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SGLT-2 inhibitors in chronic peritoneal dialysis patients: a follow-up study

BMC Nephrology volume 25, Article number: 238 (2024) Cite this article

Abstract

Background

Sodium-glucose transporter-2 inhibitors (SGLT-2i) are recommended for use in patients with type 2 diabetes comorbid atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. Limited reports are currently available for their use in dialysis patients. In an observational, retrospective follow-up study, we reported the clinical characteristics of chronic peritoneal dialysis (PD) patients on SGLT-2i.

Methods

We enrolled 50 diabetic chronic PD patients, and 11 continued SGLT-2i after PD treatment. We reported the patients’ ultrafiltration, HbA1c, urinary tract infection episodes, and venous CO2 during follow-up and compared the differences in these factors between patients with and without SGLT-2i.

Results

The mean age of the patients was 65 ± 15 years, and 16 (32%) patients were female. The age, gender, heart failure, and primary kidney disease were not different between patients with and without SGLT-2i at enrollment. In an average of 31 months follow-up, patients with SGLT-2i had higher ultrafiltration (1322 ± 200 ml/day vs. 985 ± 415 ml/day, p = 0.013), hemoglobin (11.2 ± 1.7 vs. 10.2 ± 1.7 g/dl), white blood cell count (9.2 ± 3.7 vs. 7.4 ± 2.1 109/L), and a lower venous CO2 (p = 0.036). The urine amount, the overall survival, the technical survival, and the chance of UTI were not different between patients with and without SGLT2i.

Conclusion

SGLT-2i may increase ultrafiltration volume and hemoglobin levels in chronic PD patients. SGLT-2i did not increase urinary tract infection but was linked to subclinical metabolic acidosis.

What was known

The effect of SGLT-2i in chronic PD patients is not clear?

This study adds

SGLT-2i is associated with increased ultrafiltration, hemoglobin, white blood cell counts, and a decreased CO2 in PD patient.

Potential impact

SGLT-2i may increase ultrafiltration in PD patients.

Peer Review reports

Introduction

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) work by inhibiting glucose reabsorption in the kidneys, increasing urinary glucose excretion. This mechanism helps lower blood sugar levels in people with diabetes. Additionally, SGLT-2i has cardiovascular benefits [1, 2]. Studies such as the EMPA-REG OUTCOME trial [3] and the DAPA-HF trial [4] have demonstrated that SGLT-2i can reduce the risk of heart failure in individuals with or without diabetes. These findings have led to the incorporation of SGLT-2i into heart failure treatment guidelines. SGLT-2i also showed promising results in slowing the progression of chronic kidney disease. The DAPA-CKD [5] and EMPA-KIDNEY trials [6] have provided evidence that SGLT-2i can reduce the risk of kidney failure and cardiovascular events in individuals with or without diabetes.

In an animal model, SGLT-2i may decrease glucose absorption from PD solution by inhibiting SGLT-2 on the peritoneum [7]. Ultrafiltration may increase because the PD solution’s glucose may last longer and provide more extended osmotic water transport. In a case report, we reported increased ultrafiltration in incident PD patients [8]. We reported an observational, retrospective, and follow-up study of patients who continued on SGLT-2i after PD treatment and compared the characteristics of the patients to those without SGLT-2i.

Methods

This study complied with the Declaration of Helsinki and was performed according to ethics committee approval. The study was approved by the institutional review board of China Medical University Hospital (CMUH111-REC1-183). We reviewed all chronic PD patients (on PD for over 3 months) with diabetes from Jan 2019 to Dec 2021. We identified 50 chronic PD patients with diabetes, and all patients were followed until Dec 2022. Eleven patients continued to have SGLT-2i after PD treatment (eight patients had dapagliflozin, and three patients had empagliflozin), and 39 discontinued SGLT-2i. We performed a fast peritoneal equilibration test (PET) on the day of the PD catheter insertion; effluent samples were collected at 1 h, and a blood sample was collected at 1 h [10]. The 1-hour D/P ratios of creatinine were calculated in all patients. Patient characteristics, including age, gender, hypertension, diabetes, congestive heart failure (CHF), primary kidney disease, body mass index (BMI), Kt/V, D/P creatinine, urine, anti-diabetic medications, and PD formula, were collected at the enrollments. CHF was defined as Killip Class II or higher at the time of admission or the development of congestive heart failure after hospitalization [9]. The ultrafiltration, urine, blood pressure, sodium, potassium, white cell count (WBC), hemoglobin, blood urea nitrogen (BUN), calcium, and phosphorus were recorded monthly. HbA1c, CO2, magnesium, and iPTH (intact parathyroid hormone) were recorded every 3 months. The average values were used if the patients had more than two readings. A urinary tract infection was defined as > 105 cfu/mL of a uropathogen in midstream urine culture with the presence of an irritative voiding symptom [10]. Patient-reported genital infections were recorded.

Statistical analysis

Data are reported as the means (standard deviations) or frequencies (percentages) where appropriate. The differences between the patients with and without SGLT-2i were compared using a t-test in continuous variables and a chi-square test in categorical variables. Overall survival and technical survival were drawn using Kaplan-Meier analysis. All analyses were performed using R Statistical Software (version 4.2.1, R Foundation for Statistical Computing, Vienna, Austria) and finalfit, survminer packages. A p < 0.05 was considered statistically significant.

Results

The mean age of the patients was 65 ± 16 years, and 32% were female (Table 1). The BMI was higher in patients with SGLT-2i (28.2 ± 4.1 vs. 25.1 ± 4.5 kg/m2, p = 0.044). Eleven patients (22%) patients had CHF. The percentage of patients with CHF was not different between patients with SGLT-2i and those without. Diabetes was the primary kidney disease in 35 (70%) patients, hypertension in 6 (12%) patients, and chronic glomerulonephritis in 9 (18%) patients. Sixteen (41%) of 39 patients without SGLT-2i had insulin, 16 had dipeptidyl peptidase-4 inhibitor (DPP4), and 8 had sulfonylurea as the anti-diabetic treatment. The use of anti-diabetic medications was not different from the patients on SGLT-2i. The Kt/V, D/P creatinine, and urine amounts were not different between the two groups at the enrollment. The rate of patients with IPD was not different between the two groups. The 1.5% and 2.5% dextrose PD solutions were the most prescribed formulas in the two groups of patients.

Table 1 Characteristics of all participants
Full size table

In an average 31-month follow-up (Table 2), the daily ultrafiltration was higher in patients on SGLT-2i (1322 ± 200 ml/day) than in the patients without SGLT-2i (985 ± 415 ml/day, p = 0.013). Six patients had urinary tract infections (UTIs), five patients died (cardiovascular death N = 3, infection N = 1, traffic accident N = 1), and 9 patients dropped out of PD. The mortality, dropout rate, the rate of UTIs, and the rate of genital infection were not different between the two groups. The overall survival curve of patients with SGLT-2i was not different from that of the patients without SGLT-2i (Fig. 1, p = 0.54). No difference in technical survival was found in two groups of patients (Fig. 2, p = 0.96). The SBP and DBP were not different in the two groups. The average HbA1c was 7.2 ± 1.4 in patients without SGLT-2i and 6.7 ± 1.2 in patients with SGLT-2i. The venous CO2 was significantly lower in patients on SGLT-2i (p = 0.036). The white cell counts (WBC), hemoglobin, and, hematocrit were significantly higher in patients with SGLT-2i (p = 0.037, 0.045, and 0.031). The sodium, potassium, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, magnesium, and intact parathyroid hormone (iPTH) were not different between the two groups.

Table 2 Characteristics of 50 chronic peritoneal dialysis patients in follow-up
Full size table
Fig. 1
figure 1

Overall Survival curve

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Fig. 2
figure 2

Technical survival curve

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Discussion

This 31-month follow-up study showed an increased ultrafiltration volume and higher hemoglobin levels in chronic PD patients with SGLT-2i. We previously reported an increased ultrafiltration volume in four incident PD patients [8]. This follow-up study further confirmed the increased ultrafiltration in chronic PD, because SGLT-2i. decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume [11]. A randomized, double-blind, placebo-controlled crossover trial is currently undergoing to prove the increased ultrafiltration in PD [12]. The increased hemoglobin in diabetic patients on SGLT-2i has been reported in previous studies, [13] because SGLT-2i may increase erythropoietin and expand red blood cell mass [14] through the downregulation of hypoxia-inducible factor 1α [15]. The higher hemoglobin may be related to the decreased volume status because the WBC was significantly higher in patients with SGLT-2i. In our clinical observations, patients with SGLT-2i were less likely to have pitting edema.

The decrease of venous CO2 in patients on SGLT-2i may suggest a subclinical metabolic acidosis. The subclinical metabolic acidosis may be explained by euglycemic ketoacidosis, which is a potential complication of SGLT-2i [16]. Because the ketone body was not measured in this study, we cannot confirm the presence of ketoacidosis. Small increases in serum magnesium, potassium, and phosphate levels have been reported in the previous studies [17,18,19]. In this study, we did not observe a significant difference in serum magnesium, potassium, and phosphate levels in patients on SGLT-2i.

The study has some limitations. First, the overall survival and technical survival were not different in patients with and without SGLT-2i because of the limited study size. Second, the average ultrafiltration volume under different PD prescriptions because of the study’s observational nature. Third, all patients had SGLT-2i before PD started. We did not know if SGLT-2i is linked to increased urine amount.

Conclusions

SGLT-2i is linked to increased ultrafiltration volume and hemoglobin levels in chronic PD patients. The chance of UTI was not increased, and a subclinical metabolic acidosis may be present in patients on SGLT-2i. The overall survival and technical survival were not different in patients with and without SGLT-2i.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. Dapagliflozin and Cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.

    Article  CAS  PubMed  Google Scholar 

  2. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.

    Article  CAS  PubMed  Google Scholar 

  3. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, Cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    Article  CAS  PubMed  Google Scholar 

  4. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.

    Article  CAS  PubMed  Google Scholar 

  5. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436–46.

    Article  CAS  PubMed  Google Scholar 

  6. The E-KCG, Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–27.

    Article  Google Scholar 

  7. Zhou Y, Fan J, Zheng C, Yin P, Wu H, Li X, Luo N, Chen XYC. SGLT-2 inhibitors reduce glucose absorption from peritoneal dialysis solution by suppressing the activity of SGLT-2 Biomed Pharmacother, 2019. 109: 1327–1338.

  8. Lai JW, Chou HJLCY. SGLT-2 inhibitors may increase ultrafiltration in incident peritoneal dialysis patients: a case report. BMC Nephrol. 2023;24(1):106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Washio T, Nomoto K, Watanabe I, Tani S, NagaoA K, Hirayama. Relationship between plasma homocysteine levels and congestive heart failure in patients with acute myocardial infarction. Homocysteine and congestive heart failure. Int Heart J. 2011;52(4):224–8.

    Article  CAS  PubMed  Google Scholar 

  10. Gopal M, Arya GNL. Clinical symptoms predictive of recurrent urinary tract infections Am J Obstet Gynecol, 2007. 197(1): 74 e1-4.

  11. Balzer MS, Rong S, Nordlohne J, Zemtsovski JD, Schmidt S, Stapel B, Bartosova M, von Vietinghoff S, Haller H, Schmitt CP et al. SGLT2 inhibition by Intraperitoneal Dapagliflozin mitigates peritoneal fibrosis and Ultrafiltration failure in a mouse model of chronic peritoneal exposure to High-Glucose Dialysate. Biomolecules, 2020. 10(11).

  12. Doi Y, Shinzawa M, Arisato T, Oka H, Matsumoto A, Kitamura H, Nakazono Y, Nishiya Y, Ueda Y, Kamimura T, et al. Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED). Clin Exp Nephrol; 2024.

  13. Kanbay M, Tapoi L, Ureche C, Tanriover C, Cevik E, Demiray A, Afsar B, CherneyA DZI, Covic. Effect of sodium-glucose cotransporter 2 inhibitors on hemoglobin and hematocrit levels in type 2 diabetes: a systematic review and meta-analysis. Int Urol Nephrol. 2022;54(4):827–41.

    Article  CAS  PubMed  Google Scholar 

  14. Packer M. Mechanistic and clinical comparison of the Erythropoietic effects of SGLT2 inhibitors and prolyl hydroxylase inhibitors in patients with chronic kidney disease and renal Anemia. Am J Nephrol. 2024;55(2):255–9.

    Article  CAS  PubMed  Google Scholar 

  15. Huang X, Guo X, Yan G, Zhang Y, Yao Y, Qiao Y, Wang D, Chen G, Zhang W, Tang C, et al. Dapagliflozin attenuates contrast-induced acute kidney Injury by regulating the HIF-1alpha/HE4/NF-kappaB pathway. J Cardiovasc Pharmacol. 2022;79(6):904–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Palmer BFDJ, Clegg. Euglycemic ketoacidosis as a complication of SGLT2 inhibitor therapy. Clin J Am Soc Nephrol. 2021;16(8):1284–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. de Jong MA, Petrykiv SI, Laverman GD, van Herwaarden AE, de Zeeuw D, Bakker SJL. HeerspinkM.H. De Borst, effects of Dapagliflozin on circulating markers of phosphate homeostasis. Clin J Am Soc Nephrol. 2019;14(1):66–73.

    Article  PubMed  Google Scholar 

  18. Tsimihodimos V, Elisaf TDFMS. Effects of sodium-glucose co-transporter 2 inhibitors on metabolism: unanswered questions and controversies. Expert Opin Drug Metab Toxicol. 2017;13(4):399–408.

    Article  CAS  PubMed  Google Scholar 

  19. Tsimihodimos V, Filippatos TD, Filippas-NtekouanM S, Elisaf. Renoprotective effects of SGLT2 inhibitors: beyond glucose reabsorption inhibition. Curr Vasc Pharmacol. 2017;15(2):96–102.

    Article  CAS  PubMed  Google Scholar 

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Funding

Asia University Hospital Research Grant (11151008, 11251005). The funders had no role in study design, data collection, analysis, publication decision, or manuscript preparation.

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Author notes

  1. Jia-Wen Lai and Charles C.N. Wang contribute equally to the work.

Authors and Affiliations

  1. Division of Nephrology, Asia University Hospital, Taichung, Taiwan

    Jia-Wen Lai & Che-Yi Chou

  2. Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

    Charles C.N. Wang & Che-Yi Chou

  3. College of Medicine, China Medical University, Taichung, Taiwan

    Che-Yi Chou

  4. Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan

    Che-Yi Chou

Authors
  1. Jia-Wen Lai
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Contributions

CY: Draft article, JW: collect the data and the patient recruitment, Charles C.N.: conceptualization, and formal analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Che-Yi Chou.

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The authors declare no competing interests.

Ethics approval

The study was approved by the institutional review board of China Medical University Hospital (CMUH111-REC1-183).

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Written informed consent was obtained from all participants.

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Lai, JW., Wang, C.C. & Chou, CY. SGLT-2 inhibitors in chronic peritoneal dialysis patients: a follow-up study. BMC Nephrol 25, 238 (2024). https://doi.org/10.1186/s12882-024-03683-y

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BMC Nephrology

ISSN: 1471-2369

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