary risk of CVAEs associated with PAM inhibitors exposure.

Statistical analysis

We performed a randomized effects meta-analysis with quantitative data extracted as event frequencies and sample sizes for the treatment and control groups, respectively, with outcomes of interest including the incidence of all grades and severe grades of CVAEs. Effect sizes were recalculated as ORs and 95% confidence intervals (CIs), and Peto ORs were used to calculate the outcome of the incidence of severe CVAEs due to the sparsity of events in both groups^[13]. Heterogeneity between studies was assessed using the inconsistency index I² statistic and its P -value assessment. According to the Cochrane Manual for Systematic Evaluation of Interventions, an I² value > 50% indicates significant heterogeneity between studies^[14]. The quality of each included study was assessed using the ROB 2.0 tool of the Cochrane Collaboration Network, and sensitivity analyses were performed for all included studies by constructing funnel plots as well as subgroup analyses in order to assess the heterogeneity of effects of the different PAM drugs^[15].

Data management and meta-analysis of pooled data were performed using R (version 4.3.1) and the R package Meta and are shown as forest plots. A two-sided P value of < 0.05 in all analyses was considered statistically significant.

Descriptions of included studies

The flowchart for study selection is shown in Fig. 1, and details of study characteristics of the included trials are summarized in Table 1. We evaluated 2,138 records in the database, including studies, reviews, and retrospective studies, and selected 469 of these RCTs, which were further screened to meet the inclusion criteria of 33 unique RCTs with a usable CVAEs (22 phase III RCTs and 11 phase II RCTs). These 33 RCTs were registered with 28 unique identifiers on ClinicalTrials.gov (5 NCTs used for > 1 RCT).

A total of 12,351 patients were enrolled, of whom 6,896 were in the PAM inhibitors -containing arms (55.8%) and 5,455 were in the control arms (44.2%). The administered PAMs (PAM alone, PAM + other anticancer drug(s), other than PAM) were everolimus in 63.3%, alpelisib in 6.7%, idelalisib in 7.2%, temsirolimus in 13.5%, copanlisib in 3.7%, duvelisib in 3.3%, and capivasertib in 2.3% of the studies. Breast cancer was the most frequent cancer types in 36.3% (12/33) of studies.

Incidence of CVAEs associated with PAM inhibitors in different types of cancer

For CVAEs of any grade, 33 studies with a cumulative sample size of 12,351 participants. A total of 3,326 trial participants (48.2%) reported CVAEs of any grade in the treatment groups compared with 1,722 (31.6%) among the controls, translating to a pooled OR of 2.52 (95%CI, 1.82–3.49) (Fig. 2 and Table 2). There was substantial heterogeneity in reporting of this outcome (I² = 91%, Q = 56.82). Sensitivity analyses did not reveal any changes in pooled results. There was no evidence of publication bias statistically or asymmetry of the funnel plot (Egger regression P = 0.17; supporting data shown in eFigure 2 and Table S2).

Incidences of severe CVAEs (≥ 3) were reported in 29 studies with a cumulative sample size of 11, 897 trial participants. There was significant statistical heterogeneity (I² = 65%, Q = 80.57) in reporting of these outcomes, yielding a pooled Peto OR of 1.41 (95% CI, 1.04–1.93, I² = 64.8%) with an incidence of 7.1%(Table 3 and Fig. 3). Sensitivity analyses did not yield changes in the significance of pooled results after removal of studies one by one. The funnel plot was slightly asymmetric, Egger’s regression was non significant (P = 0.64; Supplementary material online, eFigure 3 and Table S3).

Risk of CVAEs associated with PAM inhibitors

As shown in the Table 4, among the 14 different types of CVAEs, PAM significantly increased the risk of 5 CVAEs including peripheral edema (Peto OR: 2.34, 95% CI: 1.86–2.95, P < 0.01; I² = 65%, P = 0.93), lymphoedema (Peto OR:2.81, 95% CI:1.44–5.94, P < 0.01; I² = 0%, P = 0.96).hypercholesterolemia (Peto OR:3.80,95% CI:2.47–5.86, P < 0.01; I² = 56%, P = 0.006), hypertriglyceridemia (Peto OR:2.50, 95%CI:1.81–3.45, P < 0.01; I² = 56.1%, P = 0.005), and hyperlipidemia (Peto OR:3.53. 95%CI:1.70–7.32, P < 0.01; I² = 19.3%, P = 0.29)(Supplementary material online, Fig. 4). Sensitivity analyses were consistent with the main result. The inverted funnel plot for the primary outcome did not suggest publication bias. (Supplementary material online, Fig. 5 and Table 5). Subgroup analyses with regard to the types of PAM inhibitors that PI3K inhibitors increased the risk of hypertension (Peto OR: 2.97, 95% CI: 1.98–4.45, P < 0.01; I² = 50%, P = 0.06). No interaction between PAM inhibitors and CVAE reporting was found (Supplementary material online, Table 6).

To our knowledge, this study is the first large-scale analysis of RCTs that comprehensively captured the incidence and the increased risk of CVAEs associated with PAM inhibitors. We made two major discoveries. First, we reported that PAM inhibitors in different types of cancers are significantly associated with a higher risk of mild-to-severe CVAEs. Second, PAM inhibitors resulted in an increased risk of peripheral edema, lymphoedema and dyslipidemia.

Our study highlights the potential variation in CVAEs among different PAM inhibitors type^[16]. We found that the risk of CVAEs with AKT inhibitors was lower than that with PI3K inhibitors and mTOR inhibitors. Capivasertib, as the only approved AKT inhibitor, was shown to benefit both the PIK3CA/AKT1/PTEN pathway aberrant population and also had an overall manageable safety profile^[17]. Additionally, we have observed favorable efficacy in patients with visceral diseases and bone and soft tissue disorders^[18]. The most common adverse reactions observed are rash and diarrhea, with no reports of hyperglycemia commonly seen with PI3Kα inhibitors and no found of meaningful cardiovascular safety signals.

We also found that PI3K inhibitors increased the risk of hypertension. Consistent with clinical trial data, hypertension was reported as a common adverse effect^[19], while deaths attributed to CVAEs, such as heart failure and circulatory collapse, were also documented. In a clinical study of copanlisib in combination with rituximab for the treatment of relapsed or refractory inert non-Hodgkin's lymphoma, the incidence of grade 3 or 4 hypertension was found to be higher than the cumulative value of placebo in combination with rituximab treatment^[20]. Although this may be due to the longer duration of treatment. However, there are differences between Pan-PI3K and subtype-specific PI3K inhibitors. There are four type I PI3 K (p110) isoforms, α, β, γ and δ^[21]. As pan-PI3K inhibitor, copanlisib inhibit all four isoforms^[22]. In contrast, alpelisib specifically inhibits the PI3K α isoform^[23], idelalisib and duvelisib inhibit the PI3K δ isoform, which avoids the cumulative toxicity associated with inhibition of all four PI3K isoforms.

The mTOR inhibitors increased the risk of peripheral oedema, hypertriglyceridemia, hypercholesterolemia, and hyperlipidemia. The most commonly reported CVAEs were hypercholesterolemia and peripheral edema, aligning with the findings of this meta-analysis^[24]. Nevertheless, there have been reported deaths attributed to ischemic stroke, heart failure, and cardiac arrest, as well as patient discontinuations due to decreased ejection fraction, hypertension, and peripheral edema, although these occurrences are uncommon.

A careful balance between efficacy and toxicity of PAM inhibitors is necessary to accurately interpret the benefits and risks of such drugs in clinical. Because CVAEs are often debilitating and even have outcomes worse than the primary disease, prioritizing the reporting of risks, even when final attribution is unknown, is critical to accurately determine risk^[25–27]. However, reported adverse events represent a consistent definition used globally for the collection of adverse events in clinical trials that are publicly available on the Uniform Reporting Site (URS), and the adoption of and adherence to systematic reporting of adverse events is the standard for clinical data evaluation ^{[28, 29]} and consistency of reporting in supportive clinical trials informs the decisions of clinicians and patients when utilizing potentially life-saving anticancer therapies^{[28, 29]}. However, significant heterogeneity in the frequency and interpretation of CVAEs events was observed. In addition, there were differences in the threshold definition of CVAEs across clinical studies (e.g., in some trials, cardiomyopathy was defined as clinical HF, whereas in others, ejection fraction objectively decreased to < 50%)^{[30, 31]}. Coupled with the fact that in many clinical trials, the primary focus has been on anticancer efficacy, there may be limited understanding of the impact of CVAEs, still underestimating the prevalence of CVAEs events on patients' adherence to anticancer drug use, especially in the general population^{[32, 33]}. Given the high morbidity and mortality associated with CVAEs, the adoption of and adherence to systematic reporting of adverse events in relevant clinical trials, emphasizing more objective thresholds, and rigorous reporting of potentially limiting or impactful adverse events on ClinicalTrials.gov registries are standard in clinical data evaluation^{[28, 29]}.

Treatment adherence in patients with cancer are critical for optimal therapeutic benefit. A major challenge of PAM inhibitors arises from toxicity events associated with both on-target and off-target effects. The results of this review and meta-analysis provide an important basis for the reporting of CVAEs complicating clinical studies of PAM inhibitors in the treatment of malignant tumors. With the increased risk of cardiovascular toxicity, there are specialized cardiology guidelines to provide more accurate treatment options to protect the cardiovascular health of patients with cancer. The ESC guidelines recommend an annual cardiovascular risk assessment, including measurement of NT- pro BNP and management of cardiovascular risk factors, for all patients receiving potentially cardiotoxic anticancer therapy^[34]. It is therefore crucial that the incidence and grade of CVAEs are appropriately understood to inform patients of these possibilities and to manage them with preventive, supportive care and active interventions when needed. Enhance and implement post-completion surveillance and cardiovascular risk factor management to reduce long-term cardiovascular complications of anticancer therapy in the rapidly growing population of cancer survivors^[35].

Limitations

This systematic review and meta-analysis suffers from several limitations. First, there was a lack of harmonized primary source data among the included trials due to heterogeneity in differences in treatment groups, dosage regimens, and follow-up durations, and variations in the combinations of different treatment regimens. In addition, CVAEs thresholds and definitions were not consistently specified, except for the use of the CTCAE cardiac classification, and methods of collecting and adjudicating CVAEs events varied across trials. Therefore, these results should be generalized with caution.

The PAM inhibitors in malignant tumors increased the incidence of CVAEs, including CVAEs of any grade and severity, and increased the risk of peripheral edema, lymphoedema and dyslipidemia. Subgroup analyses based on the classification of PAM inhibitors showed that the PI3K inhibitors increased the risk of hypertension.

Author Contribution

Xiao Liang wrote the main manuscript text and prepared figures.All authors reviewed the manuscript.

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Tables 1-3 are available in the Supplementary Files section.

Table 4. Summary pooled analysis on the risk of PAM-associated cardiovascular adverse events vs. controls in RCTs

Reaction	n/N PAM	n/N ctrl	Peto OR	N stud/I2
Acute myocardial infarction	18/3406	16/2852	0.73(0.36;1.44)	16/0%
sinus tachycardia	24/2564	6/1751	1.50(0.67;3.36)	12/0%
Atrial fibrillation	23/3271	27/2517	NA	12/NA
Cardiac failure	29/3532	12/2776	1.36(0.69;2.66)	15/0%
Hypertension	589/5187	472/3992	1.22(0.73;2.05)	24/90%
Hypotension	85/3636	87/3078	0.85(0.49;1.48)	18/37%
Pulmonary embolism	55/4963	37/3907	1.09(0.68;1.75)	20/0%
Venous thrombo-embolic events	23/4622	14/3739	1.06(0.53;2.10)	20/0%
Peripheral oedema	1246/6124	492/4908	2.34(1.86;2.95)	25/65%
Lymphoedema	46/1642	10/1190	2.81(1.44;5.49)	5/0%
Hot flush	53/1240	69/997	0.88(0.21;3.71)	5/68%
Hypercholesterolemia	382/3351	99/2713	3.80(2.47;5.86)	14/56%
Hypertriglyceridaemia	484/3358	224/2626	2.50(1.81;3.45)	14/56%
Hyperlipidemia	93/989	33/987	3.53(1.70;7.32)	4/19%

Table 5. Sensitivity analyses on the summary risk of cardiovascular adverse events based on removal of each study sequentially
CVAE	Sensitivity analysis	n stud/I2	OR (95%CI)	p
Peripheral oedema	Andre et al,2014	24/67.6%	2.39 [1.87; 3.04]	＜0.001
	Choueiri et al,2016	24/68.1%	2.36 [1.84; 3.02]	＜0.001
	Lombard-Bohas et al,2015	24/64.5%	2.27 [1.80; 2.87]	＜0.001
	Fazio et al,2014	24/68.0%	2.34 [1.83; 3.00]	＜0.001
	Yao et al,2011	24/64.2%	2.25[1.80; 2.82]	＜0.001
	Fazio et al,2017	24/61.3%	2.23 [1.80; 2.75]	＜0.001
	Jerusalem et al,2018	24/67.5%	2.39 [1.88; 3.04]	＜0.001
	Choueiri et al,2015	24/67.7%	2.333 [1.82; 2.98]	＜0.001
	Baselga et al,2012	24/68.0%	2.34 [1.83; 2.99]	＜0.001
	Motzer et al,2015	24/66.7%	2.39 [1.87; 3.06]	＜0.001
	Porta et al,2012	24/66.3%	2.41 [1.89; 3.06]	＜0.001
	Yao et al,2016	24/65.1%	2.27 [1.81; 2.84]	＜0.001
	Ohtsu et al,2013	24/64.5%	2.43 [1.93; 3.07]	＜0.001
	Yardley et al,2013	24/65.8%	2.28 [1.80; 2.89]	＜0.001
	Mayer et al,2019	24/68.0%	2.35 [1.85; 2.98]	＜0.001
	Andre et al,2019	24/67.1%	2.31 [1.81; 2.93]	＜0.001
	Jones et al,2017	24/68.0%	2.36 [1.85; 3.01]	＜0.001
	Furman et al,2014	24/66.2%	2.42 [1.92; 3.05]	＜0.001
	Zelenetz et al,2017	24/64.9%	2.44 [1.94; 3.06]	＜0.001
	Dreyling et al,2016	24/67.9%	2.37 [1.86; 3.03]	＜0.001
	Wolff et al,2013	24/67.6%	2.33 [1.82; 2.98]	＜0.001
	Flinn et al,2023	24/66.6%	2.35 [1.86; 2.96]	＜0.001
	Flinn et al,2018	24/68.0%	2.34 [1.84; 2.98]	＜0.001
	Crabb et al,2020	24/65.9%	2.43 [1.93; 3.05]	＜0.001
	Schmid et al,2019	24/67.9%	2.37 [1.87; 3.00]	＜0.001
Hypercholesterolemia	Andre et al,2014	14/58.4%	4.10 [2.54; 6.61]	0.0041
	Jovanovic et al,2017	14/57.9%	4.06 [2.57; 6.41]	0.0046
	Baselga et al,2009	14/58.9%	3.99 [2.47; 6.46]	0.0037
	Kornblum et al,2018	14/54.9%	3.62 [2.3636; 5.5433]	0.0088
	Lombard-Bohas et al,2015	14/50.3%	3.4163 [2.27; 5.15]	0.0195
	Fazio et al,2014	14/58.9%	3.98 [2.47; 6.42]	0.0036
	Fazio et al,2017	14/58.5%	3.83 [2.42; 6.06]	0.0040
	Jerusalem et al,2018	14/58.9%	3.92 [2.46; 6.24]	0.0037
	Baselga et al,2012	14/58.9%	3.92 [2.46; 6.24]	0.0037
	Motzer et al,2015	14/44.8%	3.24 [2.21; 4.76]	0.0404
	Porta et al,2012	14/49.0%	4.20 [2.72; 6.50]	0.0237
	Yao et al,2016	14/58.6%	3.84 [2.42; 6.07]	0.0040
	Dreyling et al,2016	14/54.3%	3.56 [2.31; 5.49]	0.0098
	Wolff et al,2013	14/56.1%	4.16 [2.58; 6.70]	0.0069
Hypertriglyceridaemia	Andre et al,2014	13/59.1%	2.54 [1.77; 3.64]	0.0035
	Choueiri et al,2016	13/59.5%	2.66 [1.82; 3.88]	0.0032
	Kornblum et al,2018	13/56.6%	2.39 [1.74; 3.28]	0.0062
	Fazio et al,2017	13/57.3%	2.44 [1.77; 3.35]	0.0054
	Jerusalem et al,2018	13/59.2%	2.64 [1.84; 3.78]	0.0035
	Choueiri et al,2015	13/59.5%	2.64 [1.81; 3.85]	0.0032
	Baselga et al,2012	13/57.2%	2.40 [1.74; 3.32]	0.0054
	Motzer et al,2015	13/48.6%	2.23 [1.65; 3.03]	0.0250
	Porta et al,2012	13/55.9%	2.70 [1.91; 3.82]	0.0073
	Yao et al,2016	13/57.4%	2.44 [1.77; 3.35]	0.0052
	Zelenetz et al,2017	13/46.3%	2.69 [1.96; 3.71]	0.0339
	Dreyling et al,2016	13/47.8%	2.31 [1.72; 3.11]	0.0277
	Mascarenhas et al,2019	13/55.8%	2.40 [1.75; 3.28]	0.0073
	Matasar et al,2021	13/58.3%	2.66 [1.87; 3.79]	0.0043

Table 6. Subgroup analysis was performed by drug type

CVAEs	PAM class	n stud/I2	OR (95%CI)	p
Acute myocardial infarction	mTOR inhibitors	11/0%	0.68 [0.31; 1.50] P=0.34	0.99
	PI3K inhibitors	5/0%	0.88 [0.22; 3.55] p= 0.86	0.62
sinus tachycardia	mTOR inhibitors	8/0%	1.57 [0.50; 4.93] P= 0.44	1.0
	PI3K inhibitors	4/41.8%	1.07 [0.22; 5.28] p= 0.94	0.16
Atrial fibrillation	PI3K inhibitors	3/0%	1.04 [0.29; 3.77] p= 0.95	0.82
Cardiac failure	mTOR inhibitors	10/0%	1.40 [0.64; 3.06] P=0.40	0.92
	PI3K inhibitors	5/0%	1.23 [0.32; 4.73] P= 0.76	0.83
Hypertension	mTOR inhibitors	17/ 89.3%	0.88 [0.49; 1.59] P= 0.68	< 0.01
	PI3K inhibitors	7/ 50.0%	2.97 [1.98; 4.45] P < 0.01	0.06
Hypotension	mTOR inhibitors	13/50.5%	1.09 [0.46; 2.61] P= 0.84	0.02
	PI3K inhibitors	5/0%	0.75 [0.46; 1.22] P= 0.24	0.59
Pulmonary embolism	mTOR inhibitors	13/7.3%	1.17 [0.62; 2.18] P= 0.63	0.37
	PI3K inhibitors	7/0%	0.92 [0.39; 2.15] P= 0.84	0.83
VTE	mTOR inhibitors	13/0%	0.91 [0.39; 2.12] P= 0.82	0.83
	PI3K inhibitors	7/0%	1.41 [0.43; 4.57] P= 0.57	0.90
Peripheral oedema	mTOR inhibitors	16/ 71.0%	2.65 [2.02; 3.48] P＜0.01	＜0.01
	PI3K inhibitors	7/43.4%	1.85 [1.16; 2.96] P=0.01	0.10
	AKT inhibitors	2/0%	1.08 [0.52; 2.21] P=0.84	0.48
Lymphoedema	mTOR inhibitors	4/0%	3.01 [1.19; 7.66] P= 0.02	0.89
Hot flush	mTOR inhibitors	3/ 65.1%	0.36 [0.23; 0.58] P＜0.01	0.06
	PI3K inhibitors	2/ 81.8%	2.08 [0.07; 65.76] P=0.68	0.02
Hypercholesterolemia	mTOR inhibitors	14/ 55.5%	3.80 [2.47; 5.86] P＜0.01	0.006
Hypertriglyceridaemia	mTOR inhibitors	12/ 46.8%	2.89 [2.04; 4.08] P＜0.01	0.04
	PI3K inhibitors	2/0%	1.39 [0.97; 1.98] P= 0.07	0.90
Hyperlipidemia	mTOR inhibitors	4/ 19.3%	3.53 [1.70; 7.32] P＜0.05	0.29

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A meta-analysis of the risk of adverse cardiovascular events in patients with cancer treated with inhibitors of the PI3K/AKT/mTOR signaling pathway

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Incidence of CVAEs associated with PAM inhibitors in different types of cancer

Risk of CVAEs associated with PAM inhibitors

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