Introduction
There has been a paucity of evidence for treatments that can improve the prognosis of patients with heart failure with preserved ejection fraction (HFpEF), although various medications have resulted in improved prognosis of patients with heart failure with reduced ejection fraction (HFrEF).1–7 Some clinical trials have evaluated the effectiveness of medical treatments for HFpEF but have not established their benefits.8–11
Sodium glucose co-transporter 2 (SGLT2) inhibitors are antidiabetic drugs that promote urinary glucose excretion. SGLT2 inhibitors seem to have some benefits beyond their glucose-lowering effects, promoting natriuresis and osmotic diuresis based on glycosuria.12 Previous studies have shown that SGLT2 inhibitors reduce the rehospitalization of patients with type 2 diabetes due to heart failure and renal function deterioration.13,14 In addition, recent studies reported that SGLT2 inhibitors improved the prognosis of patients with HFrEF, regardless of the presence or absence of type 2 diabetes mellitus (T2DM).15 Moreover, some previous studies have shown that SGLT2 inhibitors reduce hospitalization for heart failure (HF) in patients with HFpEF. 16,17 Recently, SGLT2 inhibitors have been reported to reduce estimated plasma volume (ePV).18–21 Although these results suggest that SGLT2 inhibitors may be effective in reducing intravascular volume, which may improve heart failure prognosis, there is little evidence of the efficacy of SGLT2 inhibitors on intravascular volume in patients with HFpEF.
In the Management of Diabetic Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction (MUSCAT-HF) trial, brain natriuretic peptide (BNP) concentrations decreased after initiation of either luseogliflozin, an SGLT2 inhibitor, or voglibose, an alpha-glucosidase inhibitor, at Week 12.22 However, the difference in change in BNP levels was not statistically significant [percent change, −9.0% vs. −1.9%; ratio of change with luseogliflozin vs. voglibose, 0.93; 95% confidence interval (CI), 0.78–1.10; P = 0.26].
In this post-hoc analysis of the MUSCAT-HF trial, we compared the impact of luseogliflozin and of voglibose on the reduction of ePV and evaluated the correlation of change in ePV with BNP level and other clinical parameters in patients with T2DM and HFpEF.
Materials and methods
Study design and participants
This was a post-hoc analysis of the MUSCAT-HF trial, a multicentre, prospective, open-label, randomized controlled trial to assess the effect of luseogliflozin compared with voglibose on left ventricular load in patients with T2DM and HFpEF.22 Details of the study design and results have been published previously.22,23 The original study examined the effects of a 12 week treatment of patients with T2DM and HFpEF with luseogliflozin (2.5 mg) once daily vs. voglibose (0.2 mg) three times daily in 165 patients aged ≥ 20 years who required additional treatment for T2DM, despite ongoing treatment. HFpEF was defined as a left ventricular ejection fraction (EF) ≥ 45%, BNP concentrations ≥ 35 pg/mL, and any symptoms. Patients treated with alpha-glucosidase inhibitors, SGLT2 inhibitors, glinides, or high-dose sulfonylurea; renal insufficiency [estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2); a history of severe ketoacidosis or diabetic coma within 6 months prior to participation; and poorly controlled T2DM [haemoglobin A1c (HgbA1c) > 9.0%) were excluded. Patients were randomly assigned to the two drug arms, and post-randomization follow-up visits were scheduled at Weeks 4, 12, and 24. The primary outcome of the original study was the change in the ratio of BNP concentrations from baseline to 12 weeks of treatment. The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by the Ethics Committee of Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences. All patients enrolled in this study provided written informed consent. The trial was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR, UMIN000018395).
Outcomes
The primary outcome of this post-hoc analysis was the between-group differences in the percentage change in ePV from baseline to 12 weeks. Additionally, in the luseogliflozin group, the association between changes in ePV and changes in other clinical parameters was evaluated.
Estimated plasma volume
The ePV at baseline was measured using the Hakim formula as follows: (1 − haematocrit) × (1530 + [41 × body weight (kg)]) in male patients and (1 − haematocrit) × (864 + [47.9 × body weight (kg)]) in female patients.24 The percentage change in ePV at Weeks 4, 12, and 24 from baseline was calculated using the Strauss formula as follows: 100 × [haemoglobin (at baseline)/haemoglobin (at visit)] × [1 − haematocrit (at visit)]/[1 − haematocrit (at baseline)] − 100.25 We measured BNP levels in a central laboratory (SRL, Inc. Hachioji, Tokyo, Japan). Haemoglobin, haematocrit, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, serum creatinine, eGFR, and HgbA1c were also evaluated. These parameters were measured in each institution.
Statistical analysis
Categorical variables are presented as numbers (%) and were compared using the χ2 test. Normally distributed continuous variables are presented as mean ± standard deviation and were compared using Student's t-test. Continuous variables that were not normally distributed are presented as medians with interquartile ranges and were compared using the Mann–Whitney U-test. The normality of the data distribution was evaluated using the Shapiro–Wilk test. We estimated group differences in the mean percentage change in ePV from baseline to Weeks 4, 12, and 24, and the interaction between follow-up periods and groups using mixed-effect linear regression models. The effects of luseogliflozin vs. voglibose on ePV after 12 weeks were assessed in several subgroups defined by sex, body weight, prior atherosclerotic cardiovascular disease, and factors used at randomization: age (<65 years, ≥65 years), sex, baseline HgbA1c values (<8.0%, ≥8.0%), baseline BNP concentrations (<100 pg/mL, ≥100 pg/mL), baseline renal function (eGFR ≥ 60 mL/min/1.73 m2, <60 mL/min/1.73 m2), use of thiazolidine (yes or no), presence or absence of atrial fibrillation or flutter at baseline, presence or absence of prior atherosclerotic cardiovascular disease, use of β-blocker (yes or no), use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (yes or no), and use of diuretic (yes or no). We assessed the associations between changes from baseline to Week 12 in the ePV, BNP levels, and other parameters using Pearson's correlation analyses and linear regression models. Continuous variables that were not normally distributed underwent natural logarithmic transformation prior to use in regression analysis. Statistical significance was defined as P < 0.05. These analyses were performed using SPSS statistical software (Version 25; IBM Corp., Armonk, NY, USA).
Patient and public involvement
This research was done without patient and public involvement.
Results
Patient characteristics
This post-hoc analysis included 165 patients with T2DM and HFpEF from 16 hospitals and clinics. The baseline characteristics of the patients are shown in Table 1. The baseline variables, including laboratory data and echocardiographic parameters, were similar between the luseogliflozin and voglibose groups, except for the patients' age, aspartate aminotransferase, and alanine aminotransferase.
Table 1 Baseline clinical characteristics of this study
Variables | Luseogliflozin ( |
Voglibose ( |
|
Age (years) | 71.7 ± 7.7 | 74.6 ± 7.7 | 0.017 |
Male | 55 (66) | 48 (59) | 0.31 |
Body mass index (kg/m2) | |||
Systolic blood pressure (mmHg) | 131 ± 17 | 128 ± 14 | 0.168 |
Diastolic blood pressure (mmHg) | 71 ± 11 | 71 ± 10 | 0.52 |
Heart rate (beats per minute) | 69 ± 13 | 70 ± 12 | 0.53 |
Hypertension | 72 (89) | 64 (79) | 0.087 |
Dyslipidaemia | 65 (80) | 61 (75) | 0.45 |
Prior ASCVD | 48 (59) | 50 (62) | 0.75 |
Atrial fibrillation or flutter | 18 (22) | 15 (18) | 0.59 |
Medications on admission | |||
β-blocker | 51 (61) | 47 (57) | 0.39 |
ACEI/ARB | 51 (61) | 47 (57) | 0.59 |
MRA | 19 (23) | 20 (24) | 0.97 |
Loop diuretic | 19 (23) | 19 (23) | 0.97 |
Thiazide | 5 (6.0) | 5 (6.1) | 0.98 |
Antidiabetic medication | 53 (65) | 50 (61) | 0.74 |
Laboratory data | |||
HgbA1c (%) | 7.0 ± 0.7 | 6.9 ± 0.8 | 0.52 |
Haemoglobin (g/dL) | 13.5 ± 1.6 | 13.1 ± 1.6 | 0.114 |
Haematocrit (%) | 41.4 ± 4.8 | 40.4 ± 4.2 | 0.159 |
AST (IU/L) | 27.2 ± 16.8 | 23.2 ± 7.0 | 0.048 |
ALT (IU/L) | 25.3 ± 18.5 | 19.4 ± 9.8 | 0.010 |
Blood urea nitrogen (mEq/L) | 17.7 ± 5.5 | 19.1 ± 6.0 | 0.119 |
Serum creatinine (mg/dL) | 0.94 ± 0.30 | 0.96 ± 0.29 | 0.70 |
Estimated GFR (mL/min/1.73 m2) | 60.6 ± 19.4 | 56.8 ± 16.5 | 0.185 |
BNP (pg/mL) | 63.7 (46.8–115.8) | 75.1 (42.4–120) | 0.87 |
Echocardiographic data | |||
LVEF (%) | 57 ± 9.4 | 58 ± 9.4 | 0.41 |
E/A | 0.77 ± 0.21 | 0.85 ± 0.29 | 0.094 |
e' (cm/s) | 5.4 ± 1.5 | 5.6 ± 1.8 | 0.66 |
E/e' | 13.0 ± 4.5 | 13.3 ± 5.6 | 0.67 |
LAD (mm) | 42.0 ± 7.4 | 42.5 ± 7.9 | 0.69 |
LAVI (mL/m2) | 37.9 ± 16.3 | 38.4 ± 13.5 | 0.84 |
LVMI (g/m2) | 93.0 ± 23.2 | 91.3 ± 27.5 | 0.71 |
Comparison of the estimated plasma volume between groups
In the mixed-effect models for repeated measures, there was a statistically significant interaction between the effect of the study drugs and the follow-up periods (P < 0.001 for interaction) (Figure 1). ePV was reduced more by luseogliflozin than by voglibose from baseline to Week 4 [adjusted mean group-difference, −6.43% (95%CI: −9.11 to −3.74%)], Week 12 [−8.73% (95%CI: −11.40 to −6.05%)], and Week 24 [−11.02% (95%CI: −13.71 to −8.33%)].
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The effects of luseogliflozin vs. voglibose on ePV observed in the overall population at Week 12 were similar to those in the various patient subgroups (Figure 2). Specifically, compared with voglibose, luseogliflozin reduced ePV by −7.978% (95%CI: −11.81 to −4.14%) in patients with BNP < 100 pg/mL and by −10.94% (95%CI: −18.64 to −3.24%) in patients not using diuretics (P value for treatment by subgroup interaction = 0.45). Among patients with an eGFR < 60 mL/min/1.73 m2, luseogliflozin compared with voglibose reduced ePV by −10.83% (95%CI: −15.28 to −6.37%). In patients with eGFR ≥ 60 mL/min/1.73 m2, ePV was reduced by −6.01% (95%CI: −11.17 to −4.19%), as compared with voglibose (P value for treatment by subgroup interaction = 0.166). Among patients with a body weight < 60 kg, luseogliflozin compared with voglibose reduced ePV by −6.17% (95%CI: −11.78 to −0.56%). In patients with body weight ≥ 60 kg, ePV was reduced by −10.45% (95%CI: −14.85 to −6.04%), as compared with voglibose (P value for treatment by subgroup interaction = 0.23). Luseogliflozin decreased ePV by 8.78% in patients with a history of atherosclerotic cardiovascular disease, as well as in patients without atherosclerotic cardiovascular disease (P value for treatment by subgroup interaction = 0.54). All P values for interaction, except for β-blocker use, were > 0.05.
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Association between the estimated plasma volume and clinical parameters
In the Pearson correlation analyses, the change from baseline to Week 12 in log-transformed BNP concentration was positively correlated with the percentage change in ePV (Figure 3). There were statistically significant correlations between changes in ePV at Week 12 and concurrent changes in haemoglobin levels and the left atrial volume index (Table 2).
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Table 2 Pearson correlations between percentage change from baseline at 12 weeks in e PV and various clinical parameters
Body weight | 0.026 | 0.579 |
Systolic blood pressure | 0.055 | 0.509 |
Diastolic blood pressure | 0.045 | 0.583 |
Heart rate | −0.010 | 0.905 |
HgbA1c | −0.151 | 0.061 |
Haemoglobin | −0.958 | <0.001 |
AST | 0.048 | 0.550 |
ALT | −0.041 | 0.609 |
eGFR | 0.139 | 0.084 |
LVEF | 0.042 | 0.711 |
E/e' | −0.088 | 0.446 |
LAD | −0.253 | 0.033 |
LAVI | 0.283 | 0.019 |
Discussion
In this post-hoc analysis of the MUSCAT-HF trial, the impact of luseogliflozin on the change in ePV at Weeks 4, 12, and 24 from baseline was superior to that of voglibose in patients with T2DM and HFpEF. Changes in ePV were significantly associated with changes in BNP and left atrial volume index. To the best of our knowledge, no previous study had demonstrated that SGLT2 inhibitors can reduce fluid volume in patients with T2DM and HFpEF.
Efficacy of sodium glucose co-transporter 2 inhibitors for reduction in the estimated plasma volume
Sodium glucose co-transporter 2 inhibitors have some favourable effects on heart failure beyond their glucose-lowering effects.12 Previous studies have reported that SGLT2 inhibitors reduced both the plasma volume measured by 125I-labelled human serum albumin and ePV by using laboratory data in patients with T2DM.18,19 Other studies have also reported that SGLT2 inhibitors reduced the ePV in patients with T2DM complicated by cardiovascular diseases or HFrEF.20,21 In addition, SGLT2 inhibitors reduced pulmonary arterial pressure in patients with heart failure.26 These results support that SGLT2 inhibitors can reduce intracellular volume by diuretic effects related to both glycosuria and natriuresis, consistent with the results of this study.
Impact of sodium glucose co-transporter 2 inhibitors on heart failure with preserved ejection fraction
It has been reported that SGLT2 inhibitors decreased worsening heart failure in patients with HFrEF, regardless of the presence or absence of diabetes mellitus in a randomized trial.15 The present study showed that SGLT inhibitors have a favourable effect on ePV reduction in patients with HFpEF. ePV has been reported to be associated with a risk of worse prognosis in patients with heart failure.27,28 Although the benefit of SGLT2 inhibitors in patients with HFpEF is not yet established, our results showed the possibility that SGLT2 inhibitors could contribute to improving clinical outcomes in patients with HFpEF by reducing plasma volume.
Relationship between estimated plasma volume and cardiac preloads
In the initial investigation of the MUSCAT-HF study, the primary finding was that the SGLT2 inhibitor, luseogliflozin, and the alpha-glucosidase inhibitor did not differ significantly in reducing BNP concentrations after 12 weeks. In contrast, this post-hoc analysis showed a significant reduction in ePV by luseogliflozin, as compared with voglibose, and that the change in ePV was negatively associated with haemoglobin and positively associated with changes in BNP and the left atrial volume index. These results suggest that SGLT inhibitors may reduce intravascular volume and cardiac preload.
Some studies have shown that the level of natriuretic peptides in patients with HFpEF was significantly lower than that in patients with HFrEF, although an increase in natriuretic peptides was associated with a worse clinical outcome in patients with HFpEF.29,30 Additionally, when heart failure is due to a cause upstream from the left ventricle, pericardial abnormalities, or right-sided heart failure alone, natriuretic peptide concentrations may be initially low, despite severe symptoms, because of the absence of a significant increase in LV wall stress.31 Changes in BNP may sometimes underestimate the evaluation of the change in intravascular volume in patients with HFpEF because HFpEF has various aetiologies. In this situation, measurement of the change in ePV in addition to that in BNP may add sensitive and valuable information about cardiac preload in patients with HFpEF.
Limitations
This study has several limitations. First, this was a post-hoc analysis of a previous study's results, which included a relatively small number of patients, and had a short follow-up duration. Second, this study targeted the change in ePV from baseline after a period of treatment, but there was no actual measurement of plasma volume, such as by dilution methods using radioisotopes. Actual plasma volume and ePV may differ, because ePV is calculated from laboratory data, which may be influenced by other factors, such as plasma volume and erythropoietic parameters, which may also be influenced by SGLT2 inhibitors.32 Third, some patients with mild heart failure were included in this study. In this study, patients with a left ventricular EF of ≥45% were enrolled because this study enrolment had started before the latest definition of HFpEF in the ESC Heart Failure Guidelines was changed in 2016.33,34 In the 2016 ESC Heart Failure Guidelines, heart failure with a left ventricular EF ranging from 40% to 49% were defined as HF with midrange EF. The effect of luseogliflozin on ePV in patients with HFpEF might thus not have been accurately estimated.
Conclusions
In conclusion, ePV in patients with T2DM and HFpEF was significantly reduced by luseogliflozin compared with voglibose. SGLT2 inhibitors may therefore be effective in reducing intravascular volume and cardiac preload in these patients.
Acknowledgements
We thank Tetsutaro Hamano, MS, for his assistance with the study design and statistical analysis.
Conflict of interest
Dr Miyoshi received a trust research/joint research fund from Novartis Pharma K. K. Dr Ito received a trust research/joint research fund from Novartis KK. The other authors declare no conflicts of interest.
Funding
This work was supported by Novartis Pharma K. K.
Appendix - The MUSCAT-HF Study Investigators
Kentaro Ejiri (Tamano City Hospital and Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences); Toru Miyoshi, Kazufumi Nakamura, and Hiroshi Ito (Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences); Hajime Kihara (Kihara Cardiovascular Clinic); Yoshiki Hata (Minamino Cardiovascular Hospital); Toshihiko Nagano (Iwasa Hospital); Atsushi Takaishi (Mitoyo General Hospital); Hironobu Toda (Okayama East Neurosurgery Hospital and Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences); Seiji Namba (Okayama Rosai Hospital); Yoichi Nakamura (Specified Clinic of Soyokaze CardioVascular Medicine and Diabetes Care); Satoshi Akagi (Akaiwa Medical Association Hospital and Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences); Satoru Sakuragi (Iwakuni Clinical Center); Taro Minagawa (Minagawa Cardiovascular Clinic); Yusuke Kawai (Okayama City Hospital); Nobuhiro Nishii (Yoshinaga Hospital and Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences); Tetsuya Sato and Soichiro Fuke (Japanese Red Cross Okayama Hospital); Masaki Yoshikawa and Hiroyasu Sugiyama (Fukuyama City Hospital); Michio Imai (Imai Heart Clinic); Naoki Gotoh (Gotoh Clinic); Tomonori Segawa (Asahi University Hospital); Toshiyuki Noda (Gifu Prefectural General Medical Center); and Masatoshi Koshiji (Gifu Seiryu Hospital); Yutaka Kajikawa (Fukuyama Medical Center): Hiroshi Morita (Kurashiki Municipal Hospital); Masashi Yoshida (Marugame Medical Center); Masayuki Doi (Kagawa Prefectural Central Hospital): Takafumi Oka (Tsuyama Chuo Hospital).
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Abstract
Aims
Sodium glucose co‐transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF).
Methods and results
This study was a post‐hoc analysis of the MUSCAT‐HF trial (UMIN000018395), a multicentre, prospective, open‐label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed‐effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group‐difference −6.43% [95% confidence interval (CI): −9.11 to −3.74]}, at Week 12 [−8.73% (95%CI: −11.40 to −6.05)], and at Week 24 [−11.02% (95%CI: −13.71 to −8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log‐transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019).
Conclusions
Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF.
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Details
1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
2 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, Department of Internal Medicine, Tamano City Hospital, Okayama, Japan
3 Department of Internal Medicine, Kihara Cardiovascular Clinic, Asahikawa, Japan
4 Department of Cardiology, Minamino Cardiovascular Hospital, Hachioji, Japan
5 Department of Internal Medicine, Iwasa Hospital, Gifu, Japan
6 Department of Cardiology, Mitoyo General Hospital, Kanonji, Japan
7 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, Department of Internal Medicine, Okayama East Neurosurgery Hospital, Okayama, Japan
8 Department of Cardiology, Okayama Rosai Hospital, Okayama, Japan
9 Department of Cardiovascular Medicine, Specified Clinic of Soyokaze CardioVascular Medicine and Diabetes Care, Matsuyama, Japan
10 Department of Internal Medicine, Akaiwa Medical Association Hospital, Okayama, Japan
11 Department of Cardiovascular Medicine, Iwakuni Clinical Center, Iwakuni, Japan
12 Department of Internal Medicine, Minagawa Cardiovascular Clinic, Gifu, Japan
13 Department of Cardiovascular Medicine, Okayama City Hospital, Okayama, Japan
14 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, Department of Internal Medicine, Yoshinaga Hospital, Bizen, Japan
15 Department of Cardiovascular Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan
16 Department of Cardiology, Fukuyama City Hospital, Fukuyama, Japan