- Open Access
Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study
Cancer & Metabolism volume 11, Article number: 6 (2023)
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC’s excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.
We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.
Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.
Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.
Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal with an overall 5-year survival rate of ~11%, and the survival rate for those with distant metastases is a dismal 3% [1, 2]. Combination chemotherapies such as Gemcitabine plus nab-paclitaxel (GnP) and FOLinic Acid, 5-Fluorouracil, IRINotecan, and OXaliplatin (FOLFIRINOX) remain the mainstay of treatment over the past decade [3, 4]. However, these regimens are associated with significant side effects and treatment responses are typically short-lived. Therefore, therapeutic strategies that can augment treatment response without incurring further toxicities are an urgent, unmet clinical need.
Deregulation of cellular metabolism is an established hallmark of tumorigenesis and a clinically relevant avenue for new therapeutics . In fact, several lines of evidence have demonstrated the prognostic potential of glucose utilization in pancreatic cancer. Fluorodeoxyglucose positron emission tomographic (FDG-PET) imaging has been shown to be a highly sensitive modality for pancreatic cancer detection with a pooled sensitivity of 90% [6, 7]. Enhanced glycolysis has also been recognized as an important metabolic alteration in PDAC metastasis that involves the epithelial–mesenchymal transition, angiogenesis, and subsequent seeding of cancer cells in distant organs [8, 9]. One mechanism for this phenomenon is the conversion of glucose into energy, anabolic pathways, and reducing equivalents to mitigate oxidative stress [10, 11]. This has clinical significance, as the presence of diabetes and increased circulating glucose increases the risk of PDAC . Thus, novel anti-diabetic interventions that inhibit tumor glucose uptake or metabolism may have efficacy in patients with PDAC.
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new, FDA-approved class of glucose-lowering drugs that inhibit renal glucose reabsorption and reduce plasma glucose through increased urinary glucose excretion. SGLT2i improves all-cause survival and decreases major cardiovascular events in patients with type 2 diabetes and in those with heart failure [13, 14]. Although SGLT2 protein (from SLC5A2) is expressed primarily in normal kidneys, recent data show that several human tumors upregulate SGLT2, including PDAC, brain, lung, colon, and prostate [15,16,17,18,19]. In fact, functional SGLT2 protein is expressed in human PDAC tumors. Moreover, SGLT2 has been recently shown to promote PDAC progression by activation of Hippo signaling via the hnRNPK-YAP1 axis . Inhibition of SGLT2 in preclinical PDAC models results in tumor necrosis and decreased growth . Not only do SGLT2 inhibitors (SGLT2i) have direct anti-tumor effects, but this class of drugs has beneficial pleiotropic effects including reversing hyperinsulinemia [21, 22], decreasing plasma glucose, producing a mild ketonemia, and reducing visceral obesity [23,24,25,26,27,28,29,30], all of which can improve survival in patients with cancer, particularly PDAC [31,32,33,34,35].
We conducted a phase 1b clinical trial combining the SGLT2i dapagliflozin with standard GnP chemotherapy for patients with newly diagnosed, advanced PDAC. We chose dapagliflozin because of its efficacy in xenograft models of PDAC  and our team’s extensive experience administering dapagliflozin.
Study design and participants
This study was approved by the Washington University in St. Louis Institutional Review Board (HRPO#202011019) and registered as NCT04542291 on September 09, 2020. The study was conducted in accordance with the Declaration of Helsinki. Inclusion criteria included histologically or cytologically confirmed metastatic or locally advanced pancreatic ductal adenocarcinoma or pancreatic adenosquamous carcinoma, ≥ 18 years of age, no prior systemic treatment, preserved organ and hematologic functions, lack of brain metastases, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, and in which GnP therapy was deemed appropriate by the treating oncologists. Exclusion criteria included current or previous treatment with an SGLT2i, thiazolidinedione, or insulin use for diabetes at baseline, chronic steroid use, baseline HbA1c > 10%, history of stroke or transient ischemic attack in preceding 5 years, and uncontrolled intercurrent illnesses. All subjects provided written informed consent.
Following enrollment, patients were treated with Gemcitabine and nab-Paclitaxel starting from 1000 mg/m2 and 125 mg/m2, respectively, on days 1, 8, and 15 of every 28-day cycle. Dapagliflozin treatment was initiated at 5 mg once daily for the first 2 weeks and escalated to 10 mg once daily after assessment by an endocrinologist for an additional 6 weeks, totaling 8 weeks or 2 cycles of GnP. If a patient was deemed to have a progression of pancreatic insulin insufficiency and/or significantly increasing blood glucose levels during the study, the treating endocrinologist was allowed to add other glucose-lowering medications to the study drug (dapagliflozin) for clinical purposes. Patients were seen in the clinic or followed up via phone visits every 3–4 days and weekly for a check on ketone status and side effects according to medical need. Repeat imaging studies were performed after 8 weeks of treatment, and the overall response was classified as stable disease (SD), partial response (PR), or progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST 1.1; discussed below) [36, 37]. Patients stayed on GnP alone until PD occurred or drug intolerance developed. Patients were evaluated for toxicity and adverse events for 3 months after discontinuation of dapagliflozin. In addition, patients were instructed to measure urine ketones routinely on a weekly basis or when feeling sick (Ketodiastix; Bayer, Germany) to monitor for ketoacidosis.
Treatment-related adverse events were documented during every clinic visit and the severity scored using the Common Terminology Criteria for Adverse Events (CTCAE) v.5 classifications (Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening requiring urgent interventions; Grade 5: death).
Laboratory value analysis
The following blood laboratory values were assessed prior to and at the end of study treatment (EOT; 8 weeks): fasting glucose, c-peptide (a biomarker for endogenous insulin production), glucagon, beta-hydroxybutyrate ketone, and pancreatic polypeptide (a secreted biomarker for the endocrine pancreas). The tumor marker CA19-9 was monitored during treatment, along with a complete blood count (CBC) and comprehensive metabolic panel (CMP). Any value reported as less than the threshold (e.g., < 0.2 mmol/L) was treated as below the detection limit and not plotted in the analyses. Percent change of values at EOT relative to baseline was calculated as (− 1) × [1-(EOT value/baseline value)] × 100%.
Tumor imaging/quantification analysis
CT examinations in Digital Imaging and Communications in Medicine (DICOM) format at baseline and EOT were transferred to a workstation equipped with Mint Lesion software (Mint Medical; Hamilton, NJ). Tumor measurements were performed by a single radiologist using RECIST 1.1 criteria, and an overall response assessment was generated [36, 37]. Both target and non-target lesions were assessed. Percent change in the sum of the diameters (SODs) of the target lesions relative to baseline was calculated as (− 1) × [1-(EOT value/baseline value)] × 100%. Although baseline and EOT imaging were the primary emphases for this trial, CT scans performed following the completion of the study (when available) as part of the standard of care were also analyzed to measure tumor response.
CT-based quantitative body composition assessment
DICOM-formatted abdominal CT examinations that were used for RECIST measurements at baseline and EOT were obtained. Scans were transferred to a workstation equipped with the data analysis facilitation suite (DAFS; Voronoi Health Analytics; British Columbia, Canada). This software platform has been previously validated to assess the effects of body composition on the mortality of patients with cancer [38,39,40,41]. Automated segmentation of the fat and muscle was performed by the software and verified by a board-certified abdominal radiologist (JEI). Volumetric analyses were performed from the L1–L4 levels, as these levels were present in their entirety in a single continuous scan for all patients at both baseline and EOT.
Continuous variables were reported as means (± standard deviation), and categorical variables were reported as proportions, unless otherwise specified. Comparisons of measurements between baseline and EOT were performed by using the Student’s paired t test. Correlations were assessed by using the Pearson correlation coefficient (r). Statistical analyses were performed by using Prism 9.1.0 (GraphPad Software, La Jolla, CA, USA). Two-tailed statistical tests were performed where applicable, and p < 0.05 was considered to indicate a statistically significant difference.
Between March and September 2021, 23 patients with newly diagnosed locally advanced or metastatic PDAC were screened, and 15 patients were enrolled (Fig. 1). Of these 15 patients, three patients dropped out during the first 4 weeks of treatment start. One patient developed severe upper gastrointestinal hemorrhage secondary to primary tumor invasion and after clinical stabilization decided to pursue hospice. Two patients elected to withdraw from the study due to intolerance to GnP chemotherapy as determined by the treating oncologists and were treated with a reduced dose of GnP or single-agent gemcitabine. The baseline characteristics of the remaining 12 evaluable patients are shown in Table 1. Ten patients had ductal adenocarcinoma and two had a mixed adenosquamous (> 50% adenocarcinoma) histology. The average age was 66.8 years, and 92% of patients were white. The baseline plasma CA19-9 was elevated in nine of twelve evaluable patients. Only one patient had a history of type 2 diabetes at the time of entry into the study, but two other patients met the criteria for diabetes by either a fasting glucose concentration > 126 mg/dL and/or a hemoglobin A1c > 6.5% during the study. None was taking any glucose-lowering medications at baseline (Supplementary Table 1). However, during the study, the two who developed diabetes despite dapagliflozin treatment were started on glucose-lowering therapy (one on basal insulin and one on metformin). The most common medications taken by the patients in addition to dapagliflozin and GnP included acetaminophen (92%), opiates (67%), and antiemetics (42%).
Compliance, safety, and tolerability
Eleven of the 12 evaluable patients completed 2 weeks of 5 mg/day of dapagliflozin followed by 6 weeks of 10 mg/day as planned. One patient had 2+ urinary ketones on urinalysis, albeit without clinical ketoacidosis or increased anion gap, and was instructed to discontinue dapagliflozin 2 weeks before the end of the trial. He completed the post-study imaging and blood sampling. All other patients completed 8 weeks of dapagliflozin without deviation. Prior to his discontinuation, he had been 100% compliant. Dapagliflozin compliance for all other patients enrolled (N = 14) was 99.4%. Side effects were attributed to dapagliflozin, GnP, or both by the treating oncologists for each patient and presented in Table 2. There were no grade 3–4 side effects attributed to dapagliflozin alone. Side effects attributed to dapagliflozin were infrequent and mild (grades 1–2) and included fatigue, nausea, dry mouth, and plasma sodium levels. The majority of side effects attributed to the study regimen overall were related to the known side effects of GnP (Table 2). The treating physicians in charge of monitoring side effects concluded that the addition of dapagliflozin to GnP was generally well-tolerated and did not inflict additional toxicities on almost all participants in this study.
Metabolic responses (assessed by plasma chemistries) of the 12 patients who completed the protocol were measured at baseline before initiation of dapagliflozin and at EOT. There was no significant change in plasma glucose or beta-hydroxybutyrate levels (Fig. 2A, B). The lack of significant change in beta-hydroxybutyrate is supported by the concomitant lack of change in the anion gap, an indirect measure of circulating ketoacids (Fig. 2C). However, plasma glucagon levels significantly increased (average 2.8-fold increase; Fig. 2D). In contrast, plasma c-peptide levels (a marker for endogenous insulin production) were not significant (Fig. 2D). Change in pancreatic polypeptide (a marker of pancreatic endocrine and exocrine function) concentrations  trended toward significance (p = 0.078) with an average 1.6-fold increase at EOT (Fig. 2E).
The response to therapy was assessed using RECIST 1.1 criteria as well as plasma CA19-9 levels, a clinical biomarker used for PDAC. Of the 12 evaluable patients, after the first 8 weeks/2 cycles of treatment, two had a partial response (PR), defined as greater than 30% reduction in target lesion size. The majority (9/12) had stable disease (SD), and only one patient had progressive disease (PD), defined as a greater than 20% increase in target lesion size (Fig. 3A). RECIST analysis was expanded for these patients outside of the dapagliflozin treatment window when they were only receiving GnP. After dapagliflozin treatment ended, with subsequent imaging, the majority (7/11) of patients experienced progression of the disease characterized by either (i) the presence of new metastatic lesions or (ii) the increase in target lesion size greater than 30% relative to baseline (Fig. 3B), despite continuing on GnP therapy.
These imaging data were compared to plasma CA19-9 levels. Three of the twelve patients had normal CA19-9 levels at diagnosis and hence not included. For the remaining 9 patients, the percent change of CA19-9 largely mirrored the changes in tumor size as measured using RECIST. Only one patient experienced an increase (~ 50%) in tumor biomarker burden, as well as tumor size (Fig. 3A–D). Moreover, there was a significant positive correlation (r = 0.729; p = 0.026) between the percent change in RECIST tumor size and the percent change in CA19-9 (Fig. 3D).
Change in body composition
Because SGLT2i therapy as well as pancreatic cancer are known to alter fat and muscle mass, [27, 43, 44], volumetric abdominal muscle and fat measurements were obtained from CT scans on the patients performed at baseline and at EOT. First, every patient lost weight during the course of treatment with GnP + dapagliflozin (Fig. 4A). A validated automated body composition algorithm was used to compute changes in total abdominal skeletal muscle and fat volumes (Fig. 4B) . On average, both fat and muscle mass decreased in these patients (Fig. 4D, E). However, when the muscle-to-fat ratio was computed for these patients, no overall significant differences were identified. One patient had a greater than twofold increase in the muscle-to-fat ratio over the course of dapagliflozin therapy (Fig. 4E). This patient was also the patient that had the best RECIST response (Fig. 3A, B). To evaluate this effect further, a correlation was performed on the change in the muscle-to-fat ratio versus the change in the RECIST quantitative measurements (SOD). A modest but significant correlation existed between muscle-to-fat ratio and RECIST measurements. Patients who maintained more muscle mass and lost more fat mass during dapagliflozin therapy had better quantitative RECIST responses than those who did not (Fig. 4F).
To our knowledge, this is the first prospective study in humans to evaluate the safety and tolerability of the SGLT2i, dapagliflozin, as adjunctive therapy in combination with chemotherapy for patients with PDAC. It is also the first to preliminarily explore the potential efficacy of dapagliflozin on PDAC. This phase 1b study demonstrated that dapagliflozin, added to standard GnP chemotherapy, was very well-tolerated and associated with few adverse symptoms. Moreover, patients were highly compliant with dapagliflozin. There was also evidence suggesting that dapagliflozin, in addition to GnP, was associated with salutary effects on PDAC. Stable disease and partial response were maintained in 11 of 12 patients that were accompanied by a decrease in CA19-9. In addition, quantitative changes in body composition were identified where maintenance of muscle mass and loss of fat mass were associated with better quantitative tumor response measurements. In sum, there is evidence that dapagliflozin may potentially be efficacious as adjunctive therapy for advanced PDAC treatment, and dapagliflozin is generally very well-tolerated and generally safe to use in this very ill population.
Before this trial, it was not clear that SGLT2i therapy would be generally well-tolerated by this population of patients with advanced, inoperable PDAC because they are often symptomatic and have an average survival of ~12 months [3, 4]. Patients taking any SGLT2i therapy need to stay hydrated and take in adequate amounts of carbohydrates to avoid ketoacidosis, and patients with advanced PDAC often experience nausea and vomiting as hallmark manifestations of their disease and/or treatment with GnP chemotherapy. Knowing this, patients in this trial were instructed on recommended carbohydrate intake, encouraged to stay hydrated, and were instructed to measure their ketone levels frequently. They were also followed closely by our interdisciplinary study team, including board-certified endocrinologists. Likely in part due to this proactive protocol, the vast majority of patients were able to complete the study and avoid ketoacidosis. The one patient who was told near the end of the study to discontinue dapagliflozin due to 2+ urine ketone levels was likely dehydrated, as evidenced by a urine specific gravity > 1.03, due to episodes of nausea and vomiting. However, the overall treated-related adverse event profile, as shown in Table 2, was very favorable for dapagliflozin, and most adverse events and all grade 3–4 adverse events during the trial were attributed to GnP. The low percentage of side effects seen in the current study is similar to that seen in other larger multicenter controlled studies, such as the DECLARE-TIMI 58 trial . In that study of patients who had type 2 diabetes and cardiovascular disease or who were at increased risk for cardiovascular disease, most side effects occurred in 1% or less of the patients studied. Of note, no patient had a significantly elevated creatinine that was attributed to dapagliflozin. This is consistent with the known small decrease in glomerular filtration rate that can occur in shorter-term interventions (after ~2–4 weeks, likely due to a decrease in intraglomerular pressure) which typically recovers at least in part in subsequent weeks and is often followed by preservation of renal function in the long term [45, 46]. In short, dapagliflozin was well-tolerated by almost all patients with PDAC in the current trial, which likely contributed to the extremely high drug compliance rate in our study.
Dapagliflozin was not only well-tolerated in the current trial, but there were also potential signs of its efficacy as a treatment for PDAC when added to standard GnP therapy. Eleven of twelve evaluable patients had either stable disease or partial response during the initial 8 weeks of study treatment. Plasma CA19-9 levels showed similar trends. Perhaps most indicative of a therapeutic effect of the dapagliflozin, several patients had an increase in tumor size or developed new lesions after the dapagliflozin was stopped, even though the patients were continued on standard-of-care chemotherapy. These data suggest that direct metabolic modulation with SGLT2i is not only safe and generally well-tolerated but also potentially an efficacious treatment versus PDAC. To give context to our findings, a phase 3 randomized clinical trial assessed the efficacy of GnP in patients with metastatic PDAC . 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 dapagliflozin in our study, several patients had an increase in tumor size or developed new lesions after the dapagliflozin was stopped, even though the patients were continued on standard-of-care GnP. Although caution is recommended in extrapolating these results to dapagliflozin efficacy because of its limited duration in this study, these data indicate that direct metabolic modulation with SGLT2i is safe and generally well-tolerated and support future phase II studies combining SGLT2i with GnP until disease progression to better assesses the efficacy of this strategy.
Systemic metabolic effects were also seen after treatment with SGLT2i therapy in these patients with PDAC. Though at first glance it may be surprising that there was no change in fasting plasma glucose levels (Fig. 2A), 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). However, the lack of significant overall change in plasma glucose or ketone levels suggests that direct inhibition of glucose uptake through SGLT2 expression on PDAC  may play a more important anti-tumor role than indirect systemic changes in glucose. Though measurement of SGLT2-mediated glucose uptake in vivo with [18F]Me-4FDG positron emission tomography [17, 19] or SGLT2 expression in biopsy tissues pre- and post-dapagliflozin treatment were beyond the scope of this phase 1b trial, it would surely add to future studies of SGLT2i for human PDAC.
Although plasma ketone and glucose levels did not change overall, other systemic metabolic effects were noted with dapagliflozin treatment. Plasma glucagon levels increased in all subjects. This is a well-described effect of SGLT2i therapy and may suggest reduced beta-cell insulin secretion . Supporting this notion, there was also a borderline increase in pancreatic polypeptide levels though C-peptide concentrations did not change. These systemic effects are very relevant for cancer therapy, as glucagon can have anti-tumor effects through unknown mechanisms [48, 49]. Though the primary aim of the current study was not to evaluate the change in pancreatic function, the increase in glucagon and borderline increase in pancreatic polypeptide levels suggest there may be an improvement in pancreatic function, as has been described in other studies of SGLT2i treatment in diabetes .
SGLT2i are known to decrease abdominal fat by increasing fatty acid oxidation [27, 44], which could be a reason why patients lost abdominal fat during the trial. However, this change can be confounded by the systemic metabolic effects of PDAC and chemotherapy that are also known to decrease body fat, mediated by anorexia, malabsorption, and/or tumor metabolic effects . Paralleling the loss of abdominal fat, abdominal muscle mass also decreased during the trial. There has been some concern that the negative energy balance from SGLT2i therapy can result in loss of muscle mass as well as fat; free amino acids are released and transported to the liver for gluconeogenesis. Although this has been observed with other SGLT2i, this has not yet been documented with dapagliflozin . Interestingly, although there were no significant effects on the abdominal muscle/fat ratio, patients who had a higher ratio at the end of therapy (i.e., retained more muscle mass and burned more fat) had better tumor response. This is supported by a multitude of data indicating that sarcopenia (i.e., low muscle mass), in addition to sarcopenic obesity (i.e., low muscle mass and high adiposity) are associated with poor outcomes in PDAC as well as multiple additional malignancies [31, 53,54,55,56]. In fact, our data are similar to a study by Babic et al. that examined the effects of postdiagnosis loss of skeletal muscle on outcomes in patients with advanced PDAC . We observed an overall average 9% decrease in the skeletal muscle mass (over 8 weeks) which is strikingly similar to the ~ 10% decrease (over 8–16 weeks) observed by Babic et al., who demonstrated a correlation between preserved skeletal muscle mass and increased survival. Further, our findings relating to fat loss (− 18%) were also similar to those of Babic et al. (− 15%). These observations would be in line with our findings that less muscle mass loss during treatment correlated with greater response to therapy. Together, these data suggest that (i) metabolically targeted therapies that facilitate fat loss but maintain muscle mass may have a clinically significant impact on better PDAC patient outcomes and (ii) quantitative body composition assessment with CT can be used to potentially assess treatment response and predict better outcomes.
There are limitations to the current study. It is a small study by design as its primary aim was to evaluate safety and tolerability in patients with advanced PDAC. The size of the study necessarily limits the conclusions that can be drawn from it. Our study findings cannot be extrapolated to patients who did not fit our inclusion/exclusion criteria (e.g., who received different treatment options for PDAC or patients with other malignancies). Our study was not randomized or placebo-controlled, which would add to the study’s rigor. However, it did provide reassuring safety findings and intriguing efficacy signals.
In sum, our study findings demonstrate that 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.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.
Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Primers. 2016;2:16022.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12(1):31–46.
Wang X-Y, Yang F, Jin C, Fu D-L. Utility of PET/CT in diagnosis, staging, assessment of resectability and metabolic response of pancreatic cancer. World J Gastroenterol. 2014;20(42):15580–9.
Jha P, Bijan B. PET/CT for pancreatic malignancy: potential and pitfalls. J Nucl Med Technol. 2015;43(2):92–7.
Yan L, Raj P, Yao W, Ying H. Glucose metabolism in pancreatic cancer. Cancers. 2019;11(10):1460.
Yang J, Ren B, Yang G, Wang H, Chen G, You L, et al. The enhancement of glycolysis regulates pancreatic cancer metastasis. Cell Mol Life Sci. 2020;77(2):305–21.
Dang CV. Links between metabolism and cancer. Genes Dev. 2012;26(9):877–90.
Payen VL, Porporato PE, Baselet B, Sonveaux P. Metabolic changes associated with tumor metastasis, part 1: tumor pH, glycolysis and the pentose phosphate pathway. Cell Mol Life Sci. 2016;73(7):1333–48.
Koo D-H, Han K-D, Park C-Y. The incremental risk of pancreatic cancer according to fasting glucose levels: nationwide population-based cohort study. J Clin Endocrinol Metab. 2019;104(10):4594–9.
Inzucchi SEZB, McGinniss J, Schnee J, George J, Fitchett D. Consistent effect of empagliflozin on composite outcomes related to heart failure: results from EMPA-REG outcome. J Am Coll Cardiol. 2017;69:1656.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
Okada J, Matsumoto S, Kaira K, Saito T, Yamada E, Yokoo H, et al. Sodium glucose cotransporter 2 inhibition combined with cetuximab significantly reduced tumor size and carcinoembryonic antigen level in colon cancer metastatic to liver. Clin Colorectal Cancer. 2018;17(1):e45–8.
Wright EM. SGLT2 and cancer. Pflugers Arch. 2020;472(9):1407–14.
Scafoglio C, Hirayama BA, Kepe V, Liu J, Ghezzi C, Satyamurthy N, et al. Functional expression of sodium-glucose transporters in cancer. Proc Natl Acad Sci U S A. 2015;112(30):E4111–9.
Scafoglio CR, Villegas B, Abdelhady G, Bailey ST, Liu J, Shirali AS, et al. Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci Transl Med. 2018;10(467):eaat5933.
Kepe V, Scafoglio C, Liu J, Yong WH, Bergsneider M, Huang S-C, et al. Positron emission tomography of sodium glucose cotransport activity in high grade astrocytomas. J Neurooncol. 2018;138(3):557–69.
Ren D, Sun Y, Zhang D, Li D, Liu Z, Jin X, et al. SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis. Cancer Lett. 2021;519:277–88.
Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28(10):1028–35.
Nasiri AR, Rodrigues MR, Li Z, Leitner BP, Perry RJ. SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia. Cancer Metab. 2019;7:10.
Vardeny O, Vaduganathan M. Practical guide to prescribing sodium-glucose cotransporter 2 inhibitors for cardiologists. JACC Heart Fail. 2019;7(2):169–72.
Blunck JR, Newman JW, Fields RK, Croom JE. Therapeutic augmentation of ketogenic diet with a sodium-glucose cotransporter 2 inhibitor in a super-refractory status epilepticus patient. Epilepsy Behav Case Rep. 2018;10:61–4.
Pfützner A, Klonoff D, Heinemann L, Ejskjaer N, Pickup J. Euglycemic ketosis in patients with type 2 diabetes on SGLT2-inhibitor therapy-an emerging problem and solutions offered by diabetes technology. Endocrine. 2017;56(1):212–6.
Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs. 2019;79(3):219–30.
Tosaki T, Kamiya H, Himeno T, Kato Y, Kondo M, Toyota K, et al. Sodium-glucose co-transporter 2 inhibitors reduce the abdominal visceral fat area and may influence the renal function in patients with type 2 diabetes. Intern Med. 2017;56(6):597–604.
Skinner R, Trujillo A, Ma X, Beierle EA. Ketone bodies inhibit the viability of human neuroblastoma cells. J Pediatr Surg. 2009;44(1):212–6.
Magee BA, Potezny N, Rofe AM, Conyers RA. The inhibition of malignant cell growth by ketone bodies. Aust J Exp Biol Med Sci. 1979;57(5):529–39.
Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD. Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int. 2009;9:14.
Okumura S, Kaido T, Hamaguchi Y, Kobayashi A, Shirai H, Yao S, et al. Visceral adiposity and sarcopenic visceral obesity are associated with poor prognosis after resection of pancreatic cancer. Ann Surg Oncol. 2017;24(12):3732–40.
Sandini M, Patino M, Ferrone CR, Alvarez-Perez CA, Honselmann KC, Paiella S, et al. Association between changes in body composition and neoadjuvant treatment for pancreatic cancer. JAMA Surg. 2018;153(9):809–15.
Bian X, Dai H, Feng J, Ji H, Fang Y, Jiang N, et al. Prognostic values of abdominal body compositions on survival in advanced pancreatic cancer. Medicine. 2018;97(22):e10988.
Sah RP, Sharma A, Nagpal S, Patlolla SH, Sharma A, Kandlakunta H, et al. Phases of metabolic and soft tissue changes in months preceding a diagnosis of pancreatic ductal adenocarcinoma. Gastroenterology. 2019;156(6):1742–52.
Cooper AB, Slack R, Fogelman D, Holmes HM, Petzel M, Parker N, et al. Characterization of anthropometric changes that occur during neoadjuvant therapy for potentially resectable pancreatic cancer. Ann Surg Oncol. 2015;22(7):2416–23.
Schwartz LH, Seymour L, Litiere S, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1 - standardisation and disease-specific adaptations: perspectives from the RECIST Working Group. Eur J Cancer. 2016;62:138–45.
Schwartz LH, Litiere S, de Vries E, Ford R, Gwyther S, Mandrekar S, et al. RECIST 1.1-update and clarification: from the RECIST committee. Eur J Cancer. 2016;62:132–7.
Dabiri S, Popuri K, Cespedes Feliciano EM, Caan BJ, Baracos VE, Beg MF. Muscle segmentation in axial computed tomography (CT) images at the lumbar (L3) and thoracic (T4) levels for body composition analysis. Comput Med Imaging Graph. 2019;75:47–55.
Popuri K, Cobzas D, Esfandiari N, Baracos V, Jägersand M. Body composition assessment in axial CT images using FEM-based automatic segmentation of skeletal muscle. IEEE Trans Med Imaging. 2016;35(2):512–20.
Cespedes Feliciano EM, Popuri K, Cobzas D, Baracos VE, Beg MF, Khan AD, et al. Evaluation of automated computed tomography segmentation to assess body composition and mortality associations in cancer patients. J Cachexia Sarcopenia Muscle. 2020;11(5):1258–69.
Ma D, Chow V, Popuri K, Beg MF. Comprehensive validation of automated whole body skeletal muscle, adipose tissue, and bone segmentation from 3D CT images for body composition analysis: towards extended body composition. arXiv. 2021;3:1–9.
Lonovics J, Devitt P, Watson LC, Rayford PL, Thompson JC. Pancreatic polypeptide. A review. Arch Surg. 1981;116(10):1256–64.
Shin DW, Kim MA, Lee JC, Kim J, Hwang JH. Maintenance of skeletal muscle mass during FOLFIRINOX is a favorable prognostic factor in pancreatic cancer patients. BMC Res Notes. 2021;14(1):272.
Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R, Muramatsu Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol. 2014;727:66–74.
Meraz-Muñoz AY, Weinstein J, Wald R. eGFR decline after SGLT2 inhibitor initiation: the tortoise and the hare reimagined. Kidney360. 2021;2(6):1042–7.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–306.
Zhu X, Lin C, Li L, Hu S, Cai X, Ji L. SGLT2i increased the plasma fasting glucagon level in patients with diabetes: a meta-analysis. Eur J Pharmacol. 2021;903:174145.
Goranson ES, Cinits E, Hercz A. The effect of glucagon on tumor growth. Can Res. 1959;19(5):512–4.
Godfrey J, Riscal R, Skuli N, Simon MC. Glucagon signaling via supraphysiologic GCGR can reduce cell viability without stimulating gluconeogenic gene expression in liver cancer cells. Cancer Metab. 2022;10(1):4.
Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes. 2011;60(3):890–8.
Hendifar AE, Petzel MQB, Zimmers TA, Denlinger CS, Matrisian LM, Picozzi VJ, et al. Pancreas cancer-associated weight loss. Oncologist. 2019;24(5):691–701.
Otsuka H, Yokomizo H, Nakamura S, Izumi Y, Takahashi M, Obara S, et al. Differential effect of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice. Biochem J. 2022;479(3):425–44.
Stretch C, Aubin JM, Mickiewicz B, Leugner D, Al-Manasra T, Tobola E, et al. Sarcopenia and myosteatosis are accompanied by distinct biological profiles in patients with pancreatic and periampullary adenocarcinomas. PLoS One. 2018;13(5):e0196235.
Xia L, Zhao R, Wan Q, Wu Y, Zhou Y, Wang Y, et al. Sarcopenia and adverse health-related outcomes: an umbrella review of meta-analyses of observational studies. Cancer Med. 2020;9(21):7964–78.
Ninomiya G, Fujii T, Yamada S, Yabusaki N, Suzuki K, Iwata N, et al. Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma: a retrospective cohort study. Int J Surg. 2017;39:45–51.
Sandini M, Bernasconi DP, Fior D, Molinelli M, Ippolito D, Nespoli L, et al. A high visceral adipose tissue-to-skeletal muscle ratio as a determinant of major complications after pancreatoduodenectomy for cancer. Nutrition. 2016;32(11–12):1231–7.
Babic A, Rosenthal MH, Bamlet WR, Takahashi N, Sugimoto M, Danai LV, et al. Postdiagnosis loss of skeletal muscle, but not adipose tissue, is associated with shorter survival of patients with advanced pancreatic cancer. Cancer Epidemiol Biomark Prev. 2019;28(12):2062–9.
This work was supported by the NIH grants K99/R00 CA218869 (JEI), R21 CA242221 (JEI), R61 HL155858 (LRP), R21 HL145217 (LRP), R01 AG060499 (LRP), UL1 TR000448 (JEI, LRP), and P50 CA196510 (WGH); the Alvin J. Siteman Cancer Center Investment Program/The Foundation for Barnes-Jewish Hospital (JEI) and the Barnard Research Fund (JEI); The American Heart Association (RMZ); and Michael Smith Foundation for Health Research Innovation to Commercialization Program (MFB, DM, KP, VTYC). The Imaging and Response Assessment Core of the Alvin J. Siteman Cancer Center is supported in part by the NCI Cancer Center Support Grant P30 CA91842. The authors gratefully acknowledge the Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop R25 CA203650 (PI: Melinda Irwin).
Ethics approval and consent to participate
This study was approved by the Washington University in St. Louis Institutional Review Board (HRPO#202011019) and registered as NCT04542291 on September 09, 2020. The study was conducted in accordance with the Declaration of Helsinki. All patients were prospectively consented to be in this trial.
Consent for publication
M.S. has research grants from Neurocrine Biosciences and Mylan and is a consultant for Eli Lilly and Neurocrine Biosciences.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Park, L.K., Lim, KH., Volkman, J. et al. Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study. Cancer Metab 11, 6 (2023). https://doi.org/10.1186/s40170-023-00306-2
- Pancreatic ductal adenocarcinoma
- Sodium-glucose cotransporter-2 inhibitor