SGLT2 INHIBITORS

An relatively new class of antidiabetic drugs called SGLT2 (sodium-glucose cotransporter 2 inhibitors) are being explored in oncology. The drugs are used in cardivascular and renal disease therapy, examples include dapaglifozan, empaglifozan and canagliflozin. Researchers believe these drugs can target multiple metabolic and signaling pathways used by some cancers, in particular glucose uptake which is upregulated by many cancers to drive progression.

Currrently, much of the evidence relates to lower progression risks measured in diabetic cancer patients that take these drugs before and during treatment. Notably, this patient group frequently has more advanced type 2 diabetes and a worse prognosis overall. Experience, and disappointments, of using metformin outside of diabetes has shown only too well the need for very specfic targeting. So far metabolic therapy for cancer has failed to deliver, and that includes randomly combining several drugs.

In lung cancer, a large study from patient records shows long term use in diabetic patients of SGLT2 inhibitors almost halves the post diagnostic all cause risks. Similarly, in a korean population study in diabetic cancer patients, much lower progression risk for both cancer and cardiovascular protective outcomes were found. And a 2022 analysis of diabetic liver cancer patients showed up to 40% relative risk reductions for SGLT2 inhibitors used over longer time periods. Again, this is similar to the history of metformin research.

There are initial signs specific non diabetic patient groups may benefit from SGLT2 drugs being added to treatment plans. Recent pilot trials in pancreatic cancer showed significantly higher disease control rates vs chemo alone, and the majority of patients with stable disease were seen to progress once dapagliflozin was stopped. This is clearly a promising target, and more research is really needed.

In terms of prevention, recent studies show protective effects for prostate cancer incidence, but data did not indicate effects post diagnosis.

To give context to our findings, a phase 3 randomized clinical trial assessed the efficacy of GnP in patients with metastatic PDAC [4]. The rate of disease control in patients on GnP alone for 16 weeks or more was 48%. Our disease control rate over 8 weeks was 11/12 (91%). Though our study and the randomized trial are not directly comparable because patients were not followed for the same length of time and our study was a first-in-human, smaller study, our response rate is encouraging. Moreover, suggestive of a therapeutic effect of the dapaglif...

SGLT2i users with T2DM had lower mortality rates than non-DM patients or non-SGLT2i users with T2DM [diabetes]. In human prostate and lung cancer cells, SGLT2i reduced cellular proliferation and clonogenic survival by inhibiting glucose uptake and mitochondrial function34. A similar phenomenon has been observed in other cancer cell lines, including kidney and breast. Animal models have consistently demonstrated that SGLT2i decrease the occurrence and growth of cancer cells..The findings suggest that SGLT2i may attenuate the growth of SGLT2-expres...

Our study based on the SEER-Medicare linked data, a large population-based national database, revealed that HCC patients with pre-existing T2DM treated with SGLT2 inhibitors had better prognosis relative to patients who were not on SGLT2 inhibitors, especially for those who used SGLT2 inhibitors ≥ 12 months. We further observed that SGLT2 inhibitor use was associated with a [large] reduced risk of mortality regardless of patients’ demographic, tumor characteristics and cancer treatments, despite some associations in sub-groups not reaching st...

SGLT2 inhibitors use was associated with improved overall survival of NSCLC patients with pre-existing diabetes..SGLT2 inhibitor use was associated with significantly reduced mortality risk after adjusting for potential confounders (HR = 0.68) with stronger association for longer duration of use (HR = 0.54) [Hazard ratio, 46% relative risk reduction]

TABLE OF REFERENCES

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https://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-023-00306-2	3	Dapagliflozin is generally well-tolerated and safe to use even in patients with advanced, inoperable PDAC. The favorable tolerability was accompanied by an extremely high compliance rate (> 99%). The study also suggested that dapagliflozin may have salutary effects on advanced PDAC when added as adjunctive therapy to standard GnP chemotherapy. The clinical implications of a new well-tolerated, oral medication which is potentially efficacious adjunctive therapy against metastatic PDAC are significant. A future larger randomized clinical trial is warranted to further evaluate the potential efficacy of SGLT2 inhibitor therapy in patients with PDAC	Though at first glance it may be surprising that there was no change in fasting plasma glucose levels , none of the patients had uncontrolled diabetes or required insulin at baseline per the study protocol and the majority of patients (N = 9/12) did not have diabetes, so the average baseline fasting glucose level was within normal limits < 110 mg/dL. Thus, there was relatively little room for change in systemic glucose levels in these patients. Similarly, there were no significant increases in plasma ketones on average (It is interesting to note that the patient with the greatest response to dapagliflozin in terms of tumor regression had the greatest increase in plasma ketones).
https://www.medrxiv.org/content/10.1101/2025.01.10.25320355v1.full	3	Repurposing SGLT2 inhibitors for cancer treatment could potentially improve outcomes for GI cancer patients without causing significant side effects. Further clinical trials are needed to confirm these findings and establish the optimal condition for its application in GI cancer treatment.	The study included 6,389 male and 3,457 female patients with GI cancer (ICD-10: C15-C25). The use of SGLT2i was significantly associated with improved survival for both male (HR 0.568; 95% CI 0.534-0.605) and female (HR 0.561; 95% CI 0.513-0.614) patients undergoing chemotherapy and/or radiotherapy. SGLT2i use also correlated significantly with lower hospitalisation rates both in male (OR 0.68) and female (OR, 0.59) patients
https://www.nature.com/articles/s41598-023-48678-1	3	SGLT2i users with T2DM had lower mortality rates than non-DM patients or non-SGLT2i users with T2DM [diabetes]. In human prostate and lung cancer cells, SGLT2i reduced cellular proliferation and clonogenic survival by inhibiting glucose uptake and mitochondrial function34. A similar phenomenon has been observed in other cancer cell lines, including kidney and breast. Animal models have consistently demonstrated that SGLT2i decrease the occurrence and growth of cancer cells..The findings suggest that SGLT2i may attenuate the growth of SGLT2-expressing cancer cells by inhibiting glucose uptake and blocking several subsequent intracellular metabolic pathways	Patients were classified into three groups: patients with T2DM taking SGLT2i (n = 780) and other hypoglycemic agents excluding SGLT2i (non-SGLT2i; n = 3,455) during AC chemotherapy, and the non-DM group (n = 77,337). The clinical outcome was a composite of heart failure hospitalization, acute myocardial infarction, ischemic stroke, and death...779 SGLT2i users were compared with 7800 non-DM patients and 2,337 non-SGLT2i users. The SGLT2i group had better composite outcomes compared with the non-DM group (adjusted hazard ratio [HR] = 0.35, ) and compared with the non-SGLT2i group (adjusted HR = 0.47)..SGLT2i may contribute to improving clinical outcomes in patients
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274519	2.5	Our study based on the SEER-Medicare linked data, a large population-based national database, revealed that HCC patients with pre-existing T2DM treated with SGLT2 inhibitors had better prognosis relative to patients who were not on SGLT2 inhibitors, especially for those who used SGLT2 inhibitors ≥ 12 months. We further observed that SGLT2 inhibitor use was associated with a reduced risk of mortality regardless of patients’ demographic, tumor characteristics and cancer treatments, despite some associations in sub-groups not reaching statistical significance. The associations remained significant when limiting cause of death specifically to liver cancer	The mechanisms by which SGLT2 inhibitors may contribute to better prognosis of HCC are unclear. Several possible explanations have been proposed. First, SGLT2 inhibitors may have a direct inhibitory effect on the occurrence and progression of HCC [27]. Studies have reported that SGLT2 inhibitors suppressed HCC proliferation by inducing G2/M arrest and/or promoting apoptosis of HCC cells [25–27]. Studies have also reported that SGLT2 inhibitors can exert antiproliferative effects by regulating metabolic reprograming and blocking glucose uptake by cancer cells [25, 26]. For example, Kaji observed that canagliflozin exerted antiproliferative effects on SGLT2-expressing Huh7 and HepG2 cells in a dose-dependent manner by inhibiting glycolytic metabolism. Second, SGLT2 inhibitors may contribute to better prognosis of HCC via improved liver function
https://www.nature.com/articles/s41416-023-02177-2	2.5	Our large SEER-Medicare linked data study indicates that SGLT2 inhibitors use was associated with improved overall survival of NSCLC patients with pre-existing diabetes	SGLT2 inhibitor use was associated with significantly reduced mortality risk after adjusting for potential confounders (HR = 0.68) with stronger association for longer duration of use (HR = 0.54).
https://www.jacc.org/doi/10.1016/j.jaccao.2024.08.001	2	our retrospective cohort analysis suggests that in patients with cancer and T2DM, without a prior documented history of cardiomyopathy or HF, and who received potentially cardiotoxic antineoplastic therapies, the baseline use of SGLT2is was safe and associated with a significantly reduced risk of CTRCD, HF exacerbations, all-cause mortality, all-cause hospitalizations/ED visits, new onset atrial fibrillation/flutter, new onset metastatic cancer, and the need for systemic antineoplastic therapy. More extensive prospective randomized trials are warranted to validate the role of SGLT2is as a viable primary prevention strategy for patients exposed to cancer treatment with the potential for cardiotoxicity.	Additionally, our subgroup analysis on individual SGLT2i therapies showed that empagliflozin was associated with a significantly lower risk of developing CTRCD compared to dapagliflozin and canagliflozin. Empagliflozin improves cardiac energy metabolism, anti-inflammatory and antioxidative effects, and antifibrotic effects,20 although direct comparisons of individual SGLT2i propensity for these cardioprotective mechanisms in patients with CTRCD remains unknown. There have been other retrospective studies that have shown that in patients with HF, empagliflozin was associated with improved outcomes compared to dapagliflozin and or canagliflozin
https://pmc.ncbi.nlm.nih.gov/articles/PMC11375926/	2	Empagliflozin is associated with reduced incidence of CTRCD in high-risk patients treated with anthracyclines. These data should serve as the foundation for a clinical trial to test whether SGLT2 inhibitors can reduce the incidence of heart failure in this patient group	In this prospective case‒control trial, empagliflozin administered to a high-risk group were associated with a reduction in anthracycline-induced cardiac dysfunction. Furthermore, SGLT2 inhibitors have been proven safe for patients undergoing chemotherapy.
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(24)00409-9	2	Using electronic healthcare data (nSGLT2i = 24,155; nDPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts (n4C = 57,779; nUK_Biobank = 165,430), we found little evidence to support the association of HbA1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention.	Genetically proxied SGLT2 inhibition lowered the risk of advanced (OR = 0.52) and early-onset (OR = 0.27) prostate cancer. Little evidence was observed to support an effect of SGLT2 inhibition on other prostate-cancer-related outcomes . In addition, there was little evidence to support an effect of SGLT2 inhibition on prostate-specific antigen (PSA) levels, which suggested that SGLT2 inhibition is likely to show an effect on reducing risk rather than influencing the diagnostic workup for prostate cancer. As a positive control, we confirmed the well-established effect of SGLT2 inhibition on reducing the risk of Type2 diabetes (OR = 0.66)
https://www.mdpi.com/2227-9059/11/7/1867	1	Targeting glucose transporters creates a potential avenue to starve cancer cells and reduce tumor size/progression while avoiding the undesirable side effects of current chemotherapy treatments. Over time, SGLT2 inhibitors have evolved as anticancer agents that displayed favorable results in different cancer models. By preventing glucose reabsorption and promoting urinary glucose excretion, SGLT2 inhibitors deplete energy stores for cancer cells, causing a rapid reduction in angiogenesis and environmental viability. Nevertheless, studies also showed that the anticancer effects of these agents are independent of their glucose-lowering effects as well. Pretreatment with SGLT2 inhibitors or even combining these agents with already established chemotherapeutics could be a viable option to investigate their additive or synergistic potential in oncology	Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of β-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.
https://www.mdpi.com/2673-3846/5/4/39	1	An effective cardioprotective strategy in cardio-oncology should achieve a reduction in the potential cardiotoxic effects of cancer therapies without compromising their antitumor efficacy, thus enhancing PFS and OS in cancer patients. Therefore, given the positive effects of SGLT2i in reducing cardiotoxicity associated with cancer therapies, it is crucial to explore their influence on the antitumor effectiveness of these treatments In the past, there were concerns about the potential carcinogenic risk associated with SGLT2i. Specifically, empagliflozin was suspected to be linked to an increased risk of bladder cancer [78,79]. However, subsequent evidence has dispelled these concerns, showing that SGLT2i do not increase the risk of developing malignant tumors . Instead, they are associated with improved survival rates in cancer patients	Finally, moving beyond retrospective analyses to prospective, randomized controlled trials will be essential for generating more robust clinical evidence. In this regard, the EMPACT (EMPAgliflozin in Prevention of Chemotherapy-related CardioToxicity) (NCT05271162) trial is currently underway. It is a randomized, multi-center, double-blind trial assessing the efficacy of empagliflozin in preventing LV dysfunction in cancer patients receiving high doses of anthracyclines. It will include 220 patients with cancer, no prior heart failure, and LV ejection fraction (EF) ≥ 50%, randomized to receive either 10 mg of empagliflozin daily or a placebo. The primary objective is to evaluate whether empagliflozin can prevent a reduction in LVEF, monitored by echocardiography and cardiovascular magnetic resonance (CMR). Secondary endpoints include all-cause and cardiovascular deaths, myocardial infarction, ischemic stroke, as well as structural myocardial changes, global longitudinal strain (GLS), and cardiac biomarkers.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9738342/	1	the possibility of blocking glucose uptake by cancer cells using SGLT-2 inhibitors appears to be an attractive therapeutic approach, especially in view of the expression of SGLT-2 confirmed in numerous types of cancer cells. Furthermore, SGLT-2 inhibitors are now registered and widely used in the treatment of diabetes and heart failure. Knowing the enhanced glucose dependency of tunours (Warburg effect), the interest of researchers in SGLT-2 inhibitors as a group of drugs with anticancer activity has risen in recent years. Besides blocking SGLT-2 various mechanisms of anticancer action of this group of drugs are being investigated	However, clinical trials are needed to assess the clinical benefits of doing this. As can be seen, there are many areas and potential targets for the anticancer action of SGLT-2 inhibitors. However, many questions remain unresolved, mainly regarding the safety and clinical feasibility of using SGLT-2 inhibitors in cancer treatment. Nonetheless, numerous ongoing preclinical studies and probable new clinical trials to come give hope for the future optimal use of this interesting group of drugs in clinical oncology
https://www.nature.com/articles/s41419-022-04980-w	1	SGLT2 was overexpressed in malignant cancers, including pancreatic and prostate adenocarcinomas [9], lung cancer [27], and breast cancer [28], and the overexpression of SGLT2 significantly promoted the proliferation, migration, and invasion abilities in malignant cancers [12, 13]. In our study, we found that SGLT2 was overexpressed at the protein level in osteosarcoma, which indicated that SGLT2 is a novel therapeutic target in osteosarcoma. It has been reported that specific SGLT2 inhibitors could block the functional activity of SGLT2	we demonstrated that the SGLT2 inhibitor significantly inhibited osteosarcoma tumor growth and induced infiltration of immune cells in vivo by upregulating STING expression, which could be contributed to the suppression of AKT phosphorylation (Fig. 8). Furthermore, the combined treatment with SGLT2 inhibitor and STING agonist 2’3’-cGAMP exerted synergistic antitumor effects in osteosarcoma due to the activation of the STING/IRF3/IFN-β pathway via different mechanisms. Moreover, the overexpression of SGLT2 at the protein level was correlated with the degradation of SGLT2 induced by TRIM21
https://pmc.ncbi.nlm.nih.gov/articles/PMC11103046/	1	Several comprehensive review articles have discussed the potential anticancer mechanisms of SGLT2 inhibitors...Importantly, the presence of SGLTs (SGLT1 and/or SGLT2) has been confirmed in various types of cancer cells, including hepatocellular carcinoma; pancreatic, prostate, lung, and breast cancers; and brain, head, and neck tumors....Consequently, some mechanisms underlying the anticancer effects of SGLT2 inhibitors are dependent upon the inhibition of SGLT2, whereas others are independent of SGLT2 inhibition.	Initially, concerns were raised regarding the risk for cancer with SGLT2 inhibitors, especially bladder cancer with dapagliflozin.122,123 However, subsequent studies and meta-analyses have examined these concerns, ultimately concluding that there was no overall risk for malignancy with SGLT2 inhibitors.124, 125, 126 Furthermore, recent epidemiologic studies have revealed a positive association between the use of SGLT2 inhibitors and improved overall survival among patients with non-small-cell lung cancer (NSCLC)127 and hepatocellular carcinoma128 with pre-existing diabetes, irrespective of patients’ demographics, tumor characteristics, and cancer treatments. Notably, a longer duration of SGLT2 inhibitor use, especially with canagliflozin, was associated with better survival.
https://www.nature.com/articles/s42003-023-05289-w	1	This [animal model] study provides substantial new evidence that the SGLT2 inhibitor canagliflozin, a widely used diabetes therapy, provides, within its therapeutic window, tumor suppressive and radio-sensitizing activity in PC through a complex multi-target mechanism. Canagliflozin suppresses survival and tumor growth in both androgen-sensitive and—insensitive PC models and demonstrates increased activity in radio-resistant PC cells compared to parental controls. It suppresses mitochondria respiration, but unlike other OxPhos inhibitors, it does not alter extracellular acidification. This is achieved, at least in part, through induction of mitochondria complex-I blockade and suppression of HIF-1α	The Swedish Watchful Waiting cohort (GSE16560)63 is one of the best repositories of prognostic information for PC patients, containing up to 30 years of follow-up data. The observation that low levels of the effector genes and transcription factors suppressed by canagliflozin are associated with improved survival, and that combined signatures of those genes do so with greater statistical significance (Fig. 9 and Table s1a) strengthens the notion that this agent has increased potential to provide clinical efficacy. This is further strengthened by the finding that canagliflozin-regulated genes are associated with survival outcomes in TCGA

SGLT2 INHIBITORS

TABLE OF REFERENCES

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