ORIGINAL ARTICLE

Jacek Kubica1, Aldona Kubica2, Zofia Grąbczewska1, Paweł Stróżecki3, Piotr Adamski1, Andrzej Brymora3, Rafał Donderski3, Tomasz Fabiszak1, Mariusz Flisiński3, Robert Gajda4, Beata Januszko-Giergielewicz5, Michał Kasprzak1, Agata Kosobucka2, Ewa Laskowska1, Przemysław Magielski6, Piotr Michalski2, Gavino Casu7, Eliano Pio Navarese7, Piotr Niezgoda1, Małgorzata Ostrowska1, Łukasz Pietrzykowski2, Grzegorz Skonieczny8, Beata Sulikowska3, Łukasz Szarpak9, 10, Paweł Szymański11, Julia Maria Umińska12, Paweł Zalewski13, 14

1Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

2Department of Cardiac Rehabilitation and Health Promotion, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

3Department of Nephrology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

4Gajda-Med District Hospital in Pultusk, Poland

5Department of General, Liver and Transplant Surgery, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

6Scientia Research Institute Sp. z o.o., Bydgoszcz, Poland

7Department of Clinical and Interventional Cardiology, Sassari University Hospital, Sassari, Italy

8Chair of the Cardiology Clinic Ward and Acute Cardiac Care Unit, Wojewodzki Szpital Zespolony im. L. Rydygiera, Torun, Poland

9Henry JN Taub Department of Emergency Medicine, Baylor College of Medicine Houston, Houston, TX, USA

10Institute of Outcomes Research, Maria Sklodowska-Curie Medical Academy, Warsaw, Poland

11Department of Cardiology, Interventional Cardiology and Electrophysiology with Cardiac Intensive Care Unit, Tertiary Care Hospital in Grudziadz, Poland

12Department of Geriatrics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

13Department of Exercise Physiology and Functional Anatomy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland

14Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Warsaw Medical University, Warsaw, Poland

Corresponding author:

Jacek Kubica,Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland; e-mail: jkubica@cm.umk.pl

Medical Research Journal 2023;

Volume 8, Number 3, 171–178

10.5603/mrj.97187

Copyright © 2023 Via Medica

ISSN 2451-2591

e-ISSN 2451-4101

Efficacy of double vs. standard empagliflozin dose for METabolic syndromE tReatment (DEMETER — SIRIO 11) study. Rationale and protocol of the study

ABSTRACT

Complex metabolic disorders associated with obesity and diabetes pose a serious therapeutic challenge. The DEMETER-SIRIO 11 study is a phase III, multicenter, randomized, open-label, investigator-initiated clinical trial with a 6-month follow-up aimed at performing a comparative evaluation of the effect of two empagliflozin doses (10 mg vs. 20 mg) on selected metabolic parameters in patients with metabolic syndrome. The primary hypothesis of the study is that a higher dose of empagliflozin will result in a significant reduction of BMI and HbA1c in patients with obesity and MS receiving empagliflozin 20 mg as compared to 10 mg. Sample size and power calculation were based on a superiority assumption for the primary efficacy endpoint (the difference in decrease of body weight by > 1.5 kg and HbA1c by > 0.4%) for the higher vs. standard dose arm at 6-months of follow-up. Therefore, a sample size of 79 patients per arm is required to provide 80% power to detect a higher decrease in BMI, and 85 patients per arm is required to provide 80% power to detect a higher decrease in HbA1c in the 20 mg versus 10 mg arm with a type I error rate of 0.05. Summing up, enrollment of a total of 200 patients (100 in each arm) is planned to compensate for the potential drop-out rate from the study of up to 15%. Prespecified subanalyses will be performed according to: 1) diabetes mellitus; 2) chronic kidney disease (GFR < 60 mL/min/1.73 m2); 3) gender; and 4) age.

A greater comprehensive improvement in biochemical, functional, and anthropometric parameters reflecting favorable metabolic changes is expected at the higher dose of empagliflozin compared to the standard dose.

Keywords: empagliflozin, metabolic syndrome, obesity, randomized clinical study

Med Res J 2023; 8 (3): 171–178

Introduction

The reduction in glucose renal reabsorption induced by SGLT2 inhibitors is characterized by the rapid onset of glycosuria, the dose-dependent offset of action in the range of 24–48 hr, and the glycemia-dependent entity of glycosuria [1]. Glycosuria induced by SGLT2 inhibitors results in several further metabolic changes [2]. The extracellular space is partially emptied out of glucose, whereby plasma concentrations of glucose fall during fasting and postprandially. This fasting-like effect leads to a decrease in insulin-to-glucagon ratio, inducing endogenous fasting gluconeogenesis and ketogenesis [3–6], which are regulated by endogenous nutrient deprivation sensors SIRT1 (silent information regulator T1), PGC-1a (proliferator-activated receptor gamma coactivator 1-alpha), and FGF21 (fibroblast growth factor 21), which are known to exert cardioprotective effects in experimental models [6]. This metabolic theory based on experimental studies is consistent with the rapid onset of cardiovascular and renal benefits observed in the outcome trials [7–10].

The loss of glucose on SGLT2 inhibitors translates into a substantial whole-body energy deficit, ranging from 250 to 450 kcal/day. However, the weight loss observed in clinical trials was far less than expected from the negative calorie balance. This difference was due to an increase in calorie intake [11]. The weight loss induced by SGLT2 inhibitors could be strengthened by countering the compensatory increase in caloric intake, either through dietary counseling or by pharmacological appetite quenching [11, 12]. Moreover, SGLT2 inhibitors lead to an increase of LDL cholesterol and a decrease of triglyceride plasma levels, including due to delayed clearance of LDL cholesterol from the circulation along with increased plasma lipoprotein lipase activity [13]. The SGLT2 inhibitors have also been shown to reduce serum uric acid levels in a dose-dependent manner [14] and reduce urinary albumin excretion in patients with type 2 diabetes and prevalent micro- or macroalbuminuria [15]. Furthermore, the anti-inflammatory effect of SGLT2 inhibitors with a slight reduction in serum inflammatory markers: hsCRP, tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and interferon-gamma (IFN-g) has been revealed [16] explaining the beneficial effect of SGLT2 inhibitors at the kidney and myocardium levels [2, 17, 18].

The metabolic effects of SGLT2 inhibitors are associated with hemodynamic changes caused by increased osmotic diuresis and consequently decreased plasma volume, followed by reduced preload and a reduction of interstitial fluid volume [12, 19, 20]. A concomitant decrease of arterial stiffness and blood pressure leads to an afterload reduction [12, 19]. The hemodynamic effects of SGLT2 inhibition were observed in both hyper- and euglycemic patients [1, 3]. These complex mechanisms of action of SGLT2 inhibitors make them an excellent therapeutic option for patients with HF, providing an additional nephroprotective effect [21–23]. The exceptional clinical benefits of SGLT2 inhibitors applied on top of the previously guideline-recommended treatment [24] in patients with chronic HFrEF, regardless of the coexistence of diabetes mellitus [21–23], led to fundamental changes in the recommended strategy of treatment [25, 26]. The new ESC guidelines emphasize the key role of the organization of HF management programs adapted to the local healthcare system, available resources, administrative policies, and tailored to the patient’s needs [26]. Implementation of these recommendations implies the need to monitor readiness for discharge from the hospital, the implementation of the therapeutic plan, and functioning in chronic disease [27–36].

Rationale

The cluster of metabolic factors that include abdominal obesity, high blood pressure, impaired fasting glucose, high triglyceride levels, and low HDL cholesterol levels is defined as the metabolic syndrome (MS) [37]. The complex mechanisms of action of SGLT2 inhibitors make them an optimal response to the health needs of patients with MS and its complications [2]. Both the EMPA-REG OUTCOME study, a high-scale randomized trial [38], and the meta-analysis assessing dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes [39] showed insignificantly stronger effect of higher empagliflozin dose (25 mg) as compared to standard dose (10 mg) in terms of HbA1c and weight reduction. Moreover, the EMPA-REG OUTCOME study also showed a higher increase of HDL-Cholesterol with a higher empagliflozin dose [38]. A number of other, smaller studies compared the effects of different doses of SGLT2 inhibitors, but none of these studies included exclusively patients with MS, and none of them performed a comprehensive assessment of metabolic effects [40–47]. Therefore, we have designed a randomized clinical trial to perform a comparative evaluation of the effect of two empagliflozin doses (10 mg vs. 20 mg) on selected metabolic parameters in patients with MS.

Material and methods

Study design and population

The DEMETER-SIRIO 11 study is a phase III, multicenter, randomized, open-label, investigator-initiated clinical trial with a 6-month follow-up (ClinicalTrials.gov Identifier: NCT05905965). The study population will include 200 subjects with a diagnosis of MS.

MS is defined as a cluster of comorbid conditions, including the presence of obesity [waist circumference ≥ 88 cm in women; ≥ 102 cm or body mass index (BMI) ≥ 30 kg/m2] and two of the three following criteria:

• high blood pressure (systolic blood pressure — in-office measurement: ≥ 130 mm Hg and/or diastolic blood pressure ≥ 85 mm Hg or systolic blood pressure, ambulatory measurement: ≥ 130 and/or diastolic blood pressure ≥ 80 mm Hg) or on anti-hypertensive treatment;
• impaired glucose metabolism (fasting glucose ≥ 100 mg/dL or ≥ 140 mg/dL after 120 min in oral glucose tolerance test or HbA1c ≥ 5.7%) or on glucose-lowering drug treatment;
• elevated non-high-density lipoprotein (non-HDL ≥ 130 mg/dL) cholesterol level (atherogenic dyslipidemia) or on lipid-lowering drug treatment [48].

All enrolled patients will receive optimal, personalized therapy as defined by the European Society of Cardiology guidelines including [49–51]:

• education and motivation;
• optimal lipid-lowering treatment;
• optimal hypertension treatment;
• optimal antihyperglycemic treatment.

The exclusion criteria include: on treatment with SGLT2 inhibitors, chronic kidney disease with estimated glomerular filtration rate (eGFR) < 30 mL/min or on dialysis; severely impaired liver function; age < 18 and ≥ 85 years; known hypersensitivity to the active empagliflozin or to any of the excipients contained in Jardiance; history of ketoacidosis; diabetes treated with insulin; pregnancy; decompensated heart failure; acute coronary syndrome; active thromboembolic disease; currently treated for neoplastic disease; active inflammatory disease within 1 month prior to enrollment; expected lifetime < 1 year, non-cooperative patients.

All enrolled patients (nn = 200) will be randomly assigned in 1:1 ratio to one of the two study arms:

• Empagliflozin 20 mg — experimental arm;
• Empagliflozin 10 mg — control arm.

All study participants will be provided free of charge with study drugs according to the randomized allocation. Special care will be applied with regard to adherence to the study treatment (tablets counting at follow-up visits and the Adherence in Chronic Diseases Scale) [27–29, 52–59].

The primary co-endpoints of the study include BMI and HbA1c. Secondary endpoints include: LDL-C, triglycerides, CRP, NT-proBNP, LVEF (echocardiography), body composition, VO2max (ergospirometry), waist-hip ratio (WHR), liver steatosis assessment (LSA) by computed tomography (CT), major adverse cardiovascular events — MACE (based on medical history: heart attack, stroke, death), cardiovascular hospitalizations. Other variables that are scheduled to be analyzed are: central arterial pressure, pulse wave propagation speed, ABPM (ambulatory blood pressure monitoring), endothelial function assessment by Endopath, autonomic nervous system assessment (ANSA) by Task Force Touch CARDIO (TFTC), exercise tolerance, thickness of the adipose tissue (skin fold), blood samples: blood count, serum creatinine and eGFR, ALT, AST, GGTP, total cholesterol, HDL-C, uric acid, plasma concentration of calcium, phosphate, parathormone, 25-OH-D3, cystatin C, erythropoietin; morning urine: N-acetyl-beta-D-glucosaminidase, sodium/creatinine ratio, calcium/creatinine ratio, albumin/creatinine ratio. Moreover, functioning in chronic disease and adherence to medication and diet will be assessed with dedicated questionnaires (FCIS, ACDS, ACDS diet) [54–57].

Treatment with empagliflozin is generally well tolerated, but careful monitoring will be given for safety, particularly with regard to genital infections, urinary tract infections, ketoacidosis, hypoglycemia, dyslipidemia, bladder cancer, and amputations.

The study will be conducted in accordance with the principles contained in the Declaration of Helsinki, and the study sites received approval from the Ethics Committee to conduct the study (study approval reference number KB KB 240/2022). Each patient will provide written informed consent to participate in the study.

Prespecified subanalyses will be performed according to: 1) diabetes mellitus; 2) chronic kidney disease (GFR < 60 mL/min/1.73 m2); 3) gender; and 4) age (Tab. 1).

Statistical analysis

Sample size and power calculation were based on a superiority assumption for the primary efficacy endpoint (the difference in decrease of body weight by > 1.5 kg and HbA1c by > 0.4%) for higher vs. standard dose arm at 6 moths of follow-up. Previously reported decrease of body weight was –2.93 (SE: 0.47) (95% CI –3.85, –2.01) p < 0.0001 and –2.11 (SE: 0.46) (95% CI –3.02, –1.21) p < 0.0001 in patients (with body weight > 90 kg at baseline) receiving 25 mg and 10 mg of empagliflozin, respectively, as compared with placebo [60]. The mean difference in weight reduction between study arms was 0.82 kg, with a standard error (SE) of 0.47 corresponding to a standard deviation (SD) of 3.76. Based on the analysis of candidates for the study in our outpatient department, we assume higher body weight at baseline (mean > 100 kg) expecting higher decrease and higher difference between both study arms of > 1.5 kg with similar SD. Therefore, a sample size of 79 patients per arm is required to provide 80% power to detect a higher decrease of BMI (directly proportional to body weight: BMI = body weight [kg])/height2 [m]) in the 20 mg vs. 10 mg arm with a type I error rate of 0.05.

The observed decrease of HbA1c was –0.97 (SE: 0.15) (95% CI –1.26, –0.68) p < 0.0001 and –0.73 (SE: 0.14) (95% CI –1.01, –0.46) p < 0.0001 in patients (with initial HbA1c ≥ 8.5% at baseline) receiving 25 mg and 10 mg of empagliflozin, respectively, as compared with placebo [60]. The mean difference in HbA1c reduction between study arms was 0.24% with SE of 0.15 corresponding to the standard deviation (SD) of 1.05. Based on the analysis of candidates for the study in our outpatient department, we assume higher HbA1c at baseline (mean > 9.5%) expecting higher decrease and higher difference between both study arms of > 0.4% with similar SD. Therefore, a sample size of 85 patients per arm is required to provide 80% power to detect a higher decrease in HbA1c.

Summing up, enrollment of a total of 200 patients (100 in each arm) is planned to compensate for the potential drop-out rate from the study of up to 15%.

Study organisation

The Steering Committee of the DEMETER-SIRIO 11 study is responsible for the scientific content of the protocol, oversees the study steps, and checks adherence to “Good Clinical Practice” and the study protocol as well as performance. The Endpoint Adjudication Committee will adjudicate clinical endpoints based on data provided by the clinical trial sites. Patient data are collected systematically online. Data quality and completeness is of prime importance in SYSTEMI. Upon formal request, according to our internal SOP, access to primary data can be granted.

Discussion

Complex metabolic disorders associated with obesity and diabetes pose a serious therapeutic challenge, and due to the huge scale of this phenomenon, they are also a social problem. According to the US National Diabetes Statistics Report, more than 50% of patients with T2D have a BMI higher than 30 kg/m2 [61].

The primary hypothesis of the DEMETER-SIRIO 11 study is that a higher dose of empagliflozin will result in a significant reduction of BMI and HbA1c in patients with obesity and metabolic syndrome receiving empagliflozin 20 mg as compared to 10 mg. A greater comprehensive improvement in biochemical, functional, and anthropometric parameters reflecting favorable metabolic changes is expected at the higher dose of empagliflozin compared to the standard dose.

Previously, greater reductions of both HbA1c and body weight at higher baseline values were observed [60, 62, 63], therefore even greater mean reduction of these parameters should be expected in patients with a diagnosis of obesity and metabolic syndrome than in the population of patients with T2 diabetes, only some of whom met the definition of obesity. Moreover, the dose-dependent effect of empagliflozin regarding these variables was reported [60]. Weight reduction has been shown to improve weight-related quality of life and satisfaction with physical and emotional health [63]. This effect is expected to improve adherence to the investigated treatment [64–70]. Better glycemic control and weight loss were associated with a marked reduction in systolic blood pressure (SBP). A significantly greater SBP reduction was observed in patients with higher baseline values [70].

Consistent benefits of SGLT2 inhibitors in patients with diabetes, heart failure, and chronic kidney disease have been shown in large-scale randomized clinical trials [8, 21, 23, 67–70]. However, a better understanding of the metabolic effects of SGLT2 inhibitors may help to introduce individual patient-centered care. Therefore, a comprehensive metabolic analysis of two different empagliflozin doses is planned in the DEMETER-SIRIO 11 study.

Article information

Data availability statement: The data support the results will be available on request from the corresponding author, after completion of the study. Moreover, the data will also be available in the Nicolaus Copernicus repository RUMAK (https://repozytorium.umk.pl).

Ethics statement: The study will be conducted in accordance with the principles contained in the Declaration of Helsinki, and the study sites received approval from the Ethics Committee to conduct the study (study approval reference number KB KB 240/2022). Each patient will provide written informed consent to participate in the study.

Author contributions: Jacek Kubica — primary investigator, study design, writing of the manuscript; Aldona Kubica — study design, writing of the manuscript; Zofia Grąbczewska — study design, coordination of the study conduction — cardiological noninvasive tests, critical evaluation of the manuscript; Paweł Stróżecki — co-primary investigator, study design, coordination of the study conduction — renal tests, critical evaluation of the manuscript; Piotr Adamski — investigator, critical evaluation of the manuscript; Andrzej Brymora — investigator, critical evaluation of the manuscript; Rafał Donderski — investigator, critical evaluation of the manuscript; Tomasz Fabiszak — investigator, critical evaluation of the manuscript; Mariusz Flisiński — investigator, critical evaluation of the manuscript; Robert Gajda — primary site investigator, critical evaluation of the manuscript; Beata Januszko-Giergielewicz — study design, coordination of the study conduction — liver tests, critical evaluation of the manuscript; Michał Kasprzak — statistical analysis, critical evaluation of the manuscript; Agata Kosobucka — investigator, critical evaluation of the manuscript; Ewa Laskowska — investigator, echocardiographic analysis, critical evaluation of the manuscript; Przemysław Magielski — investigator, coordination of data collection, critical evaluation of the manuscript; Piotr Michalski — investigator, critical evaluation of the manuscript; Gavino Casu — investigator, critical evaluation of the manuscript; Eliano Pio Navarese — primary site investigator, critical evaluation of the manuscript; Piotr Niezgoda — investigator, critical evaluation of the manuscript; Małgorzta Ostrowska — investigator, critical evaluation of the manuscript; Łukasz Pietrzykowski — investigator, critical evaluation of the manuscript; Grzegorz Skonieczny — primary site investigator, critical evaluation of the manuscript; Beata Sulikowska — investigator, critical evaluation of the manuscript; Łukasz Szarpak — primary site investigator, critical evaluation of the manuscript; Paweł Szymański — primary site investigator, critical evaluation of the manuscript; Julia Maria Umińska — investigator, critical evaluation of the manuscript; Paweł Zalewski — study design, coordination of the study conduction — autonomic system tests, critical evaluation of the manuscript.

Funding: This research received financial support from the Collegium Medicum, Nicolaus Copernicus University, Poland, through dedicated Medical Faculty grant.

Acknowledgments: None.

Conflict of interest: Jacek Kubica — received speaker fees from Boheringer Ingelheim; Aldona Kubica — received speaker fees from Boheringer Ingelheim; Other authors declare no conflict of interest with regard to the manuscript content.

Supplementary material: Will be available after completion of the study.

References

1. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014; 124(2): 499–508, doi: 10.1172/JCI72227, indexed in Pubmed: 24463454.
2. Kubica J, Kubica A, Grzelakowska K, et al. Inhibitors of sodium-glucose transport protein 2: A new multidirectional therapeutic option for heart failure patients. Cardiol J. 2023; 30(1): 143–149, doi: 10.5603/CJ.a2021.0133, indexed in Pubmed: 34708866.
3. Ferrannini E. Sodium-Glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017; 26(1): 27–38, doi: 10.1016/j.cmet.2017.04.011, indexed in Pubmed: 28506519.
4. Packer M. Molecular, cellular, and clinical evidence that sodium-glucose cotransporter 2 inhibitors act as neurohormonal antagonists when used for the treatment of chronic heart failure. J Am Heart Assoc. 2020; 9(16): e016270, doi: 10.1161/JAHA.120.016270, indexed in Pubmed: 32791029.
5. Luo G, Jian Z, Zhu Y, et al. Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress. Int J Mol Med. 2019; 43(5): 2033–2043, doi: 10.3892/ijmm.2019.4125, indexed in Pubmed: 30864731.
6. Packer M. Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. Circ Heart Fail. 2020; 13(9): e007197, doi: 10.1161/CIRCHEARTFAILURE.120.007197, indexed in Pubmed: 32894987.
7. Esterline RL, Vaag A, Oscarsson J, et al. Mechanisms in endocrinology: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism? Eur J Endocrinol. 2018; 178(4): R113–R125, doi: 10.1530/EJE-17-0832, indexed in Pubmed: 29371333.
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373(22): 2117–2128, doi: 10.1056/NEJMoa1504720, indexed in Pubmed: 26378978.
9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377(7): 644–657, doi: 10.1056/NEJMoa1611925, indexed in Pubmed: 28605608.
10. Figtree GA, Rådholm K, Neal B, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program. Circulation. 2018; 138(5): 458–468, doi: 10.1161/CIRCULATIONAHA.118.034222, indexed in Pubmed: 29526832.
11. Ferrannini G, Hach T, Crowe S, et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015; 38(9): 1730–1735, doi: 10.2337/dc15-0355, indexed in Pubmed: 26180105.
12. Lytvyn Y, Bjornstad P, Udell JA, et al. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017; 136(17): 1643–1658, doi: 10.1161/CIRCULATIONAHA.117.030012, indexed in Pubmed: 29061576.
13. Basu D, Huggins LA, Scerbo D, et al. Mechanism of increased LDL (low-density lipoprotein) and decreased triglycerides with SGLT2 (sodium-glucose cotransporter 2) inhibition. Arterioscler Thromb Vasc Biol. 2018; 38(9): 2207–2216, doi: 10.1161/ATVBAHA.118.311339, indexed in Pubmed: 30354257.
14. DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975; 55(4): 845–855, doi: 10.1172/JCI107996, indexed in Pubmed: 1120786.
15. Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016; 59(9): 1860–1870, doi: 10.1007/s00125-016-4008-2, indexed in Pubmed: 27316632.
16. Bonnet F, Scheen AJ. Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab. 2018; 44(6): 457–464, doi: 10.1016/j.diabet.2018.09.005, indexed in Pubmed: 30266577.
17. Gager GM, von Lewinski D, Sourij H, et al. Effects of SGLT2 inhibitors on ion homeostasis and oxidative stress associated mechanisms in heart failure. Biomed Pharmacother. 2021; 143: 112169, doi: 10.1016/j.biopha.2021.112169, indexed in Pubmed: 34560555.
18. Kubica J. Dapagliflozin — a key pawn on the new guidelines chessboard. Med Res J. 2021; 6(4): 342–350, doi: 10.5603/mrj.a2021.0056.
19. Dekkers CCJ, Sjöström CD, Greasley PJ, et al. Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes. Diabetes Obes Metab. 2019; 21(12): 2667–2673, doi: 10.1111/dom.13855, indexed in Pubmed: 31407856.
20. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018; 20(3): 479–487, doi: 10.1111/dom.13126, indexed in Pubmed: 29024278.
21. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381(21): 1995–2008, doi: 10.1056/NEJMoa1911303, indexed in Pubmed: 31535829.
22. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020; 396(10254): 819–829, doi: 10.1016/S0140-6736(20)31824-9, indexed in Pubmed: 32877652.
23. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383(15): 1413–1424, doi: 10.1056/NEJMoa2022190, indexed in Pubmed: 32865377.
24. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; 37(27): 2129–2200, doi: 10.1093/eurheartj/ehw128, indexed in Pubmed: 27206819.
25. Kubica J. Heart failure treatment according to the 2021 European Society of Cardiology Guidelines — experiences with SGLT2 inhibitors have changed the treatment strategy. Med Res J. 2021; 6(3): 163–165, doi: 10.5603/mrj.2021.0046.
26. McDonagh TA, Metra M, Adamo M, et al. ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021; 42(36): 3599–3726, Erratum in: Eur Heart J. 2021 Oct 14, doi: 10.1093/eurheartj/ehab368, indexed in Pubmed: 34447992.
27. Kubica A, Kosobucka A, Fabiszak T, et al. Assessment of adherence to medication in patients after myocardial infarction treated with percutaneous coronary intervention. Is there a place for newself-reported questionnaires? Curr Med Res Opin. 2019; 35(2): 341–349, doi: 10.1080/03007995.2018.1510385, indexed in Pubmed: 30091642.
28. Kosobucka A, Michalski P, Pietrzykowski Ł, et al. Adherence to treatment assessed with the adherence in chronic diseases scale in patients after myocardial infarction. Patient Prefer Adherence. 2018; 12(4): 333–340, doi: 10.2147/PPA.S150435, indexed in Pubmed: 29551891.
29. Kubica A, Obońska K, Fabiszak T, et al. Adherence to antiplatelet treatment with P2Y12 receptor inhibitors. Is there anything we can do to improve it? A systematic review of randomized trials. Curr Med Res Opin. 2016; 32(8): 1441–1451, doi: 10.1080/03007995.2016.1182901, indexed in Pubmed: 27112628.
30. Kubica A, Kasprzak M, Obońska K, et al. Discrepancies in assessment of adherence to antiplatelet treatment after myocardial infarction. Pharmacology. 2015; 95(1-2): 50–58, doi: 10.1159/000371392, indexed in Pubmed: 25592409.
31. Kubica A, Kasprzak M, Siller-Matula J, et al. Time-related changes in determinants of antiplatelet effect of clopidogrel in patients after myocardial infarction. Eur J Pharmacol. 2014; 742: 47–54, doi: 10.1016/j.ejphar.2014.08.009, indexed in Pubmed: 25199965.
32. Pietrzykowski Ł, Kasprzak M, Michalski P, et al. Therapy discontinuation after myocardial infarction. J Clin Med. 2020; 9(12): 4109, doi: 10.3390/jcm9124109, indexed in Pubmed: 33352811.
33. Kubica A, Gruchała M, Jaguszewski M, et al. Adherence to treatment — a pivotal issue in long-term treatment of patients with cardiovascular diseases. An expert standpoint. Med Res J. 2017; 2(4): 123–127, doi: 10.5603/mrj.2017.0016.
34. Pietrzykowski Ł, Michalski P, Kosobucka A, et al. Medication adherence and its determinants in patients after myocardial infarction. Sci Rep. 2020; 10(1): 12028, doi: 10.1038/s41598-020-68915-1, indexed in Pubmed: 32694522.
35. Kubica A, Adamski P, Bączkowska A, et al. The rationale for multilevel educational and motivational intervention in patients after myocardial infarction (MEDMOTION) project is to support multicentre randomized clinical trial evaluating safety and efficacy of two ticagrelor-based de-escalation antiplatelet strategies in acute coronary syndrome (ELECTRA – SIRIO 2). Med Res J. 2020; 5(4): 244–249, doi: 10.5603/mrj.a2020.0043.
36. Kubica A. Self-reported questionnaires for a comprehensive assessment of patients after acute coronary syndrome. Med Res J. 2019; 4(2): 106–109, doi: 10.5603/mrj.a2019.0021.
37. Ahmed M, Kumari N, Mirgani Z, et al. Metabolic syndrome; definition, pathogenesis, elements, and the effects of medicinal plants on it’s elements. J Diabetes Metab Disord. 2022; 21(1): 1011–1022, Erratum in: J Diabetes Metab Disord. 2022 May 3;21(1):1217, doi: 10.1007/s40200-021-00965-2, indexed in Pubmed: 35673459.
38. Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373(22): 2117–2128, doi: 10.1056/NEJMoa1504720, indexed in Pubmed: 26378978.
39. Pinto LC, Rados DV, Remonti LR, et al. Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. Arch Endocrinol Metab. 2022; 66(1): 68–76, doi: 10.20945/2359-3997000000440, indexed in Pubmed: 35263050.
40. Jabbour SA, Hardy E, Sugg J, et al. Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014; 37(3): 740–750, doi: 10.2337/dc13-0467, indexed in Pubmed: 24144654.
41. Matthaei S, Bowering K, Rohwedder K, et al. Study 05 Group. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015; 17(11): 1075–1084, doi: 10.1111/dom.12543, indexed in Pubmed: 26212528.
42. Leiter LA, Cefalu WT, de Bruin TWA, et al. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014; 62(7): 1252–1262, doi: 10.1111/jgs.12881, indexed in Pubmed: 24890683.
43. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013; 15(4): 372–382, doi: 10.1111/dom.12054, indexed in Pubmed: 23279307.
44. Roden M, Weng J, Eilbracht J, et al. EMPA-REG MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013; 1(3): 208–219, doi: 10.1016/S2213-8587(13)70084-6, indexed in Pubmed: 24622369.
45. Tikkanen I, Narko K, Zeller C, et al. EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015; 38(3): 420–428, doi: 10.2337/dc14-1096, indexed in Pubmed: 25271206.
46. Yale JF, Bakris G, Cariou B, et al. DIA3004 Study Group. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014; 16(10): 1016–1027, doi: 10.1111/dom.12348, indexed in Pubmed: 24965700.
47. Fulcher G, Matthews DR, Perkovic V, et al. Efficacy and safety of canagliflozin used in conjunction with sulfonylurea in patients with type 2 diabetes mellitus: a randomized, controlled trial. Diabetes Ther. 2015; 6(3): 289–302, doi: 10.1007/s13300-015-0117-z, indexed in Pubmed: 26081793.
48. Dobrowolski P, Prejbisz A, Kuryłowicz A, et al. Metabolic syndrome - a new definition and management guidelines: A joint position paper by the Polish Society of Hypertension, Polish Society for the Treatment of Obesity, Polish Lipid Association, Polish Association for Study of Liver, Polish Society of Family Medicine, Polish Society of Lifestyle Medicine, Division of Prevention and Epidemiology Polish Cardiac Society, “Club 30” Polish Cardiac Society, and Division of Metabolic and Bariatric Surgery Society of Polish Surgeons. Arch Med Sci. 2022; 18(5): 1133–1156, doi: 10.5114/aoms/152921, indexed in Pubmed: 36160355.
49. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). J Am Coll Cardiol. 2018; 72(18): 2231–2264, doi: 10.1016/j.jacc.2018.08.1038, indexed in Pubmed: 30153967.
50. Domienik-Karłowicz J, Kupczyńska K, Michalski B, et al. Fourth universal definition of myocardial infarction. Selected messages from the European Society of Cardiology document and lessons learned from the new guidelines on ST-segment elevation myocardial infarction and non-ST-segment elevation-acute coronary syndrome. Cardiol J. 2021; 28(2): 195–201, doi: 10.5603/CJ.a2021.0036, indexed in Pubmed: 33843035.
51. Visseren FLJ, Mach F, Smulders YM, et al. ESC National Cardiac Societies, ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021; 42(34): 3227–3337, doi: 10.1093/eurheartj/ehab484, indexed in Pubmed: 34458905.
52. Pietrzykowski Ł, Kasprzak M, Michalski P, et al. The influence of patient expectations on adherence to treatment regimen after myocardial infarction. Patient Educ Couns. 2022; 105(2): 426–431, doi: 10.1016/j.pec.2021.05.030, indexed in Pubmed: 34059362.
53. Kubica A, Kasprzak M, Obońska K, et al. Discrepancies in assessment of adherence to antiplatelet treatment after myocardial infarction. Pharmacology. 2015; 95(1-2): 50–58, doi: 10.1159/000371392, indexed in Pubmed: 25592409.
54. Kubica A, Kosobucka A, Michalski P, et al. The Adherence in Chronic Diseases Scale — a new tool to monitor implementation of a treatment plan. Folia Cardiol. 2017; 12(1): 19–26, doi: 10.5603/FC.a2016.0105.
55. Buszko K, Obońska K, Michalski P, et al. The adherence scale in chronic diseases (ASCD). The power of knowledge: the key to successful patient — health care provider cooperation. Med Res J. 2016; 1(1): 37–42, doi: 10.5603/mrj.2016.0006.
56. Buszko K, Pietrzykowski Ł, Michalski P, et al. Validation of the functioning in chronic illness scale (FCIS). Med Res J. 2018; 3(2): 63–69, doi: 10.5603/mrj.2018.0011.
57. Kubica A, Michalski P, Kasprzak M, et al. Functioning of patients with post-COVID syndrome — preliminary data. Med Res J. 2021; 6(3): 224–229, doi: 10.5603/mrj.a2021.0044.
58. Kubica A, Michalski P, Kasprzak M, et al. Two different approaches to assess adherence to medication in Polish cohort of the EUROASPIRE V registry. Med Res J. 2022; 7(2): 108–113, doi: 10.5603/mrj.a2022.0015.
59. Kubica A, Pietrzykowski Ł. The therapeutic plan implementation in patients discharged from the hospital after myocardial infarction. Med Res J. 2021; 6(2): 79–82, doi: 10.5603/mrj.a2021.0024.
60. Inzucchi SE, Davies MJ, Khunti K, et al. Empagliflozin treatment effects across categories of baseline HbA1c, body weight and blood pressure as an add-on to metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2021; 23(2): 425–433, doi: 10.1111/dom.14234, indexed in Pubmed: 33084149.
61. Wilding J, Godec T, Khunti K, et al. Changes in HbA1c and weight, and treatment persistence, over the 18 months following initiation of second-line therapy in patients with type 2 diabetes: results from the United Kingdom Clinical Practice Research Datalink. BMC Med. 2018; 16(1): 116, doi: 10.1186/s12916-018-1085-8, indexed in Pubmed: 30008267.
62. Traina S, Guthrie R, Slee A. The impact of weight loss on weight-related quality of life and health satisfaction: results from a trial comparing canagliflozin with sitagliptin in triple therapy among people with type 2 diabetes. Postgrad Med. 2014; 126(3): 7–15, doi: 10.3810/pgm.2014.05.2752, indexed in Pubmed: 24918788.
63. Pobrotyn P, Chudiak A, Uchmanowicz B, et al. Adherence problems in elderly patients with hypertension. Med Res J. 2023; 1(8): 34–42, doi: 10.5603/mrj.a2023.0004.
64. Kubica A. Adherence to medication in elderly patients. Med Res J. 2023; 1(8): 93–94, doi: 10.5603/mrj.a2023.0015.
65. Kubica A, Kubica J. Functioning in chronic disease — a key factor determining adherence to heart failure treatment. Med Res J. 2022; 7(4): 277–279, doi: 10.5603/mrj.2022.0059.
66. Anker SD, Butler J, Filippatos G, et al. EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385(16): 1451–1461, doi: 10.1056/NEJMoa2107038, indexed in Pubmed: 34449189.
67. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020; 383(15): 1436–1446, doi: 10.1056/NEJMoa2024816, indexed in Pubmed: 32970396.
68. Herrington WG, Staplin N, Wanner C, et al. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023; 388(2): 117–127, doi: 10.1056/NEJMoa2204233, indexed in Pubmed: 36331190.
69. Wiviott SD, Raz I, Bonaca MP, et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380(4): 347–357, doi: 10.1056/NEJMoa1812389, indexed in Pubmed: 30415602.
70. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015; 17(12): 1180–1193, doi: 10.1111/dom.12572, indexed in Pubmed: 26343814.