Skip to main content

Renoprotective effects of sodium glucose cotransporter 2 inhibitors in type 2 diabetes patients with decompensated heart failure

Abstract

Background

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of the composite renal endpoint and weakens the progressive decline in renal function in patients with chronic heart failure (HF). However, a detailed mechanism of SGLT2i on renal function and outcome remains uninvestigated.

Methods

We prospectively included 40 type 2 diabetic mellitus (T2DM) patients (median 68 years old, 29 male) who were hospitalized for decompensated HF and received SGLT2i during the index hospitalization. Of them, 24 patients had increases in estimated glomerular filtration rate (eGFR) at 12-month follow-up and 16 had decreases in eGFR. We investigated the baseline factors associating with the improvement in renal function.

Results

Lower plasma B-type natriuretic peptide (BNP) level and the use of renin-angiotensin system inhibitor (RASI) were independently associated with increases in eGFR during the follow-up period (p < 0.05 for both). Patients with both low plasma BNP levels and uses of RASI achieved significant increases in eGFR irrespective of the baseline HbA1c levels.

Conclusions

Lower plasma BNP level and the use of RASI at baseline were the key factors contributing to the renoprotective effects of SGLT2i among patients with decompensated HF and T2DM.

Peer Review reports

Background

Patients with heart failure (HF) have a high risk of mortality and morbidity, particularly when they have concomitant kidney impairment [1, 2]. Impaired renal function is common in patients with HF and reduced ejection fraction (HFrEF) and up to 50% of them have chronic kidney disease (CKD) [3]. Patients with CKD also commonly develop HF, and their dominant cause of death is a cardiovascular event.

The currently approved medication to protect kidney function in patients with type 2 diabetes mellitus (T2DM) is renin-angiotensin system inhibitor (RASI) [4, 5]. Sodium-glucose cotransporter 2 inhibitor (SGLT2i), which ameliorates hyperglycemia by suppressing renal glucose reabsorption in urine, has been demonstrated to have favorable effects on the kidney and cardiovascular outcomes in large clinical trials involving patients with T2DM [6,7,8]. The EMPEROR-Reduced trial further demonstrated that SGLT2i was associated with a lower risk of composite renal outcome and a slower progressive decline in renal function in patients with HFrEF, irrespective of the existence of T2DM [9]. These studies suggest that the renal benefit of SGLT2i appears to be independent of their blood glucose-lowering effects.

However, its detailed mechanism remains uninvestigated. Detailed assessments of the renoprotective effect of SGLT2i would be a key to more clarify the clinical implication and optimal patient selection to further enjoy the renoprotective effect of the SGLT2i. As a preliminary step, we investigated the factors associating with the improvement in renal function (super-response in renoprotective effect) during the SGLT2i therapy in patients with HF and T2DM.

Methods

The present study was a single-center, non-randomized, open-labeled, prospective registry study designed to assess the factors associating with the renoprotection of SGLT2i therapy for the patients with HF and T2DM. The local Institutional Ethics Board approved the study protocol (#Rin 29-94), which complied with the Declaration of Helsinki. Written informed consent was obtained from all of the patients beforehand.

Study population

This study involved consecutive T2DM patients who had received SGLT2i for the first time during their index hospitalization for decompensated HF, which was diagnosed according to the Framingham criteria, at our institute between February 2016 and September 2019. All patients had New York Heart Association (NYHA) class III/IV symptoms upon admission. Among canagliflozin (100 mg/day), dapagliflozin (5 mg/day), and empagliflozin (10 mg/day), one SGLT2i was non-randomly selected and administered. All patients had HbA1c level of 6.1% or higher and received guideline-directed medical therapy for HF.

Exclusion criteria were as follows: type 1 diabetes mellitus, end-stage renal failure (estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2), use of any mechanical circulatory supports, pregnancy or breastfeeding in the study period, history of hypersensitivity to the study drugs, severe ketosis, diabetic coma or precoma, and suspension of SGLT2i during the observation period.

Study design and data collection

Baseline characteristics including demographics and laboratory data were obtained at index discharge. eGFR at baseline and 6 and 12 months after discharge was retrospectively retrieved. A primary endpoint was defined as any increases in eGFR at 12 months after discharge compared with the index discharge (“super-response” in the achievement of renoprotection). The eGFR was calculated using the guidelines from the Chronic Kidney Disease Epidemiology Collaboration.

Statistical analyses

Continuous variables were expressed as the median and interquartile unless any specific statements. Categorical variables were expressed as absolute numbers and percentages. Wilcoxon test was applied to compare continuous parameters, and Pearson’s χ2 test was applied for comparison of categorical variables. Trends of continuous variables were compared using the Friedman test. Univariable and multivariable analyses with logistic regression models were performed to calculate the adjusted odds ratio to assess the influence of various parameters on the renoprotective effect of SGLT2i. Variables significant with p < 0.05 in the univariate analyses were included in the multivariate analyses. A cut-off of plasm B-type natriuretic peptide (BNP) concentration for any increases in eGFR after SGLT2i initiation was calculated using receiver operating characteristic analysis. The statistical analysis was performed by using JMP® 15 (SAS Institute Inc., Cary, NC, USA). The level of significance was defined as p < 0.05.

Results

Baseline characteristics

A total of 111 patients were considered to be included (Fig. 1). Of them, 65 patients continued SGLT2i without suspension for 12 months. 18 patients who were lost to follow-up or had no biochemical tests were excluded. Cardiovascular death occurred in 4 patients and non-cardiovascular death occurred in 3 patients. A total of 40 patients (median 68 years old, 29 male) were finally included in this study.

Fig. 1
figure1

Enrollment and follow-up

The baseline characteristics are summarized in Table 1. Median age was 68 years old and 29 were male. Baseline eGFR was 53.0 (36.1, 74.5) mL/min/1.73m2.

Table 1 Baseline characteristics

Discontinued group

Among 46 patients who discontinued SGLT2i during the index hospitalization, 19 were followed for 12 months. There were no statistically significant differences in the baseline characteristics except for age and the dose of furosemide (Additional file 1: Table 1).

There were no significant differences in the eGFR at baseline between both groups. By contrast, eGFR tended to be higher in continued group compared to discontinued group 6 and 12 months after discharge (Additional file 2: Figure 1). Only age and continuation of SGLT2i were significantly correlated with the changes in eGFR during the 12-month follow-up period (Additional file 3: Table 2).

Achievement of the primary endpoint

The participants were divided into two groups according to the achievement of primary endpoint: any increases in eGFR at 12-month follow-up: an increased group (N = 26) and a decreased group (N = 14). The median value of changing eGFR (eGFR at month 12—eGFR at baseline) in the two groups was + 5.5 and − 7.5, respectively (Fig. 2). 25/40 had anti-diabetic agents and 20/40 had history of hospitalization for HF at the time of index hospitalization. No patients initiated anti-heart failure medications during the observational period.

Fig. 2
figure2

Distribution of the changes in estimated glomerular filtration rate (eGFR)

Baseline characteristics stratified by the achievement of primary endpoint

There were no significant differences in most of the demographic data between the two groups. The prescription rate of RASI was higher in the increased eGFR group. The proportions of participants taking oral hypoglycemic agents were statistically not different between the two groups. Baseline plasma BNP level tended to be lower in the increased eGFR group. Of note, the baseline eGFR value was not statistically different between the two groups.

Variables associating with renoprotection during SGLT2i therapy

In univariate logistic regression analysis, body mass index, plasma BNP level, usage of RASI, and insulin administration were significantly associated with the renoprotective effect of SGLT2i (p < 0.05 for all; Table 2). Lower plasma BNP level (0.26 of odds ratio, 95% confidence interval 0.08–0.79) and the use of RASI were independently associated with the renoprotective effect of SGLT2i (p < 0.05 for both). Of note, no patients achieved the primary endpoints without RASI. This finding was not confirmed in the logistic regression analysis with both patients with and without SGLT2i continuation (Additional file 4: Table 3).

Table 2 Logistic regression analyses for any increases in eGFR

Stratification of the primary endpoint using BNP and RASI use

A cut-off of baseline plasma BNP level to predict the primary endpoint was 192 pg/mL (0.684 of area under the curve, 0.808 of sensitivity, and 0.643 of specificity; Fig. 3).

Fig. 3
figure3

Receiver operating characteristic (ROC) curve of baseline plasma BNP level

Twenty-three patients satisfied both plasma BNP < 192 pg/mL and RASI use (double-positive group). eGFR increased significantly during the 12-month follow-up in the double-positive group, whereas eGFR remained unchanged in the no double positive group (Fig. 4).

Fig. 4
figure4

Changes in estimated glomerular filtration rate (eGFR) during the 1-year observational period. Variables were expressed as mean and standard deviations

As sub-analyses, similar trends were observed irrespective of the eGFR levels stratified by 60 mL/min/1.73m2 (Fig. 5AB) and the HbA1c levels stratified by 7.0% (Fig. 6CD).

Fig. 5
figure5

Changes in estimated glomerular filtration rate (eGFR) during the one-year observational period stratified by baseline eGFR. Variables were expressed as mean and standard deviations

Discussion

We investigated the factors associating with the renoprotection during SGLT2i therapy in patients with HF and T2DM. The major finding of the present study was that lower plasma BNP level and the use of RASI at baseline were associated with the renoprotective effect of SGLT2i. Those with lower plasma BNP levels and the use of RASI had greater eGFR during the 12-month follow-up period over those with neither of them irrespective of the eGFR levels and the HbA1c levels at baseline).

Fig. 6
figure6

Changes in estimated glomerular filtration rate (eGFR) during the one-year observational period stratified by baseline glycated hemoglobin (HbA1c) levels. Variables were expressed as mean and standard deviations

SGLT2i and BNP

Both EMPEROR-Reduced trial and DAPA-HF trial demonstrated that SGLT2i prevented the occurrence of worsening HF in patients with HFrEF [9, 10]. The EMPEROR-Reduced trial further demonstrated that empagliflozin was associated with a lower risk of renal outcome and a slower progressive decline in renal function. Several large placebo-controlled trials suggested that SGLT2i might exert a beneficial effect on the renal outcome as a class effect [6,7,8]. On the contrary, the DAPA-HF trial, which used dapagliflozin, did not demonstrate the improvement of renal outcome [11].

The pattern of inconsistent findings in renal outcomes might be explained by the differences in the distribution of NYHA functional class in each trial. More patients with NYHA class II were enrolled in the EMPEROR-Reduced trial compared to the DAPA-HF trial. SGLT2i might have renoprotective effect particularly for those with less sick HF, as we also found in this study. In a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials, HFrEF patients with NYHA class II also had a lower risk of composite cardiovascular outcome compared to those with NYHA class III–IV symptoms [12].

These findings appear to be due to direct cardioprotective and nephroprotective effects of SGLT2i, which may be related to actions on sodium balance, energy homeostasis, and mitigation of cellular stress [13]. The detailed mechanism remains uncertain, but the existence of renal congestion, indicated by the elevated BNP level, might suppress the improvement in renal function during SGLT2i therapy.

SGLT2i and RASI

RASI were the only classes of medication that slows a decline in kidney function [4, 5]. The concomitant use of RASI together with SGLT2i was associated with the renoprotective effect also in the present study. Although few studies have investigated the combined effects of RASI and SGLT2i, several previous studies of SGLT2i have identified a minimal increase in plasma renin activity [14, 15]. SGLT2i can cause diuresis, natriuresis, and associated body fluid loss, resulting in renin activation, whereas RASI may counterbalance this effect. Hence, RASI may have played an important role in renal protection in the present study.

Conversely, several studies in animal models or humans have confirmed unchanged activity in the renin–angiotensin–aldosterone system following the SGLT2i administration [16, 17]. An increase in GFR associating with long-term SGLT2i therapy is thought to be secondary to tubuloglomerular feedback, which is also a response of the macula densa to the increased salt delivery via inhibition of sodium transport proximally [18]. Furthermore, an increase in sodium chloride delivery to the macula densa may suppress the renin–angiotensin–aldosterone system. These different effects of SGLT2i may explain the inconsistent data regarding the responses of renin–angiotensin–aldosterone system to SGLT2i.

Consequently, the association between SGLT2i and systemic renin–angiotensin–aldosterone system activation is not straightforward. However, since plasma renin activity is significantly higher in patients with HF compared to healthy people [19], it is plausible that the renin–angiotensin–aldosterone system is activated in participants in the present study. This hypothesis may explain the finding that the use of RASI was associated with the renoprotective effect of SGLT2i in the present study.

Limitations

The sample size was small and the observation period was only one year. If 0.05 of alpha error, 0.85 of 1-beta, and 0.9 of effect size was set, a total of 48 participants were statistically required. Given the low event number, the number of potential confounders included in the multivariate analyses was restricted. The one-year observation period may be insufficient to assess changes in eGFR after SGLT2i administration. In addition, since we investigated the changes in renal function from discharge rather than after SGLT2i administration, we could not confirm the initial changes in eGFR after starting SGLT2i in this study. A large-scale multicenter study with a longer follow-up period is required.

The multiple types of SGLT2i were used in the present study. It remains unclear whether the renal beneficial effect is consistent across any SGLT2is.

Unlike EMPEROR-Reduced trial and DAPA-HF trial, we did not have any data of proteinuria to assess renal function. Also, we defined renoprotective effect as any increase in eGFR (primary endpoint) to investigate “super-responder” to SGLT2i, whereas patients included in these trials showed gradual decline in eGFR during SGLT2i therapy. Our findings might not simply be applicable to other studies with different definition of renoprotective effect.

Lastly, the EMPEROR-Reduced trial revealed that SGLT2i reduced the risk of the composite renal endpoint, independently of diabetes status [20]. We also indicated that increases in eGFR during the observation period were independent of the HbA1c levels, whereas we did not include patients without T2DM in this study. Further studies are warranted to clarify the mechanism of SGLT2i on renal function and outcome.

Conclusions

Lower plasma BNP level and the use of RASI at baseline were the possible factors contributing to the improvement in renal function among HF and T2DM patients during the SGLT2i therapy.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

HF:

Heart failure

HFrEF:

Heart failure and reduced ejection fraction

CKD:

Chronic kidney disease

T2DM:

Type 2 diabetes mellitus

RASI:

Renin-angiotensin system inhibitor

SGLT2i:

Sodium-glucose cotransporter 2 inhibitor

NYHA:

New York Heart Association

eGFR:

Estimated glomerular filtration rate

BNP:

B-type natriuretic peptide

References

  1. 1.

    Smith DH, Thorp ML, Gurwitz JH, McManus DD, Goldberg RJ, Allen LA, et al. Chronic kidney disease and outcomes in heart failure with preserved versus reduced ejection fraction: the Cardiovascular Research Network PRESERVE Study. Circ Cardiovasc Qual Outcomes. 2013;6:333–42.

    Article  Google Scholar 

  2. 2.

    Bikbov B, Purcell CA, Levey AS, Smith M, Abdoli A, Abebe M, Adebayo OM, Afarideh M, Agarwal SK, Agudelo-Botero M, Ahmadian E. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709–33.

    Article  Google Scholar 

  3. 3.

    Damman K, Valente MA, Voors AA, O’Connor CM, van Veldhuisen DJ, Hillege HL. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014;35:455–69.

    Article  Google Scholar 

  4. 4.

    Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354:359–64.

    CAS  Article  Google Scholar 

  5. 5.

    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    CAS  Article  Google Scholar 

  6. 6.

    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    CAS  Article  Google Scholar 

  7. 7.

    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    CAS  Article  Google Scholar 

  8. 8.

    Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Eng J Med. 2019;380:347–57.

    CAS  Article  Google Scholar 

  9. 9.

    Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24.

    CAS  Article  Google Scholar 

  10. 10.

    McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Eng J Med. 2019;381:1995–2008.

    CAS  Article  Google Scholar 

  11. 11.

    Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Böhm M, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation. 2021;143:298–309.

    CAS  Article  Google Scholar 

  12. 12.

    Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819–29.

    Article  Google Scholar 

  13. 13.

    Nespoux J, Vallon V. SGLT2 inhibition and kidney protection. Clin Sci (Lond). 2018;132:1329–39.

    CAS  Article  Google Scholar 

  14. 14.

    Schork A, Saynisch J, Vosseler A, Jaghutriz BA, Heyne N, Peter A, et al. Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol. 2019;18:46.

    Article  Google Scholar 

  15. 15.

    Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15:853–62.

    CAS  Article  Google Scholar 

  16. 16.

    Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, et al. Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PLoS ONE. 2016. https://doi.org/10.1371/journal.pone.0165703.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Yoshimoto T, Furuki T, Kobori H, Miyakawa M, Imachi H, Murao K, et al. Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. J Investig Med. 2017;65:1057–61.

    Article  Google Scholar 

  18. 18.

    Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    CAS  Article  Google Scholar 

  19. 19.

    Nijst P, Verbrugge FH, Martens P, Bertrand PB, Dupont M, Francis GS, et al. Plasma renin activity in patients with heart failure and reduced ejection fraction on optimal medical therapy. J Renin Angiotensin Aldosterone Syst. 2017. https://doi.org/10.1177/1470320317729919.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-reduced trial. Circulation. 2021;143:337–49.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Affiliations

Authors

Contributions

MK wrote a draft. TI analyzed and interpreted the patient data. SJ, RU, and MK collected data and reviewed the draft. KK supervised the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Teruhiko Imamura.

Ethics declarations

Ethics approval and consent to participate

The Institutional Ethics Board of Toyama University Hospital approved the study protocol (#Rin 29-94), which complied with the Declaration of Helsinki. Written informed consent was obtained from all of the patients beforehand.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Table 1.

. Baseline characteristics.

Additional file 2: Figure 1.

Trends in eGFR between those with and without SGLT2i continuation.

Additional file 3: Table 2.

Logistic regression analyses for increases in eGFR in both patients who continued and discontinued SGLT2i.

Additional file 4: Table 3.

Logistic regression analyses for increases in eGFR in both patients who continued and discontinued SGLT2i.

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.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nakagaito, M., Imamura, T., Joho, S. et al. Renoprotective effects of sodium glucose cotransporter 2 inhibitors in type 2 diabetes patients with decompensated heart failure. BMC Cardiovasc Disord 21, 347 (2021). https://doi.org/10.1186/s12872-021-02163-7

Download citation

Keywords

  • Hemodynamics
  • Congestion
  • Chronic kidney disease