SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients
Abstract
Background:
Frailty is a multidimensional condition often diagnosed in older adults with hypertension and diabetes, and both these conditions are associated with endothelial dysfunction and oxidative stress. We investigated the functional role of the SGLT2 (sodium glucose cotransporter 2) inhibitor empagliflozin in frail diabetic and hypertensive older adults.
Methods:
We studied the effects of empagliflozin in consecutive hypertensive and diabetic older patients with frailty presenting at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to January 2022. Moreover, we performed in vitro experiments in human endothelial cells to measure cell viability, permeability, mitochondrial Ca2+, and oxidative stress.
Results:
We evaluated 407 patients; 325 frail elders with diabetes successfully completed the study. We propensity-score matched 75 patients treated with empagliflozin and 75 with no empagliflozin. We observed a correlation between glycemia and Montreal Cognitive Assessment (MoCA) score and between glycemia and 5-meter gait speed (5mGS). At 3-month follow-up, we detected a significant improvement in the MoCA score and in the 5mGS in patients receiving empagliflozin compared with non-treated subjects. Mechanistically, we demonstrate that empagliflozin significantly reduces mitochondrial Ca2+ overload and reactive oxygen species production triggered by high glucose in human endothelial cells, attenuates cellular permeability, and improves cell viability in response to oxidative stress.
Conclusions:
Taken together, our data indicate that empagliflozin reduces frailty in diabetic and hypertensive patients, most likely by decreasing the mitochondrial generation of reactive oxygen species in endothelial cells.
Graphical Abstract
Novelty and Relevance
What Is New?
The SGLT2 (sodium glucose cotransporter 2) inhibitor empagliflozin improves both cognitive and physical impairment in frail patients with hypertension and diabetes.
Empagliflozin ameliorates endothelial dysfunction induced by high glucose.
Empagliflozin reduces mitochondrial Ca2+ overload and oxidative stress in human endothelial cells.
What Is Relevant?
SGLT2 inhibitors have been shown to have beneficial effects on the cardiovascular system, but the underlying mechanisms were not fully understood.
This work indicates that SGLT2 inhibitors have favorable effects on different types of human endothelial cells, i.e. umbilical vein and brain microvascular endothelial cells.
Clinical/Pathophysiological Implications
The management of frailty in older adults should consider the expected benefits given by the treatment with SGLT2 inhibitors especially taking into account the pathophysiological rationale provided by this study, in terms of improvement of endothelial function and reduced oxidative stress.
Frailty is a systemic condition that leads to functional decline with physical and cognitive impairment.1–3 Frailty is often diagnosed in older adults with hypertension and diabetes, and both these conditions are associated with endothelial dysfunction and oxidative stress.4–6
Our group has recently evidenced the detrimental effects of hyperglycemia in frail hypertensive elders.7 Similarly, several investigators have shown that hyperglycemia drives inflammation and oxidative stress leading to endothelial dysfunction, with a negative impact that is especially evident in frail patients.8–11
In this scenario, SGLT2 (sodium glucose cotransporter 2) inhibitors, which include the Food and Drug Administration–approved drugs canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin,12 are considered among the most promising oral antidiabetic drugs to reach and maintain an optimal glycemic control in older subjects.13 The main mechanism of action of these drugs is the blockage of SGLT2 proteins in the renal proximal convoluted tubules to reduce the reabsorption of filtered glucose and decrease the renal threshold for glucose, thereby promoting urinary glucose excretion.14–17 Empagliflozin is a SGLT2 inhibitor that has been shown to reduce mortality and rehospitalization for heart failure in diabetic patients.18–23 Additional potential benefits of empagliflozin and other SGLT2 inhibitors include improved cardiovascular energetics, reduced vascular tone and blood pressure, decreased renal dysfunction, increased circulating levels of ketone bodies, protection against pulmonary ischemia/reperfusion injury, and overall reduced systemic inflammation.24–37
On these grounds, we investigated the effects of empagliflozin on frailty in diabetic and hypertensive older adults. To mechanistically confirm our results, we evaluated the effects of empagliflozin on mitochondrial oxidative stress and permeabilization in human endothelial cells.
Methods
Data Availability
The data that support the findings of this study are available from the first author upon reasonable request.
Study Participants
We designed a prospective study to enroll consecutive hypertensive and diabetic older adults presenting at the ASL (local health unit of the Ministry of Health) of Avellino, Italy, from March 2021 to January 2022 with a diagnosis of frailty. Inclusion criteria: age >65 years, a diagnosis of frailty, presence of diabetes and primary hypertension, Montreal Cognitive Assessment (MoCA) score <26, and glomerular filtration rate >30. Exclusion criteria: age <65 years and history of previous stroke. The study was approved by the local ethical committee (Campania Nord). All subjects or their legal representatives signed an informed consent. The study had been registered at https://www.clinicaltrials.gov (unique identifier: NCT04962841).
Clinical Evaluation and Assessment of Cognitive and Physical Impairment
Blood glucose, glycated hemoglobin, and creatinine were measured in all patients. Clinical assessment was completed at baseline and after 3 months. Diabetes was defined according to the American Diabetes Association guidelines.38 Hypertension was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on repeated measurements or use of antihypertensive medications.39
Frailty Assessment
A diagnosis of physical frailty was made with at least 3 of the 5 Fried criteria,40 as we described previously41,42:
•
Weight loss (unintentional loss, ≥4.5 kg in the past year)
•
Weakness (handgrip strength in the lowest 20% quintile at baseline, adjusted for sex and body mass index)
•
Exhaustion (poor endurance and energy, self-reported)
•
Slowness (walking speed under the lowest quintile adjusted for sex and height)
•
Low physical activity level (lowest quintile of kilocalories of physical activity during the past week)
Ca2+ Imaging
Ca2+ imaging experiments to measure mitochondrial Ca2+ were performed as we described previously.44,45 Human umbilical vascular endothelial cells (passages 3–7) were plated in glass-bottom culture dishes using the Ca2+ imaging solution, which consists of 138 mmol/L NaCl, 5.3 mmol/L KCl, 1.2 mmol/L NaH2PO4, 1.2 mmol/L MgCl2, and 20 mmol/L HEPES (pH 7.38, adjusted with NaOH); to this solution, we added 5 mmol/L EGTA, 1.8 mmol/L CaCl2, and 5 or 30 mmol/L glucose, according to the experimental settings. Cells were loaded with Rhod-2 AM (3 μM; catolog number R1244; Thermo Fisher Scientific, Waltham, MA) at 37 °C for 30 minutes, followed by washout and 1-hour rest at room temperature for de-esterification: indeed, since Rhod-2 AM has a delocalized positive charge, it preferentially accumulates within the mitochondrial matrix, where it is hydrolyzed and trapped. Fluorescence was detected using a pass-band filter of 545 to 625 nm in response to excitation at 542 nm.
Mitochondrial Oxidative Stress
Human umbilical vein vascular endothelial cells were plated on glass-bottom dishes and treated with different concentrations of glucose and empagliflozin for 24 hours; mitochondrial reactive oxygen species (ROS) were quantified by MitoSOX Red (catalog number M36008; Thermo Fisher Scientific) as we described,7,46 using MitoTracker Green FM (catalog number M7514; Thermo Fisher Scientific) to identify mitochondria.
Real-Time PCR
Endothelial Permeability Assay
Human brain microvascular endothelial cells (hBMECs; passages 3–6) were cultured as we described previously.7,49 In some experiments, cells were treated with empagliflozin (1 µM), adding 5 or 30 mmol/L glucose for 48 hours. The endothelial permeability assay was performed using fibronectin-coated trans-well filters (Corning, Inc, Corning, NY), as we reported previously.7,49,50
Cell Viability Assay
Cell viability was evaluated in hBMECs using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, as we described previously.44,51 Briefly, cells were pretreated for 24 hours with 1-μM empagliflozin and then incubated with progressively increasing doses of H2O2 for 5 hours.
Statistical Analysis
Data are presented as n (%) for categorical data (compared using the χ2 test) and mean±SD for normally distributed continuous data (compared via the Student t test or ANOVA followed by Bonferroni post hoc correction). Normality was verified using the Anderson-Darling test. A propensity score analysis was performed as described52 to minimize any selection bias due to the differences in clinical characteristics between the empagliflozin and the no-empagliflozin groups. Briefly, for each patient, a propensity score was calculated by the use of a nonparsimonious multivariable logistic regression, applying the 1:1 nearest neighbor propensity score matching method. Variables that could potentially affect treatment assignment or outcomes were selected, including sociodemographic characteristics, comorbidities, and concomitant drugs. We developed a dispersion model using the Pearson analysis to assess the correlation between glycemia and MoCA score and between glycemia and 5mGS. To adjust for potential confounders (selected a priori based on their clinical significance and possible confounding effect), we performed linear regression analyses with the MoCA score or 5mGS test as dependent variables.
Statistical significance was considered based on 2-tailed P<0.05. All calculations were computed using SPSS, version 26 (IBM Corporation, Armonk, NY), and GraphPad Prism, version 9 (GraphPad by Dotmatics, Boston, MA).
Results
Patient Characteristics
We evaluated 407 patients. Since 22 patients were unwilling to provide clinical information and 60 subjects did not fulfill eligibility criteria, 325 patients were enrolled. To minimize potential selection bias and confounding variables, we propensity score matched 150 patients, 75 treated with 10-mg empagliflozin in addition to standard therapy and 75 not receiving empagliflozin (Figure 1). At baseline, there were no significant differences in age, body mass index, sex distribution, comorbidities, and laboratory parameters between the two groups (Table 1). Notably, the MoCA score and 5mGS were not different among the two study arms at baseline (Table 1).
| Empagliflozin | No empagliflozin | |
|---|---|---|
| n | 75 | 75 |
| Sex (M/F) | 36/39 | 35/40 |
| Age, y | 78.05±7.5 | 78.62±6.2 |
| BMI, kg/m2 | 27.7±1.6 | 27.9±1.4 |
| SBP, mm Hg | 121.7±7.3 | 121.0±7.6 |
| DBP, mm Hg | 76.6±6.5 | 76.4±6.7 |
| Heart rate, bpm | 82.3±9.4 | 82.6±9.0 |
| 5mGS, m/s | 0.60±0.12 | 0.59±0.13 |
| MoCA score | 20.32±4.2 | 20.35±4.3 |
| Comorbidities, n (%) | ||
| Dyslipidemia | 39 (52.0) | 40 (53.0) |
| COPD | 32 (42.7) | 31 (41.0) |
| CKD | 38 (50.7) | 39 (52.0) |
| Previous stroke | 12 (16.0) | 11 (15.0) |
| Laboratory analyses | ||
| Plasma glucose, mg/dL | 153.87±71.6 | 153.36±73.1 |
| HbA1c, mmol/mol | 61±7.5 | 61±6.2 |
| Creatinine, mg/dL | 1.0±0.2 | 1.0±0.2 |
5mGS indicates 5-m gait speed; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; F, female; HbA1c, glycated hemoglobin; M, male; MoCA, Montreal Cognitive Assessment; and SBP, systolic blood pressure.
Empagliflozin Significantly Attenuates Cognitive and Physical Impairment
In our population, we observed a strong correlation between glycemia and MoCA score (r²=0.91, P<0.001; Figure 2A) and between glycemia and 5mGS (r²=0.79, P<0.001; Figure 2B).
We then evaluated the differences in MoCA score (Figure 2C) and 5mGS (Figure 2D) at baseline and at 3-month follow-up in empagliflozin-treated and nontreated patients, observing significantly different favorable effects of the empagliflozin treatment.
Lastly, we assessed how many patients in the two study arms had frailty at 3-month follow-up; the empagliflozin-treated group included only 25.3% of patients with frailty (n=19), while in the nonempagliflozin group, 73.3% of patients (n=55) had frailty (P<0.001; Figure 2E).
Importantly, the significant correlation linking glycemia with MoCA score (Figure 2C) and 5mGS (Figure 2D) was confirmed after adjusting for potential confounders in multivariable regression analyses with MoCA score or 5mGS as dependent variable (Table 2).
| OR | SE | 95% CI | P value | ||
|---|---|---|---|---|---|
| Lower bound | Upper bound | ||||
| Basal MoCA score | |||||
| Age, y | −0.024 | 0.019 | −0.062 | 0.014 | 0.211 |
| BMI | 0.017 | 0.062 | −0.105 | 0.139 | 0.781 |
| SBP | −0.009 | 0.014 | −0.036 | 0.018 | 0.530 |
| DBP | −0.002 | 0.017 | −0.035 | 0.031 | 0.903 |
| HR | 0.022 | 0.013 | −0.004 | 0.047 | 0.093 |
| Dyslipidemia | −0.099 | 0.212 | −0.518 | 0.319 | 0.640 |
| CKD | −0.140 | 0.221 | −0.577 | 0.297 | 0.527 |
| COPD | 0.051 | 0.227 | −0.397 | 0.500 | 0.821 |
| HbA1c | −0.766 | 0.422 | −1.600 | 0.069 | 0.072 |
| Glycemia | −0.046 | 0.005 | −0.056 | −0.037 | <0.001 |
| 5mGS | |||||
| Age, y | −0.001 | 0.001 | −0.003 | 0.001 | 0.418 |
| BMI | 0.002 | 0.003 | −0.004 | 0.008 | 0.451 |
| SBP | 0.000 | 0.001 | −0.001 | 0.001 | 0.739 |
| DBP | 0.000 | 0.001 | −0.001 | 0.002 | 0.620 |
| HR | 0.001 | 0.001 | 0.000 | 0.002 | 0.055 |
| Dyslipidemia | −0.010 | 0.010 | −0.029 | 0.010 | 0.339 |
| CKD | −0.001 | 0.010 | −0.021 | 0.020 | 0.946 |
| COPD | 0.004 | 0.011 | −0.017 | 0.025 | 0.711 |
| HbA1c | −0.002 | 0.020 | −0.041 | 0.038 | 0.936 |
| Glycemia | −0.002 | 0.000 | −0.002 | −0.001 | <0.001 |
5mGS indicates 5-m gait speed; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HR, heart rate; MoCA, Montreal Cognitive Assessment; OR, odds ratio; and SBP, systolic blood pressure.
Empagliflozin Reduces Mitochondrial Ca2+ Overload and Mitochondrial Oxidative Stress
To test whether empagliflozin could attenuate mitochondrial Ca2+ overload and ROS production, we cultured human endothelial cells in normal glucose (5 mmol/L), high glucose (30 mmol/L), and high glucose plus empagliflozin for 24 hours. High-glucose condition produced mitochondrial Ca2+ overload (Figure 3AE) and significantly enhanced ROS production in these organelles (Figure 3F), while empagliflozin significantly attenuated these responses (Figure 3).
SGLT2 Inhibition Mitigates Glucose-Induced Endothelial Permeabilization
Hyperglycemia has been shown to cause an augmented vascular permeability,53,54 and endothelial leakage has been associated to cognitive decline and frailty.55–60 Therefore, we tested whether inhibiting SGLT2 in hBMECs could attenuate endothelial leakage elicited by high glucose concentrations. We observed that empagliflozin significantly attenuated the endothelial permeability induced by high glucose (Figure 4A). To further confirm the effects of empagliflozin on endothelial leakage, we measured the expression levels of mRNA encoding for established junctional proteins (i.e. claudin-5 and occludin) and we found that high glucose concentrations significantly reduced the mRNA levels of both claudin-5 (Figure 4B) and occludin (Figure 4C), and these reductions were mitigated by empagliflozin (Figure 4B and 4C).
SGLT2 Inhibition Protects Human Endothelial Cells From Oxidative Stress
Since we demonstrated in human umbilical vascular endothelial cells that empagliflozin attenuates oxidative stress induced by high glucose concentrations, we sought to confirm in hBMECs that inhibiting SGLT2 could improve cell viability in response to oxidative stress. Therefore, we pretreated hBMECs with empagliflozin and then we incubated them with increasing concentrations of H2O2; after 5 hours, we observed that cell viability was significantly improved by empagliflozin (Figure 4D).
Discussion
The compelling combination of clinical data and in vitro assays provided in the present study indicates that SGLT2 inhibition significantly improves cognitive and physical impairment in diabetic and hypertensive patients, most likely reducing oxidative stress in endothelial cells (Graphic Abstract).
Oxidative stress is known to be a common pathogenic substrate in hypertension,61 diabetes,62 and frailty.63,64 Specifically, a dysregulated mitochondrial fitness has been proposed as a potential root of age-related frailty,65 and mitochondrial free radicals are crucial players in endothelial dysfunction.66,67 Henceforth, we sought to determine whether the favorable effects detected in the clinical setting could be attributable to an action on mitochondrial ROS generation at the endothelial level.
Our findings are in agreement with previous reports showing that hyperglycemia causes an augmented generation of mitochondrial ROS68,69; in fact, mitochondrial ROS are recognized as a major cause of clinical complications associated with diabetes.70,71
Hyperglycemia, alongside its actions on endothelial function, has also been associated with memory disturbances, and a potential role in the development of cognitive impairment has been proposed.72,73 Thus, a stable glycemic control is seen as imperative to reduce the incidence of functional decline and to avoid complications.74–78 Herein, we demonstrate that empagliflozin significantly improves cognitive impairment, assessed via MoCA, and physical decline, evaluated via 5mGS test, and we prove that these parameters, which we had previously shown to mutually relate with each other,79 independently correlate with blood glucose levels. Remarkably, our data also indicate a direct effect of empagliflozin on endothelial cells, which goes beyond its actions merely attributable to a reduction of blood glucose80–82 or to the offsetting of insulin resistance.83–86 Specifically, we show that SGLT2 inhibition significantly attenuates mitochondrial Ca2+ overload and the subsequent increase in ROS production in human endothelial cells.
The new 2022 guidelines on the management of heart failure87 of the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America recommend SGLT2 inhibitors as class 1A in HFrEF and class 2A in HFmrEF and HFpEF (conditions in which ARNI and MRA have weaker recommendations: class 2B). These guidelines are mainly based on the protective effects of SGLT2 inhibitors on cardiovascular outcomes, independent of the glucose-lowering effects, revealed by recent clinical trials: the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure),88 EMPEROR-HF (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction),89 and EMPEROR-PRESERVED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).21 However, the exact mechanism underlying these beneficial effects on cardiovascular outcomes has remained hitherto elusive.
Our results are consistent with a pilot study testing the acute effects of dapagliflozin in 16 diabetic patients, showing a marked reduction of urinary isoprostanes, a surrogate of systemic oxidative stress, 48 hours after administration compared to baseline values.90 In our study, we also proved that empagliflozin counteracts the increased endothelial permeability induced by high glucose, by regulating at the transcriptional level the expression of occludin and claudin-5, tight junction proteins that have been shown to partake in cognitive impairment.91–93 Claudin-5 levels were also shown to be reduced in the nucleus accumbens of patients with depression.94,95 Additionally, empagliflozin significantly prevented the death of cerebral endothelial cells induced by oxidative stress, and these data are particularly relevant when considering that ROS production is fundamental in processes like senescence and aging.96–100 Therefore, our findings are highly suggestive for a potential role of SGLT2 inhibitors in preventing neurodegenerative disorders.
Strengths of our study include its prospective nature, the analysis of a real-world homogeneous population of elderly patients with diabetes and hypertension, the integration of clinical and in vitro data, and the consistency of the beneficial effects of empagliflozin in 2 different types of human endothelial cells, namely cells obtained from the umbilical vein and brain microvascular endothelial cells. Nevertheless, our study is not exempt from limitations, including the relatively brief follow-up, having tested the effects of only one SGLT2 inhibitor, and having enrolled only Caucasian patients.
Perspectives
Based on our results and on the emerging pleiotropic effects of SGLT2 inhibitors,26 we propose SGLT2 inhibitors as anti-frailty drugs. This view is strongly supported by the beneficial effects of empagliflozin on endothelial cells, in terms of mitigated mitochondrial Ca2+ overload, reduced oxidative stress, and improved cell viability.
Footnote
Nonstandard Abbreviations and Acronyms
- 5mGS
- 5-meter Gait Speed
- ARNI
- Angiotensin Receptor-Neprilysin Inhibitors
- DAPA-HF
- Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure
- EGTA
- Ethylene Glycol-bis(β-aminoethyl ether)-N,N,N′,N′-Tetraacetic Acid
- EMPA
- Empagliflozin
- EMPEROR-HF
- Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction
- EMPEROR-PRESERVED
- Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction
- Glu
- Glucose
- hBMEC
- Human Brain Microvascular Endothelial Cell
- HUVEC
- Human Umbilical Vein Endothelial Cell
- MoCA
- Montreal Cognitive Assessment
- MRA
- Mineralocorticoid Receptor Antagonists
- MTT
- 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- Rhod 2 AM
- Rhod-2 Acetoxymethyl
- ROS
- Reactive Oxygen Species
- RT-qPCR
- Reverse Transcription quantitative Real-Time Polymerase Chain Reaction
- SGLT2
- Sodium-GLucose co-Transporter 2
Supplemental Material
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Received: 22 April 2022
Accepted: 1 June 2022
Published online: 15 June 2022
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The Santulli Lab is supported, in part, by the National Institutes of Health (NIH; R01-DK123259, R01-DK033823, R01-HL146691, R01-HL159062, and T32-HL144456, to G. Santulli), by the Irma T. Hirschl and Monique Weill-Caulier Trusts (to G. Santulli), by the Diabetes Action Research and Education Foundation (to G. Santulli), and by the American Heart Association (AHA-22POST915561 to F. Varzideh and AHA-21POST836407 to S.S. Jankauskas).
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