Investigation of the Effect of Empagliflozin on Cardiac Sympathetic and Parasympathetic Nerve Activity Analyzed From Heart Rate Variability Frequency in Japanese Patients With Type 2 Diabetes　― Results From the EMPYREAN Study ―

Abstract

Background: The EMPA-REG OUTCOME trial confirmed empagliflozin reduced mortality and heart failure hospitalization risk. These findings raised the possibility that empagliflozin may modulate cardiac autonomic function in patients with type 2 diabetes (T2D).

Methods and Results: The EMPYREAN study was a prospective randomized open-label assessor-blinded multicenter investigation of patients with T2D without prior antidiabetic therapy with sodium-glucose cotransporter 2 or dipeptidyl peptidase 4 inhibitors. Electrocardiographic monitoring was performed at study onset and after 12 and 24 weeks of treatment. Heart rate variability was analyzed using the MemCalc method. The primary endpoint was the change in the low frequency (LF; 0.04–0.15 Hz)/high frequency (HF; 0.15–0.4 Hz) ratio from baseline to 24 weeks. In all, 113 patients were randomized. The median age in the empagliflozin and sitagliptin groups was 60 and 63 years, respectively. There were no significant differences in serial changes in the LF/HF ratio (0.52, 95% confidence interval [CI] −0.15 to 1.19, P=0.126) or HF (16.13, 95% CI −11.58 to 43.84, P=0.251) between the 2 groups. In time domain analysis, serial changes in root mean square successive difference (1.90, 95% CI −0.56 to 4.38, P=0.12) and percent of difference between adjacent normal RR intervals >50 ms (1.04, 95% CI −0.32 to 2.41, P=0.13) were not significantly different.

Conclusions: The effects of empagliflozin and sitagliptin on autonomic nerve activity did not differ significantly in patients with T2D.

The advent of sodium-glucose cotransporter 2 (SGLT2) inhibitors has greatly improved the treatment of heart failure, type 2 diabetes (T2D), and chronic kidney disease (CKD). SGLT2 inhibitors reduce morbidity and mortality in patients with heart failure with both preserved and reduced ejection fraction, as well as in patients with diabetes and CKD.^1–11 However, the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors remain incompletely understood.

The recent EMPA-REG OUTCOME trial in T2D patients clarified the prognostic impact of empagliflozin in reducing mortality and heart failure hospitalization risk.⁵ A significant reduction in arterial blood pressure (BP) was observed in the absence of increased heart rate (HR) in patients treated with empagliflozin, and the incidence of sudden death was lower in the pooled empagliflozin than placebo group (1.1% vs. 1.6%).⁵ These findings raised the possibility that empagliflozin may modulate cardiac autonomic function in patients with T2D.

Measured as the variation between 2 consecutive beats, HR variability (HRV) is the gold standard for evaluating cardiac autonomic function in various conditions,^12–17 including myocardial infarction,^18,19 cardiac transplantation,²⁰ heart failure,²¹ arrhythmia,²² and diabetic neuropathy.^23–26 Impaired HRV is a marker of cardiovascular risk²⁷ and is often used for the early detection of cardiac autonomic neuropathy in T2D patients.²⁸ Although the prognostic significance of abnormal HRV in T2D has been assessed in several studies,^23–26 the effect of SGLT2 inhibitors on cardiac autonomic function is not well established.

The present study on the effect of empagliflozin on cardiac sympathetic and parasympathetic nerve activity in Japanese patients with T2D (EMPYREAN study; University Hospital Medical Information Network [UMIN] Clinical Trials Registry ID: UMIN000029194, registered September 19, 2017) was designed to investigate the hypothesis that empagliflozin modulates cardiac autonomic function in patients with T2D.

Methods

The EMPYREAN study was a multicenter randomized open-label (empagliflozin vs. sitagliptin) assessor-blinded active controlled parallel-group clinical trial using sitagliptin, which has been shown not to reduce cardiovascular mortality,²⁹ and designed to test the hypothesis that empagliflozin improves autonomic disturbance in patients with T2D during 24 weeks of treatment. Details of the study methods, design, and sample size calculations have been published elsewhere.²⁹ Briefly, the inclusion criteria were: male or female; diagnosis of T2D; HbA1c ranging from 6.5% to 10.0% (7.0–10.0% for patients treated with sulfonylureas or glinides); no antidiabetic therapy with SGLT2 inhibitors or dipeptidyl peptidase 4 inhibitors for ≥12 weeks prior to randomization; and body mass index ≥18.5 and ≤40 kg/m² at screening. The exclusion criteria were as follows: treatment with insulin or glucagon-like peptide-1 receptor agonists; neuropathy evidenced by orthostatic hypotension; estimated glomerular filtration rate <45 mL/min/1.73 m²; medications prohibited in the study protocol; atrial fibrillation or atrial flutter; implanted permanent pacemaker; sick sinus syndrome or greater than second degree atrioventricular block; treatment with systemic steroids; hyperthyroidism; and hypothyroidism under treatment.

Prior to patient enrollment, the study protocol was approved by the Certified Review Board of Shinshu University School of Medicine. This investigation was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient before enrollment. Personal information about potential and enrolled participants was kept confidential, and subject data were deidentified using participant numbers.

Randomization

Randomization was performed centrally by the data management group at the data center using a minimization algorithm implementing a random component. Baseline HR (<75 or ≥75 beats/min), age (<50 or ≥50 years), HbA1c (<8% or ≥8%), and treatment center were considered as balancing factors.

Trial Procedure

Eligible patients underwent an initial 4-week screening period, during which background glucose-lowering therapy was continued unchanged. Blood / urine sampling (on-site and central measurement), electrocardiogram (ECG) recording, the Schellong test, and 24-h Holter ECG were also performed. Following the screening period, patients still satisfying the inclusion criteria were randomized (1 : 1) to receive either empagliflozin 10 mg or sitagliptin 50 mg once daily in addition to their background therapy. Background glucose-lowering therapy was to remain unchanged for the 24-week study period after randomization if possible, although rescue therapy could be initiated. During this time, empagliflozin (10–25 mg/day) or sitagliptin (50–100 mg/day) could be adjusted to achieve desired glycemic control at the investigator’s discretion for the best standard of care according to local guidelines.³⁰ Holter ECG and blood sampling (on-site/central measurement) were performed at 12 and 24 weeks of treatment. HRV was analyzed in the time–frequency domain, as described previously.²⁹

Endpoints

The primary outcome of this study was the change in the low frequency (LF; 0.04–0.15 Hz) / high frequency (HF; 0.15–0.4 Hz) ratio from the initiation of treatment (baseline) to the study endpoint at 24 weeks. Key secondary outcomes included changes in LF, HF, and the LF/HF ratio from baseline to 12 weeks and changes in LF and HF from baseline to 24 weeks. Estimated plasma volume (EPV) was calculated using the Kaplan-Hakim formula as follows:

EPV = (1 − Ht) × (a + [b × weight in kg])

where Ht is the hematocrit, weight is in kilograms, a=1,530 in men and 864 in women, and b=41 in men and 47.9 in women.³¹

Statistical Analysis

Continuous variables are presented as the median and range, whereas categorical variables are presented as numbers and percentages. The primary efficacy population was defined as the full analysis set (patients who were randomly assigned to a group and underwent Holter ECG monitoring at least once). Intergroup comparisons (empagliflozin vs. sitagliptin) of the least squares means of the primary endpoint and the change in the LF/HF ratio at 24 weeks were made via mixed-model repeated-measures analysis. The covariates included in the model were treatment group, time point, interaction between treatment group and time point, baseline HR, age, and HbA1c. We used an unstructured correlation structure for modeling within-patient errors in the mixed-model for repeated measures and the Kenward-Roger method to calculate the degrees of freedom.³² The same analytical methods were used for the secondary endpoints. The safety population was defined as the safety analysis set (patients who were randomly assigned to a group and received at least 1 dose of the study treatment). Descriptive analysis was performed for the frequency of adverse events. Two-sided P<0.05 was considered statistically significant. All statistical analyses were conducted using SAS Version 9.4 software (SAS Institute, Cary, NC) and R Version 4.0.5.

Results

The study flow diagram is shown in Figure 1. In all, 113 patients were randomized. After randomization, 1 patient in the empagliflozin group was deemed ineligible and 3 patients in the sitagliptin group did not undergo Holter ECG monitoring. After excluding those patients, 109 patients (55 in the empagliflozin group, 54 in the sitagliptin group) comprised the full analysis set for the primary analysis. The baseline clinical characteristics of these patients are summarized in Table 1. The median age was 60 years in the empagliflozin group and 63 years in the sitagliptin group. The median body mass index for the empagliflozin and sitagliptin groups was 27.9 and 26.0 kg/m², respectively. The prevalence of cardiovascular disease was low in both groups. Laboratory data, including HbA1c, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio, are also included in Table 1. In the empagliflozin and sitagliptin groups, 76% and 67% of patients were naïve for diabetes drugs, respectively. Drug adherence was 96% in the empagliflozin group and 89% in the sitagliptin group. Baseline HRV variables were comparable between the 2 groups (Table 2).

Figure 1.

Flowchart of the EMPYREAN study design. ECG, electrocardiogram.

Table 1.

Baseline Characteristics

	Empagliflozin (n=55)	Sitagliptin (n=54)
Age (years)	60 [38, 73]	63 [30, 74]
Female sex, n (%)	21 (38)	20 (37)
Body mass index (kg/m2)	27.9 [20.2, 37.5]	26 [18.5, 35.2]
Abdominal circumference (cm)	95.5 [79.5, 119]	93 [66, 117.5]
Heart rate (beats/min)	67 [50, 97]	64 [50, 99]
Systolic blood pressure (mmHg)	135 [100, 227]	130.5 [108, 178]
Hypertension, n (%)	31 (56)	34 (63)
Ischemic heart disease, n (%)	4 (7)	7 (13)
Stroke, n (%)	3 (6)	4 (7)
Peripheral artery disease, n (%)	1 (2)	1 (2)
Heart failure, n (%)	1 (2)	0 (0)
None of ASCVD/HF, n (%)	49 (89)	44 (79)
Laboratory data
HbA1c (%)	7.0 [6.1, 9.6]	7.2 [6.2, 9.6]
Hematocrit (%)	43.8 [34.5, 50.8]	43.89 [36.4, 50.1]
eGFR (mL/min/1.73 m2)	78.3 [44.9, 133.9]	70.2 [49.7, 132.6]
eGFR ≥60 mL/min/1.73 m2	45 (82)	44 (82)
BNP (pg/mL)	9.9 [6.0, 49.1]	11.6 [7.5, 56.8]
FBS (mg/dL)	142 [97, 286]	149 [96, 334]
UACR (mg/g Cr)	0.1 [0, 37.1]	0.1 [0, 7.3]
30 mg/gCr≤UACR≤299 mg/gCr, n (%)	9 (16)	10 (19)
300 mg/gCr≥UACR, n (%)	1 (2)	2 (4)
IRI (μU/mL)	8.1 [1.9, 137]	8.4 [1.9, 69.9]
Epinephrine (ng/mL)	0.03 [0.02, 0.07]	0.03 [0.02, 0.21]
Norepinephrine (ng/mL)	0.40 [0.11, 0.99]	0.41 [0.10, 0.75]
Dopamine (ng/mL)	0.03 [0.03, 0.28]	0.04 [0.03, 0.08]
TSH (μIU/mL)	1.19 [0.43, 4.79]	1.45 [0.27, 25.6]
fT4 (ng/dL)	1.01 [0.72, 1.22]	0.99 [0.67, 1.32]
Medications
Metformin, n (%)	11 (22)	17 (32)
Sulfonylurea, n (%)	2 (4)	2 (4)
Other DM drugs, n (%)	5 (10)	6 (11)
CCB, n (%)	20 (41)	18 (36)
ACEi/ARB, n (%)	22 (45)	18 (36)
Diuretics, n (%)	3 (6)	2 (4)

ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; CCB, calcium channel blocker; eGFR, estimated glomerular filtration rate; FBS, fasting blood sugar; fT4, free thyroxine; IRI, immunoreactive insulin; TSH, thyroid-stimulating hormone; UACR, urine albumin-to-creatinine ratio.

Table 2.

Baseline Heart Rate Variation Data

	Empagliflozin (n=55)	Sitagliptin (n=54)
LF/HF ratio	4.3 (1.15, 14.85)	4.8 (2.06, 17.46)
HF (ms2)	80.7 (19.4, 414)	66.7 (13.5, 517.1)
LF (ms2)	306.1 (39.2, 1,362.6)	260.2 (71.7, 1,062.1)
AVNN (ms)	788.3 (580.0, 1,012.4)	792.7 (595.0, 1,064.7)
SDNN (ms)	128.2 (66.0, 259.1)	130.5 (61.5, 195.0)
SDANN (ms)	118.9 (53.8, 246.8)	117.3 (56.9, 183.3)
SDNNIDX (ms)	42.3 (19.2, 97.1)	42.1 (20.7, 83.6)
rMSSD (ms)	20.1 (10.4, 70.7)	18.0 (8.7, 53.3)
pNN50 (%)	1.8 (0.1, 34.1)	1.35 (0, 23.5)

AVNN, average of all N-N intervals; HF, high frequency; HRV, heart rate variability; LF, low frequency; pNN50, percentage of differences between adjacent N-N intervals >50 ms; rMSSD, root mean square of successive differences between adjacent N-N intervals; SDANN, standard deviation of averages of N-N intervals for all 5-min segments of a 24-h recording; SDNN, standard deviation of all N-N intervals; SDNNIDX, mean of standard deviations of N-N intervals for all 5-min segments of a 24-h recording.

After the 24-week treatment period, HbA1c was significantly decreased compared with baseline in both the empagliflozin (−0.50, 95% confidence interval [CI] −0.73 to −0.27, P<0.0001, and sitagliptin: −0.47, 95% CI −0.70 to −0.24, P<0.0001) (Figure 2A). Systolic BP and body weight were significantly decreased in the empagliflozin group (Figure 2B,C). Although the serial change in the LF/HF ratio did not differ significantly between the 2 groups (0.52, 95% CI −0.15 to 1.19, P=0.126) over the adjustment of the baseline LF/HF ratios statistically, the LF/HF ratio was significantly increased at 24 weeks compared with baseline in the empagliflozin group (Figure 3A). No significant difference was observed for HF between the 2 groups (16.13; 95% CI −11.58 to 43.84; P=0.251). However, HF tended to be increased in the empagliflozin group and decreased in the sitagliptin group at 24 weeks compared with baseline (Figure 3B). LF tended to decrease in the sitagliptin group, with no significant difference between the 2 treatment groups (Figure 3C).

Figure 2.

Changes in (A) HbA1c, (B) systolic blood pressure, and (C) body weight following 24 weeks treatment with empagliflozin (Emp) or sitagliptin (Sita). HbA1c (A) was significantly decreased in both groups compared with baseline. However, systolic blood pressure (B) and body weight (C) were only significantly decreased compared with in the empagliflozin group. Data show the least squares mean with 95% confidence intervals.

Figure 3.

Serial changes in the low frequency (LF) and high frequency (HF) parameters and time domain indices in empagliflozin (Emp) and sitagliptin (Sita) groups. (A) There was no significant difference in the LF/HF ratio between the Emp and Sita groups. However, the LF/HF ratio was significantly increased at 24 weeks in Emp group compared with baseline. (B) There was no significant difference in HF between the 2 groups. However, HF tended to be increased in the Emp group and decreased in the Sita group at 24 weeks compared with baseline. (C) LF tended to decrease in the Sita group, but there was no significant difference between the 2 treatment groups. (D) The average of all N-N intervals (AVNN) tended to be prolonged for Emp and shortened for Sita. (E) The standard deviation of all N-N intervals (SDNN) decreased significantly in the Sita group, although there was no significant difference between the 2 groups. (F,G) Although there were no significant differences between the Emp and Sita groups in serial changes in the root mean square successive difference (rMSSD; F) and percentage difference between adjacent normal RR intervals >50 ms (pNN50; G), both variables tended to be increased in the Emp group at 24 weeks compared with baseline. Data show the least squares mean with 95% confidence intervals. *P<0.05 compared with baseline.

In terms of time domain indices, the average of all N-N intervals (AVNN) tended to be prolonged for empagliflozin and shortened for sitagliptin; the standard deviation of all N-N intervals decreased significantly in the sitagliptin group, but there was no significant difference between the 2 groups (Figure 3D,E). Although the serial changes in root mean square successive difference (1.91; 95% CI −0.56, 4.38; P=0.129) and percentage difference between adjacent normal RR intervals >50 ms (1.05; 95% CI −0.32, 2.42; P=0.132) did not differ significantly between the 2 groups, both tended to be increased in the empagliflozin group at 24 weeks compared with baseline (Figure 3F,G).

The incidence of adverse events was comparable between the empagliflozin and sitagliptin groups (23.6% vs. 17.9%, respectively; Table 3). Regarding serum catecholamine concentrations (i.e., epinephrine, norepinephrine, and dopamine), no significant differences were observed between the 2 groups, and serial changes in catecholamine concentrations were not significant during the study period (Table 4). In post hoc analysis, EPV was significantly decreased in the empagliflozin compared with sitagliptin group at both 12 and 24 weeks (Table 5).

Table 3.

Adverse Events

	Total (n=111)	Empagliflozin (n=55)	Sitagliptin (n=56)
Adverse events	23 (20.7)	13 (23.6)	10 (17.9)
General condition	2 (1.8)	2 (3.6)	–
Chest pain	1 (0.9)	1 (1.8)	–
Fatigue	1 (0.9)	1 (1.8)	–
Infections	5 (4.5)	4 (7.3)	1 (1.8)
Bronchitis	2 (1.8)	2 (3.6)	–
Cellulitis	1 (0.9)	1 (1.8)	–
Cystitis	1 (0.9)	–	1 (1.8)
Ringworm	1 (0.9)	1 (1.8)	–
Laboratory data	3 (2.7)	–	3 (5.4)
Hyperglycemia	1 (0.9)	–	1 (1.8)
Hypertriglyceridemia	1 (0.9)	–	1 (1.8)
Ketonuria	1 (0.9)	–	1 (1.8)
Metabolism	2 (1.8)	1 (1.8)	1 (1.8)
Hypoglycemia	1 (0.9)	1 (1.8)	–
T1D	1 (0.9)	–	1 (1.8)
Neoplasms	2 (1.8)	2 (3.6)	–
Breast cancer	2 (1.8)	2 (3.6)	–
Skin disorders	2 (1.8)	–	2 (3.6)
Neurodermatitis	1 (0.9)	–	1 (1.8)
Keratosis pilaris	1 (0.9)	–	1 (1.8)

Data show n (%). T1D, type 1 diabetes.

Table 4.

Comparisons of Serum Catecholamine Concentrations

	Time (weeks)	Estimate	Standard error	95% CI	P value
Empagliflozin vs. sitagliptin
Epinephrine	12	0.001907	0.004143	−0.00635, 0.010161	0.646688
	24	0.003944	0.004816	−0.00564, 0.013528	0.415184
Norepinephrine	12	−0.02678	0.039387	−0.10496, 0.051404	0.498254
	24	0.007749	0.039685	−0.07102, 0.086523	0.845591
Dopamine	12	0.000	0.0427	−0.0877, 0.0887	0.9911
	24	−0.014	0.0125	−0.0713, 0.0427	0.3763
Least squares mean
Epinephrine
Empagliflozin	12	0.000	0.004		0.901
	24	−0.002	0.003		0.475
Sitagliptin	12	−0.002	0.004		0.524
	24	−0.006	0.003		0.105
Norepinephrine
Empagliflozin	12	−0.027	0.032		0.403
	24	−0.006	0.029		0.822
Sitagliptin	12	0.000	0.032		0.99
	24	−0.014	0.028		0.621
Dopamine
Empagliflozin	12	0.012	0.03		0.688
	24	−0.016	0.025		0.518
Sitagliptin	12	0.004	0.03		0.896
	24	0.023	0.037		0.55

CI, confidence interval.

Table 5.

Post Hoc Analysis of Estimated Plasma Volume

	Time (weeks)	Estimate	Standard error	95% CI	P value
Empagliflozin vs. sitagliptin
EPV	12	−152.005	45.79195	−242.797, −61.2137	0.0012
	24	−174.993	50.14855	−274.425, −75.5598	0.0007
Least squares mean
EPV empagliflozin	12	−171.970	32.144		<0.0001
	24	−201.140	35.194		<0.0001
EPV sitagliptin	12	−19.962	32.618		0.542
	24	−26.148	35.731		0.466

CI, confidence interval; EPV, estimated plasma volume.

Discussion

This study investigated the effect of empagliflozin on autonomic function in patients with T2D. Specifically, the study showed that: (1) serial changes in the LF/HF ratio were not significantly different between the empagliflozin and sitagliptin groups; (2) there was no significant difference in HF between the 2 groups; (3) the sitagliptin group had a tendency towards impaired autonomic nerve activity; (4) the empagliflozin group tended exhibit increased autonomic nerve activity (both sympathetic and parasympathetic nerves); and (5) EPV was significantly lower at both 12 and 24 weeks in the empagliflozin vs. sitagliptin group.

Previous clinical trials have described the effects of SGLT2 inhibitors on autonomic function in T2D. In 22 metformin-treated T2D patients, Jordan et al. reported that 4-day treatment with empagliflozin significantly increased urine volume, the reduction in BP, and weight loss, but did not increase muscle nerve sympathetic activity.³³ The EMPA-HEART CardioLink-6 trial investigated the effects of empagliflozin on left ventricular mass in patients with T2D and coronary artery disease.³⁴ A post hoc analysis of that trial indicated that empagliflozin had not produced changes in autonomic tone based on HRV variables.³⁵ The EMBODY trial investigated the effects of empagliflozin on HRV indices compared with placebo in patients with T2D and recent acute myocardial infarction.³⁶ Although the empagliflozin group exhibited significant improvements in the indices after treatment, no significant intergroup differences were detected. SGLT2 inhibitors were also expected to improve cardiac autonomic neuropathy (CAN) in those trials, but no significant findings were observed. In terms of circadian BP patterns, several clinical trials with SGLT2 inhibitors in patients with T2D and hypertension did not show restoration of sympathovagal balance in circadian BP rhythm.^37–40

In our study, there were no significant differences between the treatment groups in terms of HRV variables. However, tendencies for serial changes in HRV indices were apparent from baseline to 24 weeks of treatment in both groups. Autonomic nerve activity showed diametric changes as well. Signs of disease progression in CAN were observed in the sitagliptin group. The impairment of parasympathetic nerve activity and sympathetic augmentation followed by sympathetic denervation may occur in patients with diabetes.^41–43 CAN progression disrupts HRV variables while increasing HR and perturbing BP regulation.⁴³ In our study, impairment of HRV variables was seen in the sitagliptin group showed impairment of HRV variables to presumably lead to decreases in the LF/HF ratio, HF, and LF. The sitagliptin group had a shortened AVNN, which is indicative of increased HR and supports the notion that CAN had progressed under sitagliptin treatment during the study period. Conversely, the empagliflozin group showed a tendency for an increase in the LF/HF ratio and HF, as well as prolonged AVNN. Thus, autonomic nerve activity may have been increased in the empagliflozin group along with a reduction in HR. We therefore presume that CAN had regressed during the 24 weeks of empagliflozin treatment.

In the present study, the activity of both the sympathetic and parasympathetic nervous systems appeared to increase following the administration of empagliflozin. Our results indicate that parasympathetic nerve-dominant activation occurred in the cohort because a reduction in HR was achieved despite the decreased EPV, which would activate sympathetic nerve activity,⁴⁴ in the empagliflozin group.

The strengths of this study include its design as a multicenter randomized assessor-blinded active-control using sitagliptin parallel-group clinical trial. Furthermore, comprehensive assessment using HRV variables was used to detect serial changes in autonomic function after treatment. Because no study participants had acute cardiovascular disease, the differences between the 2 medications in patients with T2D could be clearly understood.

This study has several limitations. First, the number of subjects included in the analysis was small. However, there was no large effect on the final conclusions of this study. Second, the EMPYREAN study was underpowered to assess for prespecified differences in HRV parameters; thus, our results should be interpreted with caution. Third, only HRV was used to evaluate autonomic activity. Other modalities, such as HR recovery after exercise and metaiodobenzylguanidine scintigraphy, echocardiography parameters, and left ventricular pressure-volume loops, provide a more comprehensive understanding of the effect of cardiac sympathetic activity. Fourth, severe events were few, and so associations between changes in HRV variables and the occurrence of severe adverse events could not be investigated with sufficient statistical power. Fifth, this study compared empagliflozin to sitagliptin, with no placebo group. Despite these shortcomings, our study represents a promising and straightforward approach for assessing the impact of SGLT2 inhibitors on sympathetic nerve activity in patients with T2D. Finally, patients with severe T2D accompanied by neuropathy were excluded from the study by the Schellong test. The severity of diabetes and its relationship with HRV was not assessed in this study.

In conclusion, the effects of empagliflozin and sitagliptin on autonomic nerve activity did not differ significantly in patients with T2D. Further studies are needed on autonomic nerve activation following the administration of SGLT2 inhibitors.

Acknowledgment

The authors sincerely thank Trevor Ralph for his English editorial assistance and Mebae Kobayashi for administrative support.

Sources of Funding

This work was supported by a research grant obtained through Boehringer Ingelheim and Eli Lilly and Company. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations. Neither company had any role in designing or conducting the trial, analyzing the data, interpreting the results, or writing the manuscript. This is an investigator-driven trial designed by the steering committee and conducted by the trial bureau and local investigators. The authors are solely responsible for the design and conduct of this study, all study analysis, drafting and editing of the paper, and final study content.

Disclosures

K.K. obtained a research grant from Boehringer Ingelheim and Eli Lilly and Company to support this work, and has received lecture fees from Boehringer Ingelheim and Eli Lilly and Company. S.H. has received lecture fees from MSD and Boehringer Ingelheim. K.K. is a member of Circulation Journal’s Editorial Team. The other authors declare no relationships relevant to the contents of this paper.

IRB Information

The EMPYREAN study has been registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000029194; registered September 19, 2017). The study protocol was approved by the certified Review Board of Shinshu University School of Medicine (#18-01). This investigation was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from each patient before enrollment.

Data Availability

The deidentified participant data will be shared on a request basis. Please contact the corresponding author directly to request data sharing. The entire dataset used will be available, including the study protocol. Data will be shared as soon as the IRB at Shinshu University School of Medicine approves it, and will be available until the end of March 2026. Data will be shared with anyone wishing to access it. Any analyses on the data will be approved and data will be shared as an Excel file via email.

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