Randomized Controlled Trial of the Hemodynamic Effects of Empagliflozin in Patients With Type 2 Diabetes at High Cardiovascular Risk: The SIMPLE Trial Free

The landmark EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study demonstrated that treatment with the sodium–glucose cotransporter 2 inhibitor (SGLT-2i) empagliflozin rapidly and significantly reduced cardiovascular (CV) events in patients with diabetes, including CV mortality and hospitalization for heart failure (HF) (1). The reduction in CV events with other SGLT-2 inhibitors was subsequently confirmed by additional randomized controlled trials (2,3). Treatment with another SGLT-2i, dapagliflozin, also proved to reduce CV events independently of diabetes status in the subsequent DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial (4). The benefits reported are therefore unlikely to be related to the modest reduction in glycosylated hemoglobin achieved with members of this drug class. To date, the mechanisms behind the improved CV outcomes remain unknown. In the outcome trials, reduction in CV events appeared rapidly after the onset of treatment, indicating effects beyond, and effective prior to, potential structural vascular or cardiac changes (1–4). Patients with diabetes have a higher prevalence of increased cardiac filling pressure during exercise compared with healthy individuals (5). Increased left heart filling pressure during rest and exercise are both associated with increased mortality (6,7). Because inhibition of SGLT-2 is associated with increased diuresis and sodium excretion (8), SGLT-2i treatment could be beneficial in patients with increased cardiac filling pressure. This notion was supported by a post hoc analysis from the EMPA-REG OUTCOME trial showing a volume-reducing effect of SGLT-2i treatment (9). Whether the (diuretic) effects of SGLT-2i translate into changes in central hemodynamics is not known. Examining the effects of SGLT-2i in patients with high filling pressure on central hemodynamics during rest and exercise may increase our understanding of the mechanisms behind reductions in CV events (particularly HF hospitalizations) reported from outcome trials (1–4).

As a prespecified substudy to the SIMPLE (Effects of the SGLT-2 Inhibitor Empagliflozin on Myocardial Perfusion and Function in Patients With T2D and High CVD Risk) trial, we measured invasive hemodynamics during rest and exercise in patients with type 2 diabetes (T2D) randomly assigned to empagliflozin or placebo. The primary end point was change in pulmonary capillary wedge pressure (PCWP) at a submaximal ergometer exercise workload (25 W) after 13 weeks of SGLT-2i treatment compared with placebo. Secondary end points included changes in resting hemodynamics after 13 weeks of SGLT-2i treatment compared with placebo.

This study was a prespecified hemodynamic substudy of the SIMPLE trial. The design of the SIMPLE study has been published previously (10). In short, this was an investigator-initiated, randomized, placebo-controlled, double-blind trial. Patients from outpatient diabetes and cardiology clinics from hospitals in the greater Copenhagen area (Herlev Hospital, Gentofte Hospital, Glostrup Hospital, and Rigshospitalet) were recruited from 2017 to 2020.

The study was approved by the Ethics Committee of the Capital Region (Copenhagen, Denmark), Danish Data Protection Board, and Danish Medicines Agency and monitored by the local Good Clinical Practice Unit of the Capital Region of Copenhagen. The study complied with the principles of the Declaration of Helsinki.

Patients enrolled in the SIMPLE trial were invited to participate in this hemodynamic substudy. Patients >18 years of age were eligible for participation if they had a diagnosis of T2D for at least 3 months prior to screening. Patients had to be on stable T2D medication (no changes in medication within 30 days prior to the baseline visit). Concentrations of hemoglobin A_1c (HbA_1c) had to be in the interval of 6.5–10% (48–86 mmol/mol) and 6.5–9% (48–75 mmol/mol) for drug-naïve patients. In addition, patients had to be at high risk of CV events, defined by one or more of the following: urine albumin-to-creatinine ratio (ACR) ≥30 mg/g, N-terminal pro-BNP ≥70 pg/mL, or confirmed history of myocardial infarction >2 months prior to baseline, HF according to Framingham HF criteria, discharge from hospital with a documented diagnosis of unstable angina ≤12 months prior to baseline, or evidence of coronary artery disease by coronary angiography in one or more major coronary arteries or at least one of the following: positive noninvasive stress test, positive stress echocardiography showing regional systolic wall motion abnormalities, or positive radionuclide test showing stress-induced ischemia; history of ischemic or hemorrhagic stroke >2 months prior to informed consent; presence of peripheral artery disease, such as previous limb angioplasty, stenting, or bypass surgery; previous limb or foot amputation resulting from circulatory insufficiency; angiographic evidence of significant (>50%) peripheral artery stenosis in at least one limb; evidence from a noninvasive measurement of significant (>50% or reported as hemodynamically significant) peripheral artery stenosis in at least one limb; or ankle brachial index <0.9.

Exclusion criteria included allergic reaction to the study medication, treatment with an SGLT-2i within 1 month prior to the baseline visit, estimated glomerular filtration rate ≤30 mL/min, severe liver insufficiency (Child-Pugh class C), untreated clinically significant heart valve disease, myocardial infarction ≤30 days or percutaneous coronary intervention ≤4 weeks prior to baseline, left ventricular (LV) ejection fraction (LVEF) ≤40% by baseline echocardiography, or hypertrophic cardiomyopathy. The published design report (10) provides a full listing of inclusion and exclusion criteria.

After obtaining oral and written consent, patients were screened to ensure that inclusion and exclusion criteria were respected. Medical history and anthropometric data were collected. At randomization, before administration of study drugs, blood samples, electrocardiography, echocardiography, and hemodynamic measurements were performed. All measurements were carried out during the same time of day. Patients were told to consume their regular diet and medication. Hemodynamic examination was repeated after 13 weeks. The flowchart provides an overview (Fig. 1).

Right heart catheterization was performed using a standard 7.5-F triple-lumen Swan-Ganz catheter (Edwards Lifesciences, Irvine, CA). Using the Seldinger technique and guided by ultrasound, the catheter was introduced under local anesthesia into the internal jugular vein and advanced to the pulmonary artery, with the position of the catheter verified by identifying the signature pressure curves. The following hemodynamic data were collected: right atrial pressure (central venous pressure [CVP]); systolic, diastolic (DPAP), and mean pulmonary artery pressure (MPAP), PCWP, cardiac output (CO) using thermodilution technique, noninvasive systolic blood pressure, noninvasive diastolic blood pressure, and heart rate.

At rest, invasive pressure readings were obtained during end expiration, but this was often not possible during exercise with higher ventilatory frequency. During exercise, pressure curves were averaged over 10 s. Cardiac output was measured using thermodilution as the average of three measurements with <10% variance and was indexed to body surface area (BSA) as cardiac index (CI).

Hemodynamic variables were measured at rest and during supine ergometer exercise (ebike; GE Healthcare, Fairfield, CT) at randomization and after 13 weeks. Measurements were obtained at rest, submaximal exercise (25 W), and peak exercise. Measurements were obtained after 2 min at a given workload. After measurements at rest, workload was increased every 2 min with increments of 25 W until maximal effort was achieved. Maximal effort/peak exercise was judged by patients and physicians when patients were not able to maintain 60 revolutions per minute on the ergometer at a given workload. All measurements were carried out during the same time of day. Patients were told to consume their regular diet and medication.

BSA was calculated using the Dubois formula. Mean blood pressure was calculated as ([2 × diastolic blood pressure] × systolic blood pressure)/3. Systemic vascular resistance (SVR) was calculated as 80 × (mean arterial pressure − CVP)/CO. Pulmonary vascular resistance (PVR) in Wood units was calculated as (MPAP − PCWP)/CO. CI was calculated as CO/BSA. Stroke volume index was calculated as CI/heart rate. Work-corrected pulmonary capillary wedge pressure (PCWL) was calculated as PCWP/watts achieved during exercise/kilogram body weight. Relative changes in plasma volume were estimated using the Strauss formula (11): estimated change in plasma volume (ΔePVS) = 100 × (hemoglobin^baseline/hemoglobin^follow-up) − (1 − hematocrit^follow-up)/(1 − hematocrit^baseline) − 100.

Patients underwent the same intervention as in the primary study. Patients were randomly assigned at a one-to-one ratio to either 25 mg empagliflozin or matching placebo once daily for 13 weeks. In accordance with the EMPA-REG OUTCOME study, no dose escalation was performed.

The primary end point was change in PCWP at a submaximal ergometer exercise workload (25 W) after 13 weeks of SGLT-2i treatment compared with placebo. The secondary end points were changes in CI, CVP, PCWP, MPAP, and PCWL at rest and at peak exercise after 13 weeks of SGLT-2i treatment compared with placebo.

Based on recent experiments in a comparable study population (12), a difference of 5 mmHg in PCWP during exercise was considered clinically significant. The SD of measurements of PCWP was 5 mmHg; thus, a sample size of 16:16 was required with a power of 80% and a two-sided significance level of 5% to detect a difference of 5 mmHg between groups. In total, 38 patients were recruited in the substudy to allow for a 15% dropout rate.

Data are presented as mean ± SD or median (interquartile range [IQR]) unless otherwise indicated. Normally distributed within-individual changes from baseline to follow-up were evaluated using the Student paired t test. The χ² test was used for comparison of categorical data between groups. Between-group differences from baseline to follow-up were evaluated using a general linear model with treatment as a covariate. As prespecified, the statistical models also included the baseline value of the given measure, with age and sex as covariates to adjust for differences between groups at baseline resulting from small sample size. A regression model was used to describe the association between changes from baseline to follow-up between ePVS and PCWP. A P value of 0.05 was considered statistically significant. All analyses were conducted using STATA version 16 (College Station, TX).

The data sets generated during and/or analyzed during the current study are not publicly available. No applicable resources were generated or analyzed during the current study.

Thirty-seven patients were recruited, and all underwent baseline hemodynamic measurements. Three (8%) patients dropped out during the 13 weeks of follow-up. Therefore, 34 patients attended both baseline and follow-up hemodynamic measurements (Fig. 1). The median (IQR) time between baseline measurements and follow-up was 86 (84; 91) days. Patients were adherent to their study medications throughout the study.

The examined patients with diabetes were 64 ± 10 years of age, were obese (BMI 31 ± 6 kg/m²), and had a high comorbidity burden (Table 1). Their median duration of diabetes was 12 (8; 20) years, and a large proportion of patients were taking insulin (54%), β-blockers (49%), and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (81%). Measures of LV structure and function, including LVEF (57 ± 8%) and LV end-diastolic volume (84 ± 16 mL), were within the normal ranges, although left atrial volume was enlarged (36 ± 9 mL/m²). The median maximal workload achieved by patients at baseline was 75 (55; 95) W. Atrial fibrillation was present in nine (24%) patients. More than half of the patients fulfilled invasive hemodynamic HF without reduced ejection fraction (HFpEF) diagnostic criteria (21 [57%] of 37 patients), whereas formal noninvasive criteria were not applied.

At baseline, PCWP (SGLT-2i 14 ± 5 vs. placebo 11 ± 3 mmHg; P = 0.02) and MPAP (SGLT-2i 22 ± 5 vs. placebo 19 ± 5 mmHg; P = 0.04) differed between randomized groups. This was not statistically attributable to differences in baseline characteristics. No statistical differences were observed between groups with regard to mean arterial pressure, CVP, CI, SVR, or PVR at baseline (Table 2).

After 13 weeks of treatment, the changes from baseline in PCWP were as follows: ΔSGLT-2i −1.6 ± 5.1 mmHg (P = 0.20) and Δplacebo +2.5 ± 4.1 mmHg (P = 0.02). The difference between groups was 4.1 mmHg (treatment P = 0.006). This was reflected in a significant treatment effect on DPAP (P = 0.02).

The proportion of patients with observed decreases in PCWP at follow-up compared with baseline was greater with SGLT-2i treatment (SGLT-2i 12 of 17 vs. placebo four of 17 patients; P = 0.006). When assessing relative changes in PCWP from baseline to follow-up, patients receiving SGLT-2i had reduced PCWP, in contrast to patients who received placebo (median [IQR] SGLT-2i −22% [−35; −11] vs. placebo +20% [+78; +11]; P = 0.0006) (Fig. 2). No other hemodynamic differences between groups at rest were noted in any measured hemodynamic variables (Table 2).

ΔePVS from baseline to follow-up differed according to treatment (SGLT-2i −8.7 ± 10.6% vs. placebo 0.9 ± 8.6%; P = 0.007). In patients treated with SGLT-2i, there was not a significant association between ΔePVS and changes in resting PCWP from baseline to follow-up (P = 0.35).

At baseline, PCWP at submaximal exercise (25 W) was significantly different between groups (SGLT-2i 25 ± 8 vs. placebo 20 ± 7 mmHg; P = 0.04).

After 13 weeks of treatment, the changes from baseline in PCWP at submaximal exercise were as follows: ΔSGLT-2i −2.1 ± 7.0 mmHg (P = 0.24) and Δplacebo −0.4 ± 5.8 mmHg (P = 0.79). The difference between groups was 1.7 mmHg (treatment P = 0.14), mirrored in a similar treatment effect on MPAP (treatment P = 0.04) (Fig. 3A and D). Among secondary end points, no treatment differences between groups were observed for CVP or CI (Fig. 3B and C). Furthermore, no treatment effects were noted from baseline to follow-up in ΔSVR (SGLT-2i 143 ± 269 vs. placebo 74 ± 195 dynes ⋅ m²/s ⋅ cm⁻⁵; treatment P = 0.65), ΔPVR (SGLT-2i −0.2 ± 0.7 vs. placebo 0.1 ± 0.6 Wood units; treatment P = 0.38), or ΔPCWL (SGLT-2i −7 ± 25 vs. placebo 0.1 ± 26 mmHg/W/kg; treatment P = 0.15).

At baseline, the peak exercise workload was similar in the SGLT-2i group compared with the placebo group (SGLT-2i 72 ± 23 vs. placebo 83 ± 31 W; P = 0.23). At follow-up, this was also observed (SGLT-2i 73 ± 32 vs. placebo 87 ± 41 W; P = 0.29). Similarly, there was no statistical difference in heart rate at peak exercise between the SGLT-2i and placebo groups at baseline (111 ± 19 vs. 112 ± 13 bpm; P = 0.75) or follow-up (109 ± 18 vs. 107 ± 13 bpm; P = 0.59).

At baseline, PCWP at peak exercise was not different between groups (SGLT-2i 24 ± 10 vs. placebo 29 ± 10 mmHg; P = 0.16). After 13 weeks of treatment, the changes from baseline in PCWP at peak exercise were as follows: ΔSGLT-2i −0.6 ± 7.7 mmHg (P = 0.73) and Δplacebo −0.4 ± 8.6 mmHg (P = 0.87). The difference between groups was 0.3 mmHg (treatment P = 0.98).

After 13 weeks of treatment, the changes from baseline in SVR were as follows: ΔSGLT-2i +223 ± 253 dynes ⋅ m²/s ⋅ cm⁻⁵ (P = 0.01) and Δplacebo +4 ± 185 dynes ⋅ m²/s ⋅ cm⁻⁵ (P = 0.94). The difference between groups was 219 dynes ⋅ m²/s ⋅ cm⁻⁵ (treatment P = 0.13).

At baseline, peak CVP (SGLT-2i 17 ± 5 vs. placebo 13 ± 5 mmHg; P = 0.01) and MPAP (SGLT-2i 44 ± 8 vs. placebo 38 ± 8 mmHg; P = 0.03) differed between groups, whereas no statistical differences were noted at follow-up. None of the hemodynamic measures were statistically different at peak exercise within groups at baseline or follow-up (Table 2). There were no statistically significant treatment effects on hemodynamics at peak exercise.

In the current study, we sought to evaluate whether treatment with empagliflozin would affect central hemodynamic parameters in patients with T2D at high CV risk. We compared the changes from baseline to follow-up after 13 weeks in both groups and found that treatment with empagliflozin did not affect the primary end point (changes in PCWP during submaximal exercise), whereas there was a treatment effect on PCWP at rest (secondary end point). To our knowledge, a reduction in LV filling pressure after treatment with an SGLT-2i in patients with diabetes has not been previously demonstrated using direct invasive measurements.

In patients with diabetes, SGLT-2i treatment has reduced mortality by up to 32% (1). Data from prior studies with continuous readings from an implantable hemodynamic pressure gauge in patients with HF have shown that a 5-mmHg reduction in left heart filling pressure led to a 30% reduction in mortality (6). Importantly, the correlation between left heart filling pressure and outcome was derived from measurement of filling pressure at rest. We found a 4-mmHg reduction in PCWP at rest after SGLT-2i treatment, which is in the range of the magnitude of PCWP lowering shown to decrease CV events, as reported in the outcome trials. Because more than half of patients had HFpEF in this trial, it may be speculated that SGLT-2i treatment might also be beneficial with regard to hard end points in ongoing outcome trials involving patients with HFpEF (13).

The hemodynamic change was apparent after 13 weeks but could potentially have appeared even earlier. Data from outcome trials with patients both with and without T2D and HF have demonstrated a remarkably fast-onset treatment benefit by with an SGLT-2i (1–4). This suggests that CV changes induced by SGLT-2i treatment are not merely structural in nature. Our observation of a fast and clinically relevant reduction in PCWP at rest by SGLT-2i treatment could explain the previously reported rapid reduction in event rates, especially HF hospitalization. This rapid onset of effect is supported by data from a randomized study in patients with severe HF who experienced significant reductions in DPAP, a proxy marker of LV filling pressure, after 12 weeks of empagliflozin use (14).

Our cohort had both abnormal resting and exercise hemodynamics, indicative of high left heart filling pressure (15), although resting PCWP was not increased to the magnitude measured in patients with overt HF (16). An important difference between patients in the EMPA-REG OUTCOME trial and our study was the exclusion of patients with LVEF <40% from our trial. Indeed, the effects on CV outcomes of dapagliflozin in the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events) trial were significantly greater in patients with HF with reduced ejection fraction compared with those with HFpEF or no history of HF (17). A similar treatment interaction was observed when patients were stratified according to ejection fraction (17). It could be speculated that a larger effect on resting PCWP might have been observed if we had not excluded patients with low ejection fraction. In this regard, however, HF treatment, such as peripheral vasodilatation and management of cardiac preload using diuretics, is likely highly important for the short-term response to SGLT2i. In fact, in a recent study of optimally treated patients with HF with reduced ejection fraction examined with a protocol similar to that used in the SIMPLE study, the decrease in PCWP at rest with empagliflozin was smaller than the change observed in the current investigation (18).

Our study did not demonstrate a difference in the primary outcome measure of PCWP reduction at a submaximal workload (25 W); however, a significant reduction in MPAP was observed. Our data suggest that the treatment effect is measurable at rest and weans as exercise intensity increases (Fig. 4), contrary to our initial hypothesis. Potentially, the elevation of PCWP observed during exercise in these patients with elevated left heart filling pressure is comparable to the conditions measured in patients diagnosed with HFpEF, in whom an abnormal arterial compliance has been associated with higher ventricular filling pressure (19). The hemodynamic effects of abnormal ventriculoarterial coupling during exercise might outweigh any effects of SGLT-2i treatment on changes in plasma or extracellular volume (8,19). From a pathophysiologic viewpoint, lowering resting PCWP would confer the biggest benefit with regard to CV events, because patients likely spend more time resting than not.

Treatment with an SGLT-2i in this study resulted in a plasma volume difference of ∼10% between groups that was not associated with changes in resting PCWP. Our cohort did not have increased right heart filling pressure at rest but did display abnormal CVP at peak exercise compared with healthy individuals (15). Furthermore, the plasma volume changes attributable to the reported volume-reducing effect of SGLT-2i treatment (9) were not reflected in reductions in right heart filling pressure in this study, although CVP does not necessarily correlate with whole-body blood volume (20,21).

This study used a double-blinded randomized design with a moderate number of patients included, to mechanistically elucidate the hemodynamic effects of empagliflozin using repeated right heart catheterization at rest and during exercise. This allowed us to measure direct treatment effects rather than noninvasive proxy measurements of cardiac conditions. Obvious limitations were that the sample size of this study was not larger and that follow-up time was relatively short. We cannot exclude that the dynamic hemodynamic changes during incremental exercise could make treatment-induced changes difficult to ascertain across our population. Also, changes in plasma volume were estimated rather than directly measured.

In conclusion, treatment with empagliflozin for 13 weeks in patients with T2D at high CV did not reduce the primary end point of lower left heart filling pressure at submaximal exercise. At rest, we observed that empagliflozin reduced PCWP at a magnitude of clinical significance. These findings could explain a significant part of the CV benefits observed in outcome trials and suggest cardiac benefits beyond the diuretic effect of SGLT-2i treatment.

Funding. This work is supported by the Department of Internal Medicine at Herlev Hospital, the Research Council of Herlev Hospital, the Danish Heart Foundation (grant 16-R107-A6697), the Hartmann Foundation, the Toyota Foundation, and a Steno Collaborative Grant 2018.

Duality of Interest. C.M.K. has served on scientific advisory panels and received speaker fees from Boehringer Ingelheim, Merck Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk, and Shire. P.R. has received consultancy and/or speaking fees (to the institution) from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Novo Nordisk, and Sanofi and research grants from AstraZeneca and Novo Nordisk. S.E.I. has received consultancy and/or speaking fees from Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Merck, and Esperion Therapeutics. E.W. has received speaker fees from Orion Pharma, Novartis, Boehringer Ingelheim, and Merck. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. E.W. was responsible for data acquisition, data analysis, and manuscript draft and revision. M.J. was responsible for data acquisition, data analysis, and manuscript revision. M.S., C.M.K., and F.G. were responsible for study planning, data analysis, and manuscript revision. M.E. was responsible for data analysis and manuscript revision. P.H., A.K., B.Z., N.H.B., P.H.G., P.R., and J.F. were responsible for study planning, data acquisition, and manuscript revision. S.E.I. was responsible for study planning and manuscript revision. E.W. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.