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Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience

  • Giuseppina Piazzolla EMAIL logo , Alfredo Vozza , Sara Volpe , Alessandro Bergamasco , Vincenzo Triggiani , Giuseppe Lisco , Michela Falconieri , Cosimo Tortorella , Vincenzo Solfrizzi and Carlo Sabbà
Published/Copyright: July 7, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

We evaluated the clinical impact, in daily clinical practice, of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) therapies in patients with type 2 diabetes. Data from 500 unselected consecutive patients were retrospectively analyzed. Only those with a full assessment at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of treatment with SGLT2i or GLP1RA were included in the study (n = 167). At baseline, patients had a high mean body weight (BW), abdominal circumference (AC), body mass index (BMI), and HOMA index. Despite normal C-peptide values, 39 patients were being treated with insulin (up to 120 IU/day). During therapy, a progressive improvement in BW, BMI, and AC was observed with both the molecules. Fasting glucose and glycated Hb decrease was already significant at T3 in all patients, while the HOMA index selectively improved with SGLT2i therapy. Renal function parameters remained stable regardless of the drug used. Finally, SGLT2i reduced serum uric acid and improved the lipid profile, while GLP1RA reduced serum levels of liver enzymes. Both the therapeutic regimens allowed a significant reduction or complete suspension of unnecessary insulin therapies. Our real life data confirm the results obtained from randomized clinical trials and should be taken as a warning against inappropriate use of insulin in patients with preserved β-cell function.

Keywords: SGLT2i; GLP1RA; Type 2 diabetes; C-peptide; insulin therapy

1 Introduction

Type 2 diabetes (T2D) is considered a global health emergency, mainly due to its high prevalence. Indeed, according to the most recent epidemiological estimates of the International Diabetes Federation, the prevalence is expected to double over the next 25 years [1]. These figures may be ascribed to population aging, earlier diagnosis, and the increased survival of diabetic patients thanks to improvements in the quality of care and recent advances in the pharmacological field. Undoubtedly, the therapeutic management of T2D has undergone radical and revolutionary changes in recent years. The new therapeutic targets, in fact, are no longer simply glycemic control, the reduction in glycated Hb (HbA1c), or minimization of the hypoglycemic risk. Instead, they are now increasingly oriented toward reducing the cardiovascular risk (CVR) and the overall mortality of diabetic patients, thus moving away from a glucocentric toward a cardio-metabolic approach [2,3,4]. Such ambitious goals are currently achievable thanks to the proven nephron- and cardio-protection provided by two classes of new antidiabetic drugs, i.e., sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) [3,4]. The numerous clinical trials published in the past years highlight a broad spectrum of beneficial effects with both the drug classes, ultimately improving the outcome of diabetic disease complications. As known, however, randomized clinical trials (RCTs) enroll selected populations of subjects and create optimal conditions for achieving the desired results [5,6]. These goals are much more difficult to achieve in clinical practice, especially when dealing with patients with co-morbidities [7]. In this context, real life clinical studies are particularly useful to validate data obtained in the more artificial RCT environments and to understand how efficacious a drug really is.

The purpose of this study was to evaluate the clinical impact of SGLT2i or GLP1RA on T2D management in the context of normal clinical practice, when dealing with all the variables of everyday life. To this aim, data were collected retrospectively from a population of T2D outpatients. Patients who had been treated with one of these two classes of antidiabetic agents and having a full 1 year follow-up available, were included in the study and their baseline characteristics were analyzed and compared. The effects of SGLT2i or GLP1RA on patient biometric parameters and laboratory tests were then studied.

2 Patients and methods

2.1 Study population

In this observational retrospective study, we analyzed data from 500 consecutive T2D patients (331 males and 169 females, mean age of 63.8 ± 10.4 years), attending the Metabolic Disorders Outpatients Clinic of the Department of Internal Medicine, at the University of Bari Medical Center, from June 2018 to July 2020. Exclusion criteria were any kind of cancer within less than 5 years prior to the study, infections or systemic corticosteroid treatment in the last 4 weeks, diagnosis of type 1 diabetes, and previous use of a drug belonging to one of the two classes under study. To be included in the study, patients had to be diagnosed with T2D. Moreover, after the complete evaluation of their clinical, bio-humoral, and instrumental picture, they had to have received the prescription of a SGLT2i or a GLP1RA. Only patients who had undergone a full outpatient assessment at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of therapy with one of the two drugs were finally included in the present study (n = 167, 113 males and 54 females, mean age 62.9 ± 9.5 years). At all observations, the general visit included measurements of height, body weight (BW), body mass index (BMI), abdominal circumference (AC), systolic (SBP) and diastolic blood pressure (DBP), and heart rate (HR), as well as venous sampling for routine tests, including serum uric acid, vitamin D, HbA1c, C-peptide, and insulin after a 12 h fasting period. The HOMA index was calculated as (fasting insulin × fasting glucose)/405 (normal range 0.23–2.5). All medications taken by the patients at the time of inclusion in the study were recorded, paying particular attention to metformin, oral antidiabetics, short-acting (SA) and/or long-acting (LA) insulin analogues. Patients were subdivided into group 1 (n = 54, 37 males and 17 females) and group 2 (n = 113, 76 males and 37 females), depending on whether the drug prescribed at T0 was a SGLT2i or a GLP1RA, respectively. It should be noted that the simultaneous administration of the 2 classes of drugs was not reimbursed by the Italian National Health System during the entire study period. Consequently, since only few patients agreed to buy one of the 2 drugs for use in combination, these patients’ data were not included in the study. In group 1, 21 patients had been treated with empagliflozin, 18 with dapagliflozin, and 15 with canagliflozin. In group 2, 8 patients had been treated with daily liraglutide, 26 with once-weekly semaglutide, and 79 with once-weekly dulaglutide. The lower number of patients treated with semaglutide compared to dulaglutide depends on the fact that semaglutide was marketed much later in Puglia (October 2019).

Finally, for the duration of the study, the time trends and mean changes in 19 variables were evaluated: BMI, weight, AC, SBP, DBP, HR, HOMA index, serum levels of fasting blood glucose, HbA1c, creatinine with estimated glomerular filtration rate (eGFR), uric acid, total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (γGT). Total daily International Units (IU) of insulin (SA + LA) were also recorded at each time point.

  1. Compliance with ethics guidelines: The study was approved by the Clinical Investigation Ethics Committee of the University of Bari Medical Center (Ethical approval number: PZZ_DM2_2020), and all patients gave written informed consent to take part.

2.2 Statistical analysis

Comparisons between groups were made by Student’s t-test and Chi-square test for continuous and categorical variables, respectively. Mixed models were applied to assess trends of clinical parameters over time. To evaluate the within-subject covariance matrix, an unstructured within-subject covariance and sandwich estimator for robustness and standard error was employed. Statistical evaluations were performed with Stata software (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp, LLC). The statistical significance threshold was set at p < 0.05.

3 Results

Baseline characteristics of the study population are summarized in Table 1. The wide age range of patients treated with the new antidiabetic drugs at our center is immediately evident. The patients included in the study were mainly males, and had high mean values of BW, AC, and BMI. Like for age, there was a wide variation in these clinical parameters, ranging from normal to clearly pathological values (Table 1). Table 1 also shows that the baseline HbA1c or fasting glycemia were not necessarily high prior to prescribing these drugs and that inter-individual variability was very evident also with reference to renal function parameters. Since variable degrees of resistance to insulin action were expected in these patients, we also evaluated the main indirect indicators of insulin resistance with the HOMA index, and pancreatic function reserve by assaying serum C-peptide. As shown in Table 1, the HOMA index was actually high in the study population but a wide range of variation was observed in both HOMA index values and C-peptide serum levels. Vitamin D dosage was available in 108/167 patients and mean levels were found to be low; of note, only 18/108 patients (16.7%) exhibited normal vitamin D values. Finally, Table 1 indicates the mean total daily dose of exogenous insulin (short acting [SA] and/or long acting [LA] insulin) used at baseline by 39 of the 167 (23.4%) patients. As to other antidiabetic drugs, most patients (146/167, 87.4%) were on metformin therapy, alone or in association with other molecules, while only 9/167 (5.4%) were taking no antidiabetic therapy at baseline. With the exception of metformin, all oral antidiabetic drugs previously used by the study population had been discontinued at the time of prescribing a SGLT2i or a GLP1RA.

Table 1

Baseline characteristics of the total study population (n = 167)

Variables Values Minimum value Maximum value
(mean value ± SD)
Age (years) 62.9 ± 9.5 38 83
Gender, male/female [n (%)] 113/54 (67.7/32.3%)
Weight (kg) 91.5 ± 18.2 52 170
BMI (kg/m2) 32.7 ± 6.1 21.6 60.9
Abdominal circumference (cm) 111.2 ± 13.9 74 154
SBP (mmHg) 129.2 ± 16.4 90 180
DBP (mmHg) 76.3 ± 10.5 50 110
HR (bpm) 72.4 ± 11.0 46 120
Fasting glucose (mg/dl) 158.6 ± 52.6 87 361
HbA1c (mmol/mol) 62.4 ± 18.1 30 116
C-peptide (ng/ml) 2.9 ± 1.6 0.8 10.9
HOMA index (n = 84) 5.0 ± 3.9 0.3 21.9
Vitamin D (ng/ml) (n = 108) 22.7 ± 13.4 3 68.5
Creatinine (mg/dl) 0.93 ± 0.31 0.40 2.01
e-GFR (ml/min) 83.3 ± 20.4 26 118
BUN (mg/dl) 42.6 ± 13.1 15 93
Uric acid (mg/dl) 5.4 ± 1.7 1.7 11.3
Cholesterol (mg/dl) 146.8 ± 37.1 25 335
LDL-cholesterol (mg/dl) 75.8 ± 30.7 24 241
HDL-cholesterol (mg/dl) 45.4 ± 13.4 20 116
Triglycerides (mg/ml) 146.2 ± 93.7 46 963
AST (U/L) 24.9 ± 13.6 12 76
ALT (U/L) 34.2 ± 24.5 8 156
γ-GT (U/L) 43.0 ± 38.0 7 296
U-ACR (mg/g) (n = 104) 62.3 ± 177.1 0 1,330
SA + LA Insulin (IU) (n = 39) 36.9 ± 25.4 10 120

Data are presented as mean value ± SD or as frequency and percentage.

Abbreviations: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: glycated hemoglobin; HOMA index: fasting glucose x fasting insulin/405; e-GFR: estimated-glomerular filtration rate; BUN: blood urea nitrogen; LDL: low density lipoprotein; HDL: high density lipoprotein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: gamma-glutamyl transferase; U-ACR: urine albumin-to-creatinine Ratio; SA: short acting; LA: long acting; IU: international units.

Table 2 summarizes and compares the characteristics of the patients in the 2 groups, subdivided according to the prescribed drug, SGLT2i (Group 1, n = 54) or GLP1RA (Group 2, n = 113). As illustrated in Table 2, the patients belonging to the GLP1RA group exhibited significantly higher values of both BMI and AC, while Group 1 patients had higher fasting glucose and HbA1c levels. A significant difference was also observed as regards the renal function parameters. It must be considered that throughout the study period, patients with eGFR values <60 ml/min at T0 were not eligible for treatment with SGLT2i in Italy. Consequently, patients treated with this drug had significantly higher eGFR values and lower creatinine levels as compared with the other group (Table 2). The average daily insulin IU (SA and/or LA) per patient were comparable in the two groups. Finally, 22 out of 54 patients (40.7%) for whom SGLT2i therapy was preferred had a previous major CV event in the clinical history, 7/22 patients having suffered dilated cardiomyopathy. Of note, a lower number of patients (26/113, 23.0%) in the GLP1RA group had already experienced a major CV event, and only 1 patient suffered from dilated cardiomyopathy.

Table 2

Baseline characteristics of the study population divided according to the drug prescribed

Variables SGLT2i GLP1RA Significance
(n = 54) (n = 113)
Age (years) 61.2 ± 10.0 63.7 ± 9.1 p = 0.110
Gender, male [n (%)] 37 (68.5) 76 (67.3) p = 0.870
Weight (kg) 89.0 ± 20.2 92.7 ± 17.1 p = 0.226
BMI (kg/m2) 31.1 ± 5.4 33.5 ± 6.3 p = 0.017
Abdominal circumference (cm) 107.5 ± 15.1 112.9 ± 13.0 p = 0.021
SBP (mmHg) 127.6 ± 16.4 130.0 ± 16.5 p = 0.405
DBP (mmHg) 76.0 ± 12.1 76.4 ± 9.9 p = 0.804
Heart rate 71.9 ± 13.0 72.7 ± 10.1 p = 0.672
Fasting glucose (mg/dl) 187.6 ± 65.6 144.0 ± 37.9 p < 0.001
HbA1c (mmol/mol) 71.8 ± 21.0 57.8 ± 14.4 p < 0.001
C-peptide (ng/ml) 3.0 ± 2.0 2.9 ± 1.3 p = 0.704
HOMA index (n = 84) 5.3 ± 3.9 4.8 ± 3.9 p = 0.587
Vitamin D (ng/ml) (n = 108) 19.6 ± 13.6 24.6 ± 13.1 p = 0.062
Creatinine (mg/dl) 0.85 ± 0.25 0.97 ± 0.33 p = 0.025
e-GFR (ml/min) 90.5 ± 16.7 79.6 ± 21.2 p = 0.002
BUN (mg/dl) 40.7 ± 10.9 43.6 ± 14.2 p = 0.240
Uric acid (mg/dl) 5.3 ± 1.8 5.4 ± 1.7 p = 0.633
Cholesterol (mg/dl) 149.9 ± 34.6 145.3 ± 38.3 p = 0.469
LDL-cholesterol (mg/dl) 77.5 ± 29.8 75.0 ± 31.2 p = 0.644
HDL-cholesterol (mg/dl) 44.5 ± 12.6 45.8 ± 13.8 p = 0.555
Triglycerides (mg/ml) 165.6 ± 138.0 136.9 ± 60.8 p = 0.070
AST (U/L) 23.5 ± 14.0 25.7 ± 13.3 p = 0.353
ALT (U/L) 32.1 ± 23.0 35.4 ± 25.3 p = 0.442
γ-GT (U/L) 39.1 ± 29.9 45.3 ± 41.9 p = 0.365
U-ACR (mg/g) (n = 104) 103.5 ± 282.7 44.0 ± 97.6 p = 0.115
SA + LA insulin (IU) (n = 39) 38.7 ± 23.0 (n = 16) 35.7 ± 26.9 (n = 23) p = 0.399

Data are presented as mean value ± SD or as frequency and percentage. Statistically significant p values (<0.05) are shown in bold.

Abbreviations: BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HbA1c: glycated hemoglobin; HOMA index: fasting glucose × fasting insulin/405; e-GFR: glomerular filtration rate; BUN: blood urea nitrogen; LDL: low density lipoprotein; HDL: high density lipoprotein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: gamma-glutamyl transferase; U-ACR: urine albumin-to-creatinine ratio; SA: short acting; LA: long acting; IU: international units.

Tables 3 and 4 summarize the time trends of the 19 parameters of interest as compared to baseline at each time point (T3, T6, and T12) during therapy with SGLT2i or GLP1RA. The different basal characteristics of the 2 groups of patients led us to consider it more appropriate to analyze changes over time within each group and not between groups. Therefore, the effects of the 2 drug classes are described but not statistically compared with each other. The time analysis highlighted that BW, BMI, and AC progressively improved with both SGLT2i and GLP1RA throughout the observation period. In particular, in the SGLT2i group, a significant BW reduction was already evident after 3 months, BMI after 6 months, and AC after 12 months of therapy (Table 3), while in the GLP1RA group, all parameters were found to be significantly improved after just 3 months of therapy and showed further improvements during the 12 month follow-up (Table 4).

Table 3

Time trends of clinical parameters in patients treated with SGLT2i

Outcome Months Estimated mean values (95% CI) Estimated mean change from baseline (95% CI) P (a)
Weight (kg) 0 88.4 (83.9–93.0)
3 85.7 (81.0–90.3) −2.8 (−4.4 to –1.1) 0.001
6 86.1 (81.5–90.7) −2.3 (−3.9 to –0.7) 0.004
12 85.0 (80.4–89.6) −3.4 (−5.2 to –1.7) <0.001
BMI 0 31.0 (29.5–32.5)
3 30.3 (28.8–31.9) −0.7 (−1.4 to –0.1) 0.069
6 30.3 (28.8–31.8) −0.7 (−1.4 to –0.1) 0.04
12 29.9 (28.3–31.4) −1.1 (−1.9 to –0.4) 0.004
AC (cm) 0 107.9 (104.2–111.6)
3 107.0 (103.0–111.0) −0.9 (−3.5 to 1.7) 0.5
6 108.9 (105.1–112.8) 1.0 (−1.4 to 3.5) 0.4
12 105.2 (101.2–109.1) −2.72 (−5.3 to –0.1) 0.039
SBP (mmHg) 0 127.8 (123.5–132.2)
3 118.2 (112.8–123.5) −9.7 (−15.1 to –4.2) <0.001
6 124.5 (119.6–129.4) −3.3 (−8.3 to 1.6) 0.184
12 123.1 (117.9–128.2) −4.7 (−10.0 to 0.5) 0.077
DBP (mmHg) 0 75.8 (73.0–78.7)
3 70.2 (66.5–73.9) −5.6 (−9.6 to –1.6) 0.006
6 74.1 (70.8–77.4) −1.7 (−5.4 to 1.9) 0.353
12 72.5 (69.0–76.0) −3.3 (−7.2 to 0.5) 0.09
HR (bpm) 0 71.5 (68.4–74.6)
3 68.9 (64.2–73.6) −2.6 (−7.3 to 2.1) 0.277
6 69.9 (66.4–73.5) −1.5 (−5.0 to 2.0) 0.387
12 70.3 (66.8–73.8) −1.2 (−4.7 to 2.3) 0.512
Fasting glucose (mg/dl) 0 186.4 (173.0–199.7)
3 143.3 (127.8–158.8) −43.1 (−59.6 to –26.6) <0.001
6 141.7 (127.0–156.4) −44.6 (−60.4 to –28.8) <0.001
12 144.4 (128.3–160.5) −42.0 (−59.1 to –24.9) <0.001
HbA1c (mmol/mol) 0 71.3 (66.9–75.8)
3 62.3 (57.2–67.4) −9.0 (−14.1 to –4.0) <0.001
6 60.6 (55.7–65.6) −10.7 (−15.6 to -5.8) <0.001
12 60.8 (55.6–66.0) −10.5 (−15.7 to –5.3) <0.001
HOMA index 0 5.4 (4.3–6.5)
3 2.9 (0.9–4.9) −2.5 (−4.7 to –0.2) 0.03
6 3.0 (1.7–4.4) −2.4 (−4.0 to –0.7) 0.005
12 2.5 (1.2–3.7) −2.9 (−4.4 to –1.4) <0.001
Creatinine (mg/dl) 0 0.86 (0.80–0.91)
3 0.90 (0.83–0.96) 0.04 (−0.02 to 0.10) 0.187
6 0.89 (0.82–0.95) 0.03 (−0.03 to 0.08) 0.342
12 0.88 (0.81–0.94) 0.02 (−0.04 to 0.08) 0.534
e-GFR (ml/min) 0 89.8 (85.9–93.7)
3 85.1 (80.6–89.6) −4.7 (−9.0 to –0.3) 0.035
6 87.4 (82.9–91.9) −2.4 (−6.6 to 1.9) 0.271
12 88.5 (83.9–93.1) −1.3 (−5.7 to 3.1) 0.565
Uric acid (mg/dl) 0 5.3 (4.9–5.7)
3 4.5 (3.9–5.0) −0.8 (−1.4 to –0.2) 0.005
6 4.4 (3.9–4.8) −0.9 (−1.4 to –0.4) <0.001
12 4.3 (3.8–4.7) −1.0 (−1.5 to –0.5) <0.001
Cholesterol (mg/dl) 0 148.5 (139.7–157.3)
3 148.8 (135.9–161.7) 0.3 (−13.6 to 14.3) 0.964
6 139.3 (128.6–149.9) −9.2 (−21.1 to 2.7) 0.131
12 135.0 (123.7–146.2) −13.5 (−26.0 to –1.0) 0.034
LDL-cholesterol (mg/dl) 0 76.5 (69.5–83.6)
3 72.1 (60.8–83.4) −4.4 (−16.5 to 7.7) 0.477
6 68.4 (59.6–77.2) −8.1 (−18.0 to 1.8) 0.107
12 63.6 (54.7–72.5) −12.9 (−23.0 to –2.9) 0.012
HDL-cholesterol (mg/dl) 0 45.2 (42.2–48.1)
3 46.6 (43.1–50.1) 1.4 (−1.1 to 4.0) 0.253
6 45.6 (42.3–48.8) 0.4 (−1.8 to 2.6) 0.723
12 47.1 (43.8–50.4) 1.9 (−0.3 to 4.2) 0.092
Triglycerides (mg/dl) 0 162.4 (126.7–198.0)
3 204.2 (153.4–255.1) 41.9 (−11.2 to 95.0) 0.122
6 156.8 (115.0–198.7) −5.5 (−50.5 to 39.4) 0.809
12 134.0 (89.4–178.6) −28.3 (−75.8 to 19.1) 0.241
AST (U/L) 0 23.0 (18.1–28.0)
3 33.3 (24.6–42.0) 10.3 (1.2 to 19.4) 0.027
6 24.0 (17.0–31.1) 1.0 (−6.6 to 8.6) 0.794
12 22.4 (15.7–29.1) −0.6 (−7.8 to 6.6) 0.873
ALT (U/L) 0 31.3 (24.4–38.1)
3 40.8 (29.8–51.8) 9.6 (−1.2 to 20.4) 0.083
6 30.6 (21.4–39.8) −0.7 (−9.6 to 8.3) 0.881
12 31.8 (23.0–40.6) 0.5 (−8.0 to 9.0) 0.904
γ-GT (U/L) 0 38.0 (27.8–48.2)
3 46.8 (28.6–65.1) 8.9 (−9.7 to 27.5) 0.351
6 41.5 (26.4–56.7) 3.5 (−12.1 to 19.2) 0.657
12 31.8 (18.9–44.6) −6.2 (−19.6 to 7.2) 0.363

Data are presented as mean value; Confidence Interval (CI) is also indicated.

Notes: (a): statistical significance versus baseline values. Statistically significant p values (<0.05) are shown in bold.

Abbreviations: BMI: body mass index; AC: abdominal circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; HbA1c: glycated hemoglobin; HOMA index: fasting glucose × fasting insulin/405; e-GFR: estimated-glomerular filtration rate; LDL: low density lipoprotein; HDL: high density lipoprotein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ−GT: gamma-glutamyl transferase.

Table 4

Time trends of clinical parameters in patients treated with GLP1RA

Outcome Months Estimated mean values (95% CI) Estimated mean change from baseline (95% CI) p (a)
Weight (kg) 0 92.5 (89.6–95.3)
3 88.7 (85.7–91.7) −3.8 (−4.9 to –2.5) <0.001
6 87.7 (84.8–90.6) −4.8 (−5.8 to –3.7) <0.001
12 87.4 (84.4–90.3) −5.1 (−6.3 to –3.9) <0.001
BMI (kg/m2) 0 33.4 (32.3–34.4)
3 32.0 (30.9–33.1) −1.4 (−1.8 to –1.0) <0.001
6 31.6 (30.5–32.7) −1.8 (−2.2 to –1.4) <0.001
12 31.5 (30.4–32.5) −1.9 (−2.3 to –1.5) <0.001
AC (cm) 0 112.7 (110.4–115.1)
3 110.5 (107.8–113.1) −2.3 (−3.9 to –0.7) 0.005
6 110.3 (107.8–112.7) −2.4 (−3.8 to –1.1) <0.001
12 109.3 (106.8–111.9) −3.4 (−4.8 to –1.9) <0.001
SBP (mmHg) 0 130.0 (127.0–132.9)
3 128.4 (124.1–132.7) −1.5 (−6.1 to 3.1) 0.511
6 125.1 (121.6–128.7) −4.9 (−8.7 to −0.9) 0.016
12 127.7 (123.9–131.5) −2.3 (−6.4 to 1.9) 0.288
DBP (mmHg) 0 76.3 (74.5–78.0)
3 75.7 (73.1–78.3) −0.6 (−3.4 to −2.2) 0.676
6 73.6 (71.5–75.8) −2.7 (−5.0 to −0.2) 0.031
12 75.5 (73.2–77.8) −0.8 (−3.3 to 1.8) 0.568
HR (bpm) 0 72.7 (70.8–74.6)
3 74.9 (72.0–77.7) −2.1 (−0.8 to 5.1) 0.159
6 74.4 (71.9–76.9) 1.7 (−0.9 to 4.3) 0.200
12 75.4 (72.9–77.9) 2.7 (0.0–5.3) 0.048
Fasting glucose (mg/dl) 0 144.3 (137.2–151.3)
3 132.4 (123.3–141.4) −11.9 (−20.8 to −2.9) 0.009
6 125.4 (117.4–133.3) −18.9 (−26.7 to −11.1) <0.001
12 122.5 (113.8–131.2) −21.8 (−30.3 to −13.2) <0.001
HbA1c (mmol/mol) 0 57.7 (55.3–60.1)
3 48.3 (45.4–51.2) −9.3 (−11.8 to −6.8) <0.001
6 48.0 (45.3–50.6) −9.7 (−11.9 to −7.5) <0.001
12 48.9 (46.1–51.8) −8.7 (−11.1 to −6.3) <0.001
HOMA index 0 4.9 (4.1–5.7)
3 4.3 (2.8–5.9) −0.6 (−2.2 to 1.1) 0.508
6 4.4 (3.3–5.5) −0.5 (−1.7 to 0.7) 0.426
12 4.2 (3.2–5.2) −0.7 (−1.8 to 0.4) 0.206
Creatinine (mg/dl) 0 0.98 (0.92–1.03)
3 1.02 (0.96–1.08) 0.04 (0.00–0.09) 0.061
6 1.02 (0.96–1.08) 0.04 (0.00–0.08) 0.062
12 0.94 (0.88–1.00) −0.04 (−0.08–0.01) 0.109
e-GFR (ml/min) 0 79.2 (75.9–82.5)
3 78.6 (74.6–82.5) −0.6 (−3.9 to 2.6) 0.697
6 77.5 (73.8–81.3) −1.7 (−4.7 to 1.3) 0.269
12 81.6 (77.9–85.4) 2.4 (−0.7 to 5.4) 0.126
Uric acid (mg/dl) 0 5.4 (4.4–6.3)
3 5.3 (4.3–6.4) 0.0 (−1.4 to 1.4) 0.976
6 5.4 (4.3–6.5) 0.0 (−1.3 to 1.4) 0.969
12 5.4 (4.2–6.6) 0.0 (−1.4 to 1.4) 0.986
Cholesterol (mg/dl) 0 144.8 (138.3–151.3)
3 137.8 (128.6–147.1) −7.0 (−16.4 to 2.4) 0.147
6 139.6 (131.9–147.2) −5.2 (−13.1 to 2.6) 0.191
12 139.7 (131.6–147.9) −5.1 (−13.4 to 3.2) 0.232
LDL-cholesterol (mg/dl) 0 74.9 (69.4–80.4)
3 72.6 (64.6–80.6) −2.3 (−10.6 to 5.9) 0.581
6 69.9 (63.3–76.5) −5.0 (−11.9 to 1.9) 0.158
12 67.8 (60.8–74.8) −7.1 (−14.4 to 0.2) 0.058
HDL-cholesterol (mg/dl) 0 45.5 (43.2–47.7)
3 44.2 (41.5–47.0) −1.2 (−3.4 to 0.9) 0.272
6 46.8 (44.3–49.3) 1.3 (−0.4 to 3.1) 0.138
12 46.9 (44.3–49.4) 1.4 (−0.5 to 3.3) 0.141
Triglycerides (mg/dl) 0 136.9 (124.4–149.5)
3 133.6 (116.1–151.0) −3.4 (−20.2 to 13.4) 0.694
6 128.3 (113.7–142.9) −8.6 (−22.4 to 5.2) 0.220
12 136.6 (121.1–152.0) −0.4 (−15.1 to 14.4) 0.961
AST (U/L) 0 25.8 (23.7–27.8)
3 20.8 (17.4–24.2) −4.9 (−8.6 to −1.2) 0.009
6 19.9 (17.2–22.5) −5.9 (−8.9 to −2.9) <0.001
12 20.5 (17.8–23.3) −5.2 (−8.3 to −2.1) 0.001
ALT (U/L) 0 35.5 (31.7–39.3)
3 26.6 (20.2–33.0) −8.9 (−16.1 to −1.7) 0.015
6 24.0 (19.0–29.0) −11.5 (−17.5 to −5.6) <0.001
12 28.6 (23.5–33.7) −6.9 (−13.0 to −0.9) 0.025
γ-GT (U/L) 0 45.5 (38.3–52.7)
3 35.4 (23.9–46.9) −10.1 (−22.1 to 2.0) 0.101
6 35.5 (26.5–44.6) −9.9 (−19.7 to −0.1) 0.047
12 32.1 (22.8–41.3) −13.4 (−23.2 to −3.5) 0.008

Data are presented as mean value; Confidence Interval (CI) is also indicated.

Notes: (a): statistical significance versus baseline values. Statistically significant p values (<0.05) are shown in bold.

Abbreviations: BMI: body mass index; AC: abdominal circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; HbA1c: glycated hemoglobin; HOMA index: fasting glucose x fasting insulin/405; e-GFR: estimated-glomerular filtration rate; LDL: low density lipoprotein; HDL: high density lipoprotein; AST: aspartate aminotransferase; ALT: alanine aminotransferase; γ-GT: gamma-glutamyl transferase.

Both therapeutic regimens induced a transient reduction in SBP and DBP, although this was significant only at T3 (for SGLT2i) and T6 (for GLP1RA). The heart rate was affected only by GLP1RA, showing a significant increase, but not before 12 months of therapy (Table 4).

In both the subsets, the decrease in glucose levels compared to baseline was found to be highly significant already at T3, as well as after 6 and 12 months of therapy (Tables 3 and 4). Although the HbA1c parameter is not susceptible to sudden changes, it is interesting to note that the reduced levels induced by either class of drugs were significant compared to baseline already by the third month of therapy, and remained so up to T12 (Tables 3 and 4). As is well known, the absolute changes in both fasting blood glucose and HbA1c were proportional to their respective starting values.

The HOMA index underwent a significant and progressive decrease from T3 to T12, selectively as an effect of SGLT2i therapy (Table 3), while the GLP1RA-related reduction in the index values was negligible throughout the observation period (Table 4). As regards the renal function parameters, the mean changes in serum creatinine over the 12 months never reached statistical significance in the study population, regardless of the drug used. Also, eGFR values remained almost unchanged at each follow-up, in both GLP1RA (Table 4) and SGLT2i (Table 3) treated patients, with the exception of a transient reduction at T3 in the latter group (Table 3).

The two therapeutic regimens elicited divergent effects on uric acid and liver enzymes. SGLT2i caused an early, highly significant, and progressive decrease from T3 to T12 in serum uric acid levels, while the drug influence on AST, ALT, and γGT was mild and not significant, except for some evidence of an isolated increase in AST levels at the third month of follow-up (Table 3). On the contrary, GLP1RA did not modify uric acid levels at all, while inducing a notable reduction in both AST and ALT levels at each follow-up time, as well as reducing γGT levels after 6 and 12 months of therapy (Table 4). Finally, only SGLT2i demonstrated the ability to partially improve the lipid profile, significantly and selectively reducing serum levels of total and LDL cholesterol, but not of triglycerides, after 12 months of therapy (Table 3). Unfortunately, although of great clinical interest, it was not possible to assess the urine albumin-to-creatinine ratio (U-ACR) data during the follow-up in an adequate number of patients from either group, so the time trend analysis of this parameter could not be included in the study.

The changes in insulin therapy deserve special mention. In group 2, 12 patients treated with SA insulin regimens were informed that GLP1RA should replace insulin administration, because the reimbursement of this pharmacological association was not provided for by the Italian National Health System. It should be stressed that they had been taking SA insulin at doses ranging from 10 to 90 IU/day; in total, 372 IU of SA insulin were discontinued in this group already at T0. More gradual but still considerable changes in the use of LA insulin occurred in the same group. In fact, after 1 year of GLP1RA therapy, 9/23 (39.1%) insulin-treated patients had completely suspended any type of insulin and the others had significantly reduced overall daily insulin consumption, so that in total, 579 IU of insulin (SA + LA) were ultimately discontinued in group 2 patients. In group 1, SA insulin administration was suspended at T0 in 3 of 6 SA insulin-treated patients. During the follow-up period, the complete withdrawal of SA and/or LA insulin was achieved in 4/16 patients (25%) and, as a final result of SGLT2i therapy, 315 IU of insulin (SA + LA) were discontinued.

There were 13/167 (7.8%) cases of dropout in the entire population under study. We found that the therapy had been suspended prematurely in 4/113 (3.5%) patients in group 2 due to poor glyco-metabolic control; unexpectedly, none of the patients discontinued treatment due to gastro-intestinal effects of GLP1RA. Instead, 9/54 SGLT2i-treated patients (16.7%) stopped therapy earlier than expected due to: i) poor compliance to any therapy (1 patient); ii) worsening of renal function parameters (1 patient); iii) unsatisfactory glyco-metabolic control (6 patients, 2 of whom complained of increased appetite); and iv) lack of weight loss despite the achievement of a satisfactory glyco-metabolic control (1 patient).

4 Discussion

The advent of SGLT2i and GLP1RA has radically changed the guidelines of diabetes therapy [2,4]. Based on the results of the latest clinical trials, the new standards for T2D are no longer focused only on reducing HbA1c and minimizing hypoglycemic risk, but are aimed at reducing CVR and micro- and macrovascular adverse complications as well as global mortality of the diabetic patient. However, the RCTs inclusion criteria are known to be very selective and preclude the recruitment of “complex” patients, such as the elderly, patients with chronic kidney disease, or suffering from multiple comorbidities. Thus, when dealing with diabetic patients, real life studies are particularly interesting to evaluate treatment effectiveness in everyday life, thereby integrating RCTs, which are of course, irreplaceable. In the current study, we retrospectively analyzed data on a population of diabetic patients attending our Metabolic Disorders Outpatients Clinic in Bari, who had been treated under routine care with either a SGLT2i or a GLP1RA. First of all, the wide age range of the patients included in the study (38–83 years) indicates the extreme manageability of these two classes of drugs, that can be safely used even in older age groups. This characteristic, primarily attributable to the minimization of the hypoglycemic risk guaranteed by both categories, is one of the most important features of these pharmacological approaches. Patients were mostly males, with a slightly higher male to female ratio than in the epidemiological data in literature. The study population was heterogeneous also in terms of biometric parameters because despite the SGLT2i and GLP1RA ability to induce a significant and lasting decrease in weight, we did not use them exclusively in overweight or obese subjects. In line with this trend, the latest data provided by RCTs increasingly support the idea that the broad spectrum of biological and metabolic effects of these new antidiabetic agents makes them suitable for the treatment of normal weight patients as well. Thus, although our patients were mostly affected by abdominal obesity, the study also included subjects with normal weight, BMI, and AC values (minimum values: 52 kg, 21.6 kg/m2, and 74 cm, respectively). Similarly, our data highlight the fact that these drugs had been prescribed even in patients with normal fasting glycemia and HbA1c values (minimum values: 87 mg/dl and 30 mmol/mol, respectively), as is now suggested by the growing evidence emerging from RCTs. In these trials, both SGLT2i and GLP1RA were shown to provide such effective cardio- and nephron-protection that their use was finally recommended regardless of HbA1c values [4,8]. This was of particular importance in Italy, where this recommendation was issued by AIFA (Agenzia Italiana del Farmaco) only in July 2018; until then, GLP1RA could be reimbursed only within an HbA1c range of 53–75 mmol/mol. In particular, the REWIND study played a key role in modifying this prescription indication [9]. For the first time, this trial provided evidence of a GLP1RA-mediated “cardio-preventive effect,” demonstrating the efficacy of once-weekly dulaglutide in primary prevention, in terms of a reduced incidence of all CV outcomes [9]. Previously, both the LEADER and SUSTAIN-6 trials had shown superior results on CV outcomes of liraglutide and semaglutide versus placebo but most of the enrolled patients were undergoing secondary prevention [10,11].

Assessment of the baseline renal function of the study population highlighted, once again, a great inter-individual variability. In particular, since the safe use of most GLP1RA had been progressively extended up to eGFR values of 15 ml/min, patients with an impaired renal function could be treated with new antidiabetic drugs (minimum eGFR: 26 ml/min).

Routine determination of the pancreatic β-cell reserve has become essential in daily clinical practice for an optimal therapeutic management of diabetic patients. Inappropriate or overuse of exogenous insulin in dysmetabolic and high CVR patients is no longer acceptable and must be considered deleterious to their health and quality of life [12]. Accordingly, we usually perform a baseline assessment of the metabolic status of T2D patients, evaluating the main indirect indicators of insulin resistance and pancreatic function reserve, with the HOMA index and C-peptide, respectively. In particular, since C-peptide serum levels are not significantly affected by exogenous insulin administration, they are particularly relevant in the metabolic evaluation of patients on insulin therapy [13], in whom insulinemia cannot be used for the HOMA index calculation. Therefore, the C-peptide assay may be a simple test to identify subjects whose residual β-cell function is still sufficient to indicate the use of the new antidiabetic drugs, so as to delay the administration of exogenous insulin and progressively reduce or completely suspend unnecessary insulin therapy [12]. Notably, the evidence in our population of minimum C-peptide values within the normal range indicated a preserved β-cell ability to produce insulin in all these patients. Therefore, it seemed rational to significantly reduce the total amount of insulin globally administered to 39 of the 167 patients included in this study.

Our group had already shown that patients with metabolic syndrome have low serum levels of vitamin D [14,15]; the diabetic patients included in this study exhibited similarly low levels of the vitamin.

The comparison of the patients’ baseline characteristics after their subdivision into group 1 and group 2 (SGLT2i- and GLP1RA-treated patients, respectively) highlighted that patients belonging to the GLP1RA group had higher baseline values of BMI and AC. In this regard, a decreased appetite is a “useful side effect” that selectively characterizes GLP1RA treatment, due to the slowing of gastric emptying and an increased sense of satiety mediated by a central effect [16,17]. Conversely, despite the calorie loss/energy deficit (300 kcal/day) induced by SGLT2i therapy, this pharmacological approach is not always associated with the expected weight loss, likely as a result of “compensatory hyperphagia” and changes in energy expenditure aimed at attenuating this energy imbalance [18]. These characteristics likely led to a preference for GLP1RA when achieving a reduction in BW was a key treatment goal for the patient.

On the other hand, group 1 patients exhibited higher mean baseline values of fasting glucose and HbA1c as compared to group 2, which appears reasonable if we consider that the increased renal elimination of glucose induced by this drug class is an effective and rapid mechanism for obtaining adequate glycemic compensation. At the same time, poor glyco-metabolic control did not allow the complete discontinuation of SA insulin therapy at T0 in these patients, so making them ineligible for GLP1RA prescription, in accordance with Italian standards. These aspects contributed to influence the choice of SGLT2i that, in line with the literature data, were also the preferred therapy for those of our diabetic patients suffering from dilated cardiomyopathy.

Finally, the difference between the 2 groups as regards renal function parameters was not surprising, in view of the Italian SGLT2i prescribing limits when the study started. In fact, in Italy, with baseline eGFR values below 60 ml/min, patients were not eligible for treatment with SGLT2i until June 2020, so eGFR was a discriminating factor in the choice of therapy to be prescribed to our patients before that time. The current situation is different. There is no doubt that SGLT2i required a globally preserved renal function in order to ensure adequate glycemic control, due to their peculiar mechanism of action and glycosuric effect. Nevertheless, the EMPA-REG OUTCOME (for empagliflozin) [19], CANVAS (for canagliflozin) [20], and DECLARE-TIMI58 (dapagliflozin) [21] trials highlighted such significant benefits in terms of composite renal outcomes that nephrologists became increasingly prone to make SGLT2i their first-choice drugs in diabetic patients with evidence of initial kidney damage (microalbuminuria or renal hyperfiltration). More recently, the CREDENCE trial [22] and the DAPA-CKD [23], specifically designed to evaluate canagliflozin and dapagliflozin effects on renal outcomes, respectively, included patients with wide ranges of albuminuria (20–5,000 mg/day) and eGFR (25–90 ml/min). The results of these trials contributed to extend the prescription of these molecules to patients with eGFR values as low as 30 ml/min.

The next step was to analyze the effects of SGLTi or GLP1RA treatment in our real life setting, over a 1 year follow-up period. Our data fully confirmed the main results of RCTs. What is immediately evident from the time trend of the variables of our interest is the significant action of both therapeutic approaches on biometric parameters, with GLP1RA effects being already significant by the third month. Furthermore, an improvement in the patients’ body composition and visceral fat mass, although not directly assessed, can be presumed on the basis of the significant AC reduction induced by both drugs (mean decrease at T12 of 2.7 and 3.4 cm in groups 1 and 2, respectively).

The increase in heart rate as a result of GLP1RA administration was expected, but it did not lead to drug discontinuation in any patient and was found to be significant only after 1 year of therapy.

In line with RCTs, the SGLT2i- and GLP1RA-induced improvement in glycemic levels and glycated Hb values were very satisfactory, despite the complexity and heterogeneity of our study population. These positive effects were already significant after 3 months of treatment and persisted up to T12. The differences observed between the 2 groups were mostly attributable to the different baseline metabolic conditions of patients.

The significant decrease in HOMA index observed over time as a result of SGLT2i therapy is in line with previous in vitro studies, showing the normalization of insulin sensitivity induced by phlorizin in animal models [24]. Moreover, it should be considered that SGLT2i-induced glycosuria lowers plasma glucose and insulin levels and raises fasting and post-meal glucagon concentrations. This leads to changes in energy substrate use, fostering the utilization of lipids for energy production and the release of non-esterified fatty acids, which are converted to ketone bodies in the liver through mitochondrial beta oxidation and ketogenesis, resulting in a metabolic condition resembling a prolonged fast [25]. Multiple mechanisms might be involved in this insulin-sensitivity improvement, namely an inhibition of glucose toxicity, increase in adiponectin levels, reduction in visceral fat and lipotoxicity-induced insulin resistance [26,27], the promotion of browning adipose tissue and fat utilization by M2 macrophages [28], and attenuation of inflammatory responses [29,30,31].

The remarkable renal safety of the two therapeutic approaches was suggested by the substantial stability of the renal parameters throughout the study period. Of note, the eGFR value reduction observed in SGLT2i-treated patients, which reached statistical significance only at T3, demanded modification of the therapeutic regimen only in 1 patient, due to his lack of compliance in guaranteeing an adequate water intake.

Finally, the analysis of the last 8 variables evaluated in this study revealed important differences between the 2 classes of antidiabetic drugs. In fact, only SGLT2i were demonstrated to significantly decrease uric acid levels as well as to improve the lipid profile, selectively reducing total and LDL cholesterol serum levels. In light of the well-known ability of these parameters to affect the body’s CVR, a potential contribution of these changes to the SGLT2i-mediated cardioprotection cannot be excluded. Conversely, our finding of a significant decrease in AST, ALT, and γGT levels in GLP1RA-treated patients further supports the beneficial effect of this class on hepatic steatosis [32,33]. In regard to this aspect, it should be borne in mind that important clinical trials are underway to explore the possibility of using GLP1RA in the treatment of Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH), even in non-diabetic patients [34,35].

The main limitation of this study is ascribable to the prescription limitations of the two classes of drugs existing in Italy in the period analyzed. This inevitably had significant effects on the choice of the drug to be used, regardless of the clinical characteristics of the patients (i.e., non-reimbursement of GLP1RA in association with SA insulin or ineligibility for SGLT2i therapy in patients with eGFR <60 ml/min). These aspects faithfully reflect the problems to be solved in daily clinical practice and the consequent need to adapt. In fact, it is not always possible to prescribe the “best existing therapy” and is still necessary to prescribe the best therapy available for “that” particular patient. Another limitation, also in this case linked to the real-life nature of the study, lies in the heterogeneity of the population analyzed and in the numerical difference between the two groups of patients. Finally, the ability of both SGLT2i and GLP1RA to induce an improvement in body composition in treated patents remains a speculation in this study, but our group is currently conducting a more accurate evaluation of this hypothesis by means of specific investigations.

5 Conclusion

Our real-life data clearly confirm the main results obtained with RCTs, which instead recruit highly selected patients to verify the study outcomes. The safety and effectiveness of both SGLT2i and GLP1RA are demonstrated even in diabetic patients with heterogeneous characteristics commonly treated in everyday clinical practice. The use of these drugs is thus strongly recommended, from the perspective of no longer treating just “hyperglycemia” but a complex disease in which the most important goal should be the prevention of CV complications and reduction in overall mortality. For the same reason, the unnecessary use of insulin in patients with a preserved β-cell function should be discouraged, especially when a condition of insulin resistance is present.

Acknowledgments

We are grateful to Mary V.C. Pragnell, B.A. for language revision, and to Alessandra Delvino and Lavinia Capogna for their contribution in data collection.

  1. Funding information: No funding or sponsorship was received for this study.

  2. Author contributions: G.P.: conception and design of the work, interpretation of data, and drafting of the work; A.V.: acquisition and interpretation of data; S.V., M.F., and A.B.: acquisition of data. V.T. and G.L.: interpretation of data and revision of the work; C.T.: contribution to the drafting and revision of the work and interpretation of data; V.S.: statistical analysis of data; CS: revision of the work. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that they have no actual or potential conflict of interest in relation to this work.

  4. Data availability statement: The datasets analysed during the current study are available from the corresponding author on reasonable request.

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Received: 2022-01-19
Accepted: 2022-05-11
Published Online: 2022-07-07

© 2022 Giuseppina Piazzolla et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2022-0504
Keywords for this article
SGLT2i; GLP1RA; Type 2 diabetes; C-peptide; insulin therapy
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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