Efficacy of SGLT2 inhibitors for anthracycline-induced cardiotoxicity: a meta-analysis in cancer patients

Abstract

Aim: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower anthracycline-induced cardiotoxicity.

Methods: PubMed and Google Scholar were searched until September 2023 for studies regarding SGLT2i for treating anthracycline-induced cardiotoxicity. Overall mortality and cardiovascular events were considered. Using a random-effects model, data pooled RR and HR at a 95% confidence interval (CI).

Results: 3 cohort studies were identified, analyzing 2817 patients. Results display a significant reduction in overall mortality [RR = 0.52 (0.33–0.82); p = 0.005; I²= 32%], HF hospitalization [RR = 0.20 (0.04–1.02); p = 0.05; I²= 0%] and no significant reduction in HF incidence [RR = 0.50 (0.20–1.16); p = 0.11, I²= 0%].

Conclusion: SGLT2i mitigates mortality and hospitalization due to heart failure, improving cancer patient's chances of survival by undergoing anthracycline treatment.

Plain Language Summary

What is this article about?

This article explores the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) as a solution for reducing anthracycline-induced cardiotoxicity. Anthracycline is an established subclass of chemotherapeutic drugs which has been known to cause harm to the heart. The study, conducted a systematic search of PubMed and Google Scholar up until September 2023, assessing the effects of SGLT2i on overall mortality and cardiovascular events in cancer patients, regardless of the presence or absence of diabetes mellitus and the effectiveness of SGLT2i as a cardiotoxic therapy in cancer patients.

What were the results?

The analysis of studies involving 2817 patients showed findings indicating that giving SGLT2i could lower the chances of anthracycline-induced heart problems in cancer patients undergoing treatment. The findings showed a striking decrease in hospitalization due to heart failure and overall mortality whereas the findings for the effect of SGLT2i on incidence of heart failure were insignificant. The encouraging outcomes offer valuable insights that could help enhance the outlook and chances of survival for individuals with cancer.

What do the results of the study mean?

These findings indicate that SGLT2i notably reduces the risk of death and cardiovascular issues, like being hospitalized due to heart failure, in cancer patients undergoing anthracycline treatment. This has significant implications for how doctors might treat cancer patients in practice. Including SGLT2i in the treatment plan could improve the survival prospects of these patients, offering a promising advancement in handling anthracycline-induced heart issues with side effects that can be managed.

Graphical Abstract

Plain language summary

Article highlights.

• This meta-analysis assesses the cardio-protective effects of sodium-glucose transporter-2 inhibitor (SGLT2i) in cancer patients undergoing anthracycline therapy.

• The systematic review identified 3 cohort studies. Using a random-effects model, data for all outcomes of interest pooled risk ratio (RR) and hazard ratio (HR) at 95% confidence interval (CI) for this analysis.

• The pooled results showed a significant reduction in overall mortality and heart failure hospitalization in patients treated with SGLT2i compared with non-SGLT2i.

1. Background

Cardiovascular disease and cancer rank as the leading causes of mortality in developed nations. Despite the advancements in enhancing cancer treatment and improving patient survival rates, there has been a concurrent increase in heart-related issues [1]. Anthracyclines, a class of chemotherapeutic agents renowned for their effectiveness in treating solid tumors, especially lymphomas and breast cancer across age groups, have played a pivotal role in oncology [2]. While they are effective and commonly used, administration of anthracycline treatment also comes with a risk of causing significant cardiac muscle damage, often leading to the need to halt chemotherapy [1]. The cardio-oncology guidelines from the European Society of Cardiology (ESC) define anthracycline-induced cardiac dysfunction as a form of heart failure (HF) marked by alterations in the structure of the left ventricle and varying levels of decreased ejection fraction [3]. Anthracyclines cause distinctive morphologic and functional damage to cardiac myocytes and anthracycline regimens are also associated with a three- to five-fold greater risk for cardiotoxicity than non-anthracycline regimens [4]. Moreover, findings from a review study by Sawicki KT et al. stated that 9% of the patients undergoing anthracycline chemotherapy experienced cardiotoxic effects. Furthermore, in nearly all these instances, cardiotoxicity manifested within the first year after the chemotherapy was completed [5].

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are an efficacious class of diabetic medication which, aside from improving blood pressure, body mass, renal outcomes, and glycemic control, have demonstrated cardioprotective effects, which, even in the presence of diabetes, minimize the risk of cardiovascular death and hospitalization for HF [6,7]. Furthermore, it has been suggested that SGLT2i administration is linked to improved cardiac outcomes in anthracycline-treated patients. Studies assessing the cardio-protective effect of SGLT2i, such as empagliflozin and dapagliflozin in animal models and in-vitro studies, have concluded a protective mechanism of action against left ventricular dysfunction. These drugs are observed to enhance the survival of cardiomyocytes by decreasing the rate of cardiomyocyte apoptosis and by reducing the expression of inflammatory cytokines associated with cardiac damage [8,9]. Therefore, to assess these findings in the context of important clinical implications, this analysis aims to investigate the protective action of SGLT2i in patients undergoing anthracycline treatment at risk of cardiotoxicity.

Additionally, SGLT2 is expressed in various tumor cells, such as pancreatic, prostate, and glioblastoma cells [10]. Shoda et al.'s study confirmed that glioma cells utilize SGLT2 for glucose uptake, and SGLT2i canagliflozin inhibits this process [11]. Moreover, empagliflozin has demonstrated inhibitory effects on cervical cancer [12], breast cancer [13], hepatocellular carcinoma [13], and lung cancer [14]. The suggested mechanism involves the inhibition of glucose reabsorption by renal tubules, leading to a reduction in glucose, which is essential for tumor cell growth and metabolism [15] and, ultimately, this inhibits tumor growth and proliferation. Nevertheless, a more comprehensive and in-depth investigation is needed to fully understand the specific mechanism of action of SGLT2i. Hence, these findings underscore the potential dual role of SGLT2i, not only in managing diabetes and cardiovascular health but also as a promising agent in anticancer therapy.

2. Methods

2.1. Data sources & search strategy

The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) standards were followed for this meta-analysis [16]. An electronic search of databases including PubMed and Google Scholar was conducted from their inception to September 2023, without any language restrictions, using the following search strings: (anthracycline treatment OR anthracycline-treated cancer patients OR patients treated with doxorubicin OR Dox OR cancer patients OR cancer) AND (SGLT2 inhibitors OR Sodium-glucose Cotransporter-2 Inhibitors OR SGLT2i OR dapagliflozin OR empagliflozin OR canagliflozin OR ertugliflozin OR ipragliflozin) AND (non-SGLT2i diabetic medication OR non-SGLT2 inhibitors OR non-SGLT2i OR other diabetes medications OR control group without SGLT2 inhibitors) AND (heart failure OR HF OR HFrEF OR HFpEF OR congestive heart failure OR cardiac failure OR left ventricular dysfunction OR cardiovascular events OR cardiotoxicity OR composite cardiovascular events OR major cardiovascular events OR MACE OR cardiovascular outcomes OR mortality) and: “anthracycline treatment” OR “anthracycline-treated cancer patients” OR “patients treated with doxorubicin” OR “anthracycline-induced cardiotoxicity” OR “Dox” AND “SGLT2 inhibitors” OR “Sodium-glucose Cotransporter-2 Inhibitors” OR “SGLT2i” OR “dapagliflozin” OR “empagliflozin” OR “canagliflozin” OR “ertugliflozin” OR “ipragliflozin” AND “non-SGLT2i diabetic medication” OR “non-SGLT2 inhibitors” OR “non-SGLT2i” OR OR “control group without SGLT2 inhibitors” AND “heart failure” OR “HF” OR “HFrEF” OR “HFpEF” OR “congestive heart failure” OR “cardiac failure” OR “left ventricular dysfunction” OR “cardiovascular events” OR “cardiotoxicity” OR “composite cardiovascular events” OR “major cardiovascular events” OR “MACE” OR “cardiovascular outcomes” OR “mortality”, on the respective databases.

2.2. Study selection & eligibility criteria

The following criteria for eligibility were used to shortlist the studies for this meta-analysis: patients with cancer and diabetes mellitus (DM), receiving anthracycline treatment at the time SGLT2i treatment was initiated, a control group of patients not on SGLT2i therapy, the effect of SGLT2i on overall mortality. From the eligible studies, the following outcomes were extracted: all-cause mortality, HF incidence, and HF hospitalization. Furthermore, for this analysis, the text shall refer to the outcomes as follows: overall mortality and cardiovascular events (inclusive of HF incidence and hospitalization). Any disagreements between investigators conducting the literature search were resolved by a review and discussion of the articles.

2.3. Data extraction & analysis

Outcome data was extracted onto a designed table in Google Sheets. The risk ratio (RR) at 95% confidence interval (CI) was calculated for the studies reporting the raw outcome data. Hazard ratios (HR) at 95% CI were extracted from the studies with the outcome of interest displayed in this effect size. A detailed overview of the extracted and calculated data is provided in Table 1. Review Manager 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark) was utilized for all statistical evaluations. For this analysis, data for the outcomes of ‘Overall mortality’ and ‘HF incidence’ combined RR and HR using a random-effects model. Furthermore, the analysis of the outcome of ‘HF hospitalization’ pooled the reported HR. To examine the heterogeneity of the data, values of 25%, 50%, and 75% correlating to low, moderate, and high degrees of heterogeneity, respectively, were used [17]. Sensitivity and subgroup analyses were performed to address heterogeneity present in any outcomes of this meta-analysis. Sensitivity analysis was conducted by excluding each study individually and observing the change in heterogeneity. The quality assessment of the studies by the Newcastle Ottawa Scale was used as a factor for exclusion. Furthermore, the subgroup analysis was conducted by taking into account the respective studies with anthracyclines as the sole chemotherapeutic therapy in the SGLT2i intervention group or studies with anthracycline along with other anticancer agent-treated patients in the SGLT2i intervention groups.

Table 1.

Data used for analysis^†.

Studied outcomes	Studies reporting outcome	Effect size		Ref.
		HR (95% Cl)	RR (95% Cl)
Overall mortality	Qadir (2023)	0.63 (0.36–1.1025)	–	[18]
	Gongora (2022)	–	0.2195 (0.0729–0.6607)	[19]
	Chiang (2023)	0.58 (0.34–0.9894)	–	[20]
HF hospitalization	Qadir (2023)	–	0.1325 (0.0082–2.1494)	[18]
	Gongora (2022)	–	0.25 (0.0338–1.8479)	[19]
HF incidence	Qadir (2023)	0.55 (0.23–1.3152)	–	[18]
	Gongora (2022)	–	0.1960 (0.0115–3.3384)	[19]

^†CI: Confidence interval; HR: Hazard ratio; RR: Risk ratio.

3. Results

3.1. Literature search results

Two independent reviewers thoroughly reviewed the articles concerning the subject of this analysis from the systematic search. The initial search conducted on PubMed and Google Scholar databases yielded 49 and 625 articles, respectively. 16 articles from the search were excluded due to the text not being in the English language. The remaining 658 articles were transferred to Zotero [6.0.26], and duplicates were identified and removed. Screening of the papers based on title and abstract was done, assessing for relevance. Furthermore, after the removal of review articles, the articles were then reviewed with full text. Keeping overall mortality as the primary interest for this analysis, the reviewers shortlisted three relevant articles. Hence, this meta-analysis includes three cohort studies. We conducted a thorough and comprehensive search to shortlist any randomized clinical trials (RCTs) in existing literature but couldn't find any related to this topic. This highlights the scarcity of clinical data available on this topic. The PRISMA flow chart summarizes the results of our search in Figure 1.

Figure 1.

PRISMA flow diagram for results of literature search.

3.2. Study characteristics & quality assessment

The three eligible cohort studies included a total number of 2817 patients, with 1009 in the SGLT2i arm and 1,808 in the non-SGLT2i arm. The baseline characteristics of the eligible studies are outlined in Table 2. The subsequent outcomes were chosen from the finalized studies: all-cause mortality, HF hospitalization, and HF incidence. The risk of bias in the cohort studies was evaluated using the Newcastle-Ottawa scale (NOS) [21]. This scale consists of eight categories grouped into three dimensions: selection, comparability, and outcome. For each category, a star system is used to grade the studies. The highest quality studies are awarded a maximum of one star for each item except for the item related to the comparability dimension, which allows the assignment of a maximum of two stars. The total score for the NOS ranges between 0–9. Table 3 displays the breakdown of the quality assessment. Due to the lack of relevant studies, our analysis only included three studies. Hence, assessing for publication bias through funnel plots, Begg's test, or Egger's tests may not provide reliable results. Although we attempted to overcome this limitation with great effort by a thorough overview of the systematic search for additional literature, we were unable to identify any further relevant studies, which highlights the limited data available for our analysis.

Table 2.

Baseline characteristics^#.

Study (year)	Qadir (2023) [18]		Chiang (2023) [20]		Gongora (2022) [19]
Intervention vs. control arms	SGLT2i	Non-SGLT2i	SGLT2i	Non-SGLT2i	SGLT2i	Non-SGLT2i
Sample size (n)	99	834	878	878	32	96
Age	70 [67–73]†	71 [68–76]†	65 [58–71]†	65 [59–75]†	60 [+/-11]‡	60 [+/-10]‡
Sex, n [%]	35 [35.4]§	318 [38.1]§	475 [54]§	456 [52]§	16 [50]¶	41 [43]¶
Comorbidities, n[%]
CAD	NR	NR	NR	NR	2 [6]	10 [10]
Heart failure	NR		41 [5]	43 [5]	2 [6]	7 [7]
MI	NR		36 [4]	23 [3]	0 [0]	3 [3]
CKD	NR		123 [14]	122 [14]	0 [0]	3 [3]
COPD	7 [7.1]	45 [5.4]	88 [10]	89 [10]	NR	NR
CVD medications, n [%]
Statins	88 [88.9]	625 [74.9]	498 [57]	492 [56]	20 [62]	53 [55]
RAAS inhibitor	78 [78.8]	599 [71.8]	484 [55]	508 [58]	14 [44]	44 [46]
Aspirin	NR	NR	187 [21]	203 [23]	12 [38]	27 [28]
Beta-blockers	27 [27.3]	215 [25.8]	507 [58]	527 [60]	10 [31]	27 [28]
Calcium channel blocker	NR	NR	474 [54]	481 [55]	6 [19]	13 [14]
Diuretics	NR	NR	365 [42]	383 [44]	5 [16]	13 [14]
Inclusion criteria	Age ≥65 years; No prior HF; Receiving diabetic medications; Received anthracycline chemotherapy for cancer		Adult patients with Type II diabetes receiving cancer treatment; receiving SGLT2i after cancer diagnosis; started on SGLT2i before diagnosis of cancer and continued medications following diagnosis		Patients with pre-existing DM treated with anthracyclines
Exclusion criteria	Prior diagnosis of HF; No pre-existing diagnosis of diabetes & not receiving pharmacologic therapies for diabetes		Patients who had one hospital visit and missing data		<18 years of age; patients diagnosed with DM after anthracycline initiation
SGLT2i administered in the study	Empagliflozin, canagliflozin, dapagliflozin
Cancer type of patients in the study	Breast and lymphoma		Breast, genitourinary, gastrointestinal, thoracic, head and neck, hematologic, skin		Breast, genitourinary, gastrointestinal, lymphoma, sarcoma, leukemia
Cancer therapy of patients in the study	Anthracyclines		Alkylating agents, antimetabolites, platinum, plant alkaloids, anthracyclines, tyrosine kinase inhibitors, HER2 inhibitors, VEGF inhibitors, immune checkpoint inhibitors, radiotherapy		Anthracycline (doxorubicin)
Follow-up, median (years)	1.6		1.6		1.5

^†Age in median years [IQR].

^‡Age in mean years [SD].

^§Male.

^¶Female.

^#CAD: Coronary artery disease; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease; CVD: Cardiovascular disease; DM: Diabetes mellitus; HF: Heart failure; IQR: Interquartile range; MI: Myocardial infarction; NR: Not reported; RAAS: Renin-angiotensin-aldosterone system; SD: Standard deviation; SGLT2i: Sodium-glucose cotransporter-2 inhibitor.

Table 3.

Newcastle Ottawa scale assessment.

Dimension:	Selection				Ref.
Study	Representativeness of the exposed cohort	Selection of the non-exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at the start of the study
Qadir 2023	*		*	*	[18]
Chiang 2023	*	*	*	*	[20]
Gongora 2022	*	*	*		[19]
	Comparability
	Comparability of cohorts on the basis of the design or analysis
Qadir 2023	*				[18]
Chiang 2023					[20]
Gongora 2022	*				[19]
	Outcome
	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow-up of cohorts
Qadir 2023		*			[18]
Chiang 2023	*	*	*		[20]
Gongora 2022	*	*	*		[19]
	Score
Qadir 2023	5				[18]
Chiang 2023	7				[20]
Gongora 2022	8				[19]

3.3. Results of meta-analysis

3.3.1. Overall mortality

The use of SGLT2i resulted in a significant reduction in overall mortality [RR = 0.52 (0.33–0.82); p = 0.005, I² = 32%] Figure 2. All of the included studies reported this outcome. Moderate heterogeneity was observed in the analysis of this outcome. To address this, sensitivity analysis was done by individually excluding the lowest-graded study with a Newcastle Ottawa Scale score of 5 and performing the analysis with studies having scores of 7 and 8. As a result, the observed heterogeneity increased from a previous I² value of 32–59% (p = 0.05), highlighting the substantial influence of differences between studies (Supplementary Figure S1). In the subgroup analysis, according to only anthracycline treatment or anthracycline treatment along with other antitumor agents, there was no observed decrease in heterogeneity. The differences between the subgroups were not statistically significant (p = 0.57), further proving that the observed heterogeneity is due to differences between the studies rather than due to chance (Supplementary Figure S2).

Figure 2.

Forest plot for ‘overall mortality’.

CI: Confidence interval; IV: Inverse variance; SE: Standard error.

3.3.2. Cardiovascular events

3.3.2.1. HF incidence

Administration of SGLT2i was not associated with a significant reduction in the incidence of HF [RR = 0.50 (0.22–1.16); p = 0.11, I² = 0%] (Figure 3). This outcome was reported by two of the included studies.

Figure 3.

Forest plot for ‘heart failure incidence’.

CI: Confidence interval; IV: Inverse variance; SE: Standard error.

3.3.2.2. HF hospitalization

The occurrence of hospitalization due to HF was significantly lower with the use of SGLT2i [RR = 0.20 (0.04, 1.02); p = 0.05, I² = 0%] (Figure 4). This outcome was reported by two of the included studies.

Figure 4.

Forest plot for ‘heart failure hospitalization’.

4. Discussion

Anthracycline-based chemotherapy is a cornerstone in cancer treatment, but it poses a risk of cardiotoxicity, impacting cardiovascular outcomes in patients undergoing treatment. Cardiotoxicity is defined as the inability of the heart to pump and circulate blood through the body effectively. Several parameters support this definition, such as reduction in left ventricular ejection fraction (LVEF), signs and symptoms associated with HF, reduction in LVEF from baseline <55% in the presence of signs and symptoms of HF, and a reduction in LVEF by >10% or an LVEF of <55% with or without signs and symptoms of HF [22]. Anthracyclines can cause cardiotoxicity via various mechanisms, including oxidative stress, the generation of reactive oxygen species within cells, lipid peroxidation, dysfunction in mitochondria, intracellular calcium dysregulation, and microenvironmental cardiac inflammation [23]. The risk of anthracycline-induced cardiotoxicity is elevated in the presence of cardiovascular risk factors, concurrent use of agents known for inducing chemotherapy-related cardiac dysfunction (CTRC), such as cyclophosphamide, trastuzumab, and paclitaxel, and exposure to mediastinal radiation [24]. Addressing these factors is essential in the assessment and planning of anthracycline-based treatments to mitigate the potential adverse effects. Earlier research has also suggested a correlation between the cumulative dosage of anthracyclines and the occurrence of cardiotoxicity. To elaborate further, diastolic dysfunction has been documented at doxorubicin doses of 200 mg/m², while systolic dysfunction has been observed within the range of 400 to 600 mg/m² [25]. Moreover, recent findings have additionally highlighted that left ventricular dysfunction may manifest at doxorubicin doses as low as 240 mg/m², particularly when combined with cyclophosphamide [26]. Furthermore, the American Society of Clinical Oncology (ASCO) categorizes individuals at an elevated risk of developing cardiac dysfunction based on specific criteria, including the following: exposure to high-dose anthracycline (doxorubicin >250 mg/m² or epirubicin >600 mg/m²); administration of lower-dose anthracycline in conjunction with lower-dose radiation therapy (RT <30 Gy) where the heart falls within the treatment field; receipt of lower-dose anthracycline or trastuzumab alone, coupled with the presence of multiple cardiovascular risk factors, advanced age of greater than 60 years, or underlying structural heart disease; undergoing treatment with lower-dose anthracycline followed by trastuzumab in a sequential therapy approach [27,28]. These classifications serve to identify the populations warranting heightened vigilance and tailored cardiac monitoring during cancer treatment to mitigate the potential for any cardiac complications. The management of cardiac dysfunction associated with chemotherapy (CTRCD) is still a challenging task, made more so by the inability to identify cardiotoxicity early on. Anthracycline-induced cardiotoxicity can be detected early with electrocardiograms (ECG), where the most common abnormalities include flattening and inversion of T waves and lengthening of the QT interval in some leads. Leads I and aVL (10.66%), leads II, III and aVF (60%), and leads V3–V6 (73%) all displayed these anomalies [29]. Moreover, anthracycline-induced cardiotoxicity was found to be statistically correlated with a lower QRS voltage, a QTc interval lengthening, and left ventricular dysfunction on ECG in a study including 26 individuals. These changes in the electrical activity of the heart are directly related to anthracycline treatment [30]. In addition, findings from a study by Pecoraro et al. suggest that treatment with doxorubicin is linked to a significantly decreased expression and function of Cx43, which may cause a decrease in the myocardium's quick electrical synchronization and velocity of conduction. These findings underscore the importance of vigilant monitoring and early intervention strategies to mitigate the detrimental effects of anthracycline chemotherapy on cardiac function and potentially improve patient outcomes [31].

Type-2 DM significantly increases the risk of the occurrence of cardiovascular outcomes through various mechanisms, such as myocyte hypertrophy, microvascular dysfunction, ischemia from epicardial coronary artery disease, increased proinflammatory cytokines, dysautonomia and sodium retention from up-regulated SGLT2 [32–35]. SGLT2i, a potent medication for Type-2 DM, counteracts some of the negative effects of DM and insulin resistance on cardiovascular metabolism and function by enhancing oxygen supply, myocardial fuel energetics, and mitochondrial activity. Moreover, they provide beneficial effects on HF hemodynamics that extend beyond the scope of diabetes treatment. These include increasing sodium excretion and reducing preload, lowering blood pressure, and decreasing afterload [36]. The utilization of SGLT2i has evolved into a standard practice in the comprehensive management of HF, demonstrating its significance regardless of the presence or absence of diabetes [37]. These pharmacological agents not only manifest a noteworthy reduction in the incidence of hospitalizations associated with HF exacerbations but also portray a significant and tangible decrease in mortality rates [38,39]. Despite the well-established efficacy of SGLT2i in diminishing HF-related hospitalizations and mortality, it remains imperative to delve deeper into their specific effects on individuals undergoing cancer treatment, particularly those exposed to the cardiotoxicity induced by anthracycline-based therapies. This unexplored territory calls for further in-depth exploration and investigation to unravel the nuanced dynamics at play.

Our results conclude that SGLT2i showed favorable outcomes in the treatment arm across all studies. Anthracycline-based chemotherapy is a cornerstone in cancer treatment, but it poses a risk of cardiotoxicity, impacting cardiovascular outcomes in patients. Recent research has explored the potential cardioprotective effects of SGLT2i in individuals undergoing anthracycline treatment for cancer. A comprehensive meta-analysis spanning 8 studies conducted on mouse models revealed that rodents treated with SGLT2i exhibited notably elevated LVEF following anthracycline-based chemotherapy [40]. Furthermore, these treated rats displayed reduced plasma levels of cardiac troponin, BNP, TNF-alpha, and FGF-2. In tandem, rats subjected to both SGLT2i and anthracyclines demonstrated diminished levels of myocardial fibrosis, intracellular reactive oxygen species formation, and lipid peroxidation in comparison to rats exclusively treated with anthracyclines [36,41]. Subsequent investigations have delved into the potential cardioprotective effects of SGLT2i in individuals undergoing anthracycline treatment for cancer. Abdel-Qadir et al.'s study explores the connection between SGLT2i and a reduced risk of anthracycline-associated cardiotoxicity, emphasizing the pivotal role of SGLT2i in mitigating cardiovascular risks linked to anthracycline therapy [18]. Moreover, the evidence presented by Gongora et al. and Chiang et al. indicates that SGLT2i reduces the incidence of HF, HF hospitalizations, and the onset of new cardiomyopathy in those receiving anthracycline treatment [19,20]. These findings align with Saad et al.'s observations from the CVD-REAL study, spotlighting a decreased risk of HF and mortality among patients initiating SGLT2i compared with other glucose-lowering medications [42]. The meta-analysis featured in the JAMA network consolidates evidence from various studies, providing a holistic understanding that reinforces the consistent trend toward cardiovascular benefits associated with SGLT2i in anthracycline-treated cancer patients [43]. Additionally, The ASCO Post's report highlights considerations for older patients, concluding that SGLT2i may lower the rate of heart failure-related hospitalization after anthracycline-containing therapies. This age-specific analysis enriches our insights into the potential benefits of SGLT2i across diverse patient demographics [43].

In an effort to further understand the nuanced outcomes, an article published on Europe PMC provides a detailed breakdown of cardiovascular events, revealing reductions in HF and other significant complications. Treatment with SGLT2i in an HF population was associated with a 27% relative risk reduction (RRR) of hospitalization for HF or cardiovascular mortality [RR = 0.73, 95% CI = 0.68–0.78], 32% RRR of hospitalization for HF (RR = 0.68, 95% CI = 0.62–074), 18% RRR of cardiovascular mortality (RR = 0.82, 95% CI = 0.73–0.91) and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75–0.91) concluding that SGLT2i are associated with improved cardiovascular outcomes in patients with HF [44]. This granularity is crucial in deciphering the multifaceted impact of SGLT2i on cardiovascular health in the context of anthracycline treatment. The evolving landscape of research on this topic necessitates a forward-looking approach.

Cardoso et al.'s research not only demonstrates a reduction in the composite of HF hospitalizations or cardiovascular death with SGLT2i but also implies a potential role for these inhibitors in mitigating the incidence of HF and related hospitalizations within the context of anthracycline-induced cardiotoxicity [45]. Avula et al. conducted another study that delves into the broader efficacy of SGLT2i in enhancing outcomes for patients with HF [46]. Although this study does not specifically target anthracycline-treated cancer patients, it adds supplementary context to the potential cardiovascular advantages associated with SGLT2i. The mechanism behind the observed association is not yet fully elucidated. However, hypotheses revolve around SGLT2i's impact on glucose metabolism, oxidative stress, and inflammation. SGLT2i are known to improve cardiovascular markers, making them a subject of interest beyond their traditional use in diabetes management. This association opens avenues for further investigation into repurposing SGLT2i as cardioprotective agents in cancer patients undergoing anthracycline therapy and large-scale studies to establish the efficacy and safety of this approach comprehensively are needed.

Among the cardioprotective effects of SGLT2i previously acknowledged in this discussion, highlighting the role of SGLT2i in impeding cancer cell growth and, hence, contributing to improved treatment outcomes is also of vital interest to the subject of our study. To elaborate, the existing experimental and clinical data indicate that incorporating SGLT2i into standard chemotherapy or radiotherapy regimens can improve treatment effectiveness [47,48]. Lau KTK et al.'s study sheds light on the anticancer capabilities of SGLT2i, revealing mechanisms that hinder glucose uptake in cancer cells [49]. This establishes a new perspective, suggesting that incorporating SGLT2i into treatment plans could be a promising approach to boost therapeutic effectiveness beyond cardiovascular concerns [50]. The multifaceted anti-malignant properties of SGLT2i encompass diverse mechanisms, including the downregulation of oxidative phosphorylation, induction of cell cycle arrest and apoptosis, suppression of the β-catenin and PI3K-Akt pathways, and destabilization of the mitochondrial membrane [51]. A multitude of in-vitro investigations highlights the favorable anticancer properties of canagliflozin in diverse cancer types, including colon, liver, lung, and breast cancer cells. These effects encompass inhibiting cancer cell proliferation, suppressing anchorage growth in a dose-dependent manner, and disrupting colony formation. Canagliflozin administration has been linked to inducing cell cycle arrest, along with reducing glucose uptake and inhibiting glycolysis in cancer cells [52–55]. Furthermore, Empagliflozin emerges as another SGLT2i demonstrating anticancer activity by impeding various facets of cancer progression, including proliferation, migration, invasion, and the induction of apoptosis in specific cancer types [56]. Dutka et al.'s study further consolidates our understanding by summarizing potential mechanisms of action for SGLT2i, encompassing the inhibition of β-linked proteins, activation of the AMPK signaling pathway, induction of cell cycle arrest, and inhibition of EGFR [15]. These diverse mechanisms underscore the comprehensive anticancer effects of empagliflozin, presenting a multifaceted approach that holds promise in restraining cancer cell growth and elevating overall treatment outcomes. The intersection of cardiovascular and anticancer benefits positions SGLT2i as potential therapeutic allies in addressing the complex interplay between diabetes, cardiovascular health, and cancer.

To the best of our knowledge, this is the first meta-analysis evaluating the CV role of SGLT2i in cancer patients by providing a pooled analysis that favors the treatment arm across the studies in two of the analyzed outcomes. However, it is to be noted that there are some limitations to this study. Firstly, the results should be interpreted in the context of the study design. Due to the scarcity of RCTs, we have included retrospective cohort studies which could be influenced by several unmeasured residual confounders such as associations among SGLT2i, cardiac events, and mortality. Second, these included studies also faced a lack of data sets on clinical characteristics such as blood pressure, obesity, or smoking and they were unable to differentiate between HF with reduced and intact ejection fractions. To add, there was also a lack of potential sources of mortality decrease, wide CIs were obtained despite a substantial effect size because of the short sample size and the requirement to impute missing creatinine and HbA1c data. Moreover, since there were no minimum HF hospitalizations in the SGLT2i groups, it was not possible to calculate the CI for the possible protective effect's impact size on this outcome. Third, cancer patients also face the risk of loss to follow-up, which can potentially affect the outcomes of interest. To discuss further, two of the included studies for this analysis focused exclusively on anthracycline-induced cardiotoxicity. However, the third study of this analysis by Chiang et al. also included patients exposed to other cardiotoxic agents, including tyrosine kinase inhibitors and radiotherapy, within the same cohort. The inclusion of these cardiotoxic agents may have introduced a potential source of variability in the outcomes of interest. Therefore, the findings of our analysis should be approached with caution, considering the potential impact of these cardiotoxic agents on the overall effect estimates. In addition, it is advisable to push for efforts in conducting homogenous studies that specifically focus on the influence of SGLT2i in the context of anthracycline-induced cardiotoxicity to enhance clarity regarding its effectiveness in this specific population. Also, cardiovascular profiles vary across many populations due to differences in risk factors and sedentary lifestyles; hence, non-randomized controlled trials taking into account demographic characteristics of the patients are needed. We further acknowledge that the stated limitations outlining the various differences in the included studies of this analysis may also serve as a potential cause of the observed heterogeneity in the outcome of ‘overall mortality’ [RR = 0.52 (0.33–0.82); p = 0.005, I²= 32%]. Lastly, Despite the several suggested anticancer effects of SGLT2i in existing literature, which are also discussed in this paper, this systematic review and meta-analysis faced a challenge in identifying and concluding a potential cause for the decrease in overall mortality and HF hospitalization associated with SGLT2i administration. As a result, the lack of a distinct source may introduce uncertainty regarding the specific mechanisms possible for the observed survival benefits associated with SGLT2i in this analysis. Hence, the authors further emphasize the importance of conducting more studies in order to assess these mechanisms in relevance to anthracycline-induced cardiotoxicity to evaluate the benefits of SGLT2i as an adjunct to anthracycline treatment for cancer patients.

5. Conclusion

To conclude the discussion of this systematic review and meta-analysis, the available evidence suggests that SGLT2i plays a potential role in reducing HF hospitalizations and decreasing overall mortality in the context of anthracycline-induced cardiotoxicity. We deduce, based on our analysis, that the investigation into the association of SGLT2i and CV outcomes among cancer patients who have undergone anthracycline treatment presents a highly promising avenue for further research and exploration. The potential dual benefits emerging from effectively managing cancer while concurrently mitigating cardiotoxicity present a comprehensive and holistic strategy for enhancing patient care. However, it is also of vital importance to underscore the necessity for additional research investigations, including RCTs and studies with prolonged follow-up periods. This undertaking is essential not only for the validation of the findings of our analysis but also for determining the optimal use of SGLT2i in this specific patient population.

Supplementary material

Supplementary data for this article can be accessed at https://doi.org/10.1080/14796678.2024.2363673

Author contributions

S Mohsin: conception and administration of project and manuscript, literature search, data curation, extraction and analysis, substantial contribution to drafting and revision of manuscript. M Hasan: literature search, data curation, extraction and analysis, interpretation of results, drafting and revision of manuscript. ZM Sheikh: independent review and revision of the systematic search, data curation, drafting, and revision of the manuscript. F Mustafa: literature search, drafting of the manuscript, and revision of the manuscript. V Tegeltija, S Kumar, and J Kumar: reviewing and revising the manuscript. All authors critically revised the manuscript and provided their final approval.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.