Journal of Clinical Medicine

Editorial

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3 pages, 193 KiB

Open AccessEditorial

Clinical Research on Type 2 Diabetes: A Promising and Multifaceted Landscape

by Fernando Gómez-Peralta and Cristina Abreu

J. Clin. Med. 2022, 11(20), 6007; https://doi.org/10.3390/jcm11206007 - 12 Oct 2022

Cited by 2 | Viewed by 1420

Abstract

Type 2 diabetes constitutes an imposing epidemiological, economic, and scientific global challenge [...] Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

Research

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18 pages, 2660 KiB

Open AccessArticle

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms

by Dilvin Semo, Julius Obergassel, Marc Dorenkamp, Pia Hemling, Jasmin Strutz, Ursula Hiden, Nicolle Müller, Ulrich Alfons Müller, Sajan Ahmad Zulfikar, Rinesh Godfrey and Johannes Waltenberger

J. Clin. Med. 2023, 12(4), 1356; https://doi.org/10.3390/jcm12041356 - 8 Feb 2023

Cited by 12 | Viewed by 2995

Abstract

Purpose: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than [...] Read more.

Purpose: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. Methods: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H₂DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. Results: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. Conclusions: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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13 pages, 1277 KiB

Open AccessArticle

Hospital Readmission Risk and Risk Factors of People with a Primary or Secondary Discharge Diagnosis of Diabetes

by Daniel J. Rubin, Naveen Maliakkal, Huaqing Zhao and Eli E. Miller

J. Clin. Med. 2023, 12(4), 1274; https://doi.org/10.3390/jcm12041274 - 6 Feb 2023

Cited by 3 | Viewed by 3294

Abstract

Hospital readmission among people with diabetes is common and costly. A better understanding of the differences between people requiring hospitalization primarily for diabetes (primary discharge diagnosis, 1°DCDx) or another condition (secondary discharge diagnosis, 2°DCDx) may translate into more effective ways to prevent readmissions. [...] Read more.

Hospital readmission among people with diabetes is common and costly. A better understanding of the differences between people requiring hospitalization primarily for diabetes (primary discharge diagnosis, 1°DCDx) or another condition (secondary discharge diagnosis, 2°DCDx) may translate into more effective ways to prevent readmissions. This retrospective cohort study compared readmission risk and risk factors between 8054 hospitalized adults with a 1°DCDx or 2°DCDx. The primary outcome was all-cause hospital readmission within 30 days of discharge. The readmission rate was higher in patients with a 1°DCDx than in patients with a 2°DCDx (22.2% vs. 16.2%, p < 0.01). Several independent risk factors for readmission were common to both groups including outpatient follow up, length of stay, employment status, anemia, and lack of insurance. C-statistics for the multivariable models of readmission were not significantly different (0.837 vs. 0.822, p = 0.15). Readmission risk of people with a 1°DCDx was higher than that of people with a 2°DCDx of diabetes. Some risk factors were shared between the two groups, while others were unique. Inpatient diabetes consultation may be more effective at lowering readmission risk among people with a 1°DCDx. These models may perform well to predict readmission risk. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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12 pages, 298 KiB

Open AccessArticle

by Ana Lopez-de-Andres, Rodrigo Jimenez-Garcia, Javier de Miguel-Díez, Valentin Hernández-Barrera, Jose Luis del Barrio, David Carabantes-Alarcon, Jose J. Zamorano-Leon and Concepcion Noriega

J. Clin. Med. 2022, 11(21), 6260; https://doi.org/10.3390/jcm11216260 - 24 Oct 2022

Cited by 3 | Viewed by 1567

Abstract

(1) Background: Recent reports suggest a decrease in the prevalence of depression among people with diabetes and important sex-differences in the association between these conditions, however data from Spain is sparse. We aim to assess trends in the prevalence of depression and in-hospital [...] Read more.

(1) Background: Recent reports suggest a decrease in the prevalence of depression among people with diabetes and important sex-differences in the association between these conditions, however data from Spain is sparse. We aim to assess trends in the prevalence of depression and in-hospital outcomes among patients with type 2 diabetes (T2DM) hospitalized (2011–2020) identifying sex-differences. (2) Methods: Using the Spanish national hospital discharge database we analysed the prevalence of depression globally, by sex, and according to the conditions included in the Charlson comorbidity index (CCI). We tested factors associated with the presence of depression and with in-hospital mortality (IHM). Time trends in the prevalence of depression and variables independently associated with IHM were analyzed using multivariable logistic regression. (3) Results: From 2011 to 2020, we identified 5,971,917 hospitalizations of patients with T2DM (5.7% involved depression). The prevalence of depression decreased significantly between 2011 and 2020. The adjusted prevalence of depression was 3.32-fold higher in women than in men (OR 3.32; 95%CI 3.3–3.35). The highest prevalence of depression among men and women with T2DM was found among those who also had a diagnosis of obesity, liver disease, and COPD. Older age, higher CCI, pneumonia, and having been hospitalized in 2020 increased the risk of IHM in patients with T2DM and depression. Obesity was a protective factor for IHM in both sexes, with no differences detected for IHM between men and women. Among patients hospitalized with T2DM, concomitant depression was associated with lower IHM than among patients without depression (depression paradox). (4) Conclusions: The prevalence of depression decreased over time in both sexes. The prevalence of depression was over three-fold higher in women. Female sex and depression were not associated with higher IHM. Based on our results we recommend that clinicians screen regularly for depression in patients with T2DM, particularly women, younger patients, and those with multiple comorbidities. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

14 pages, 1322 KiB

Open AccessArticle

Once-Weekly Semaglutide Use in Patients with Type 2 Diabetes: Results from the SURE Spain Multicentre, Prospective, Observational Study

by Virginia Bellido, Cristina Abreu Padín, Andrei-Mircea Catarig, Alice Clark, Sofía Barreto Pittol and Elias Delgado

J. Clin. Med. 2022, 11(17), 4938; https://doi.org/10.3390/jcm11174938 - 23 Aug 2022

Cited by 13 | Viewed by 4747

Abstract

Type 2 diabetes (T2D) is a complex disease for which an individualised treatment approach is recommended. Once-weekly (OW) semaglutide is a glucagon-like peptide-1 receptor agonist approved for the treatment of insufficiently controlled T2D. The aim of this study was to investigate the use [...] Read more.

Type 2 diabetes (T2D) is a complex disease for which an individualised treatment approach is recommended. Once-weekly (OW) semaglutide is a glucagon-like peptide-1 receptor agonist approved for the treatment of insufficiently controlled T2D. The aim of this study was to investigate the use of OW semaglutide in adults with T2D in a real-world context. SURE Spain, from the 10-country SURE programme, was a prospective, multicentre, open-label, observational study, approximately 30 weeks in duration. Adults with T2D and ≥1 documented HbA_1c value ≤12 weeks before semaglutide initiation were enrolled. Change in HbA_1c from baseline to end of study (EOS) was the primary endpoint, with change in body weight (BW), waist circumference, and patient-reported outcomes as secondary endpoints. Of the 227 patients initiating semaglutide, 196 (86.3%) completed the study on-treatment with semaglutide. The estimated mean changes in HbA_1c and body weight between baseline and EOS were −1.3%-points (95% confidence interval (CI) −1.51;−1.18%-points) and −5.7 kg (95% CI −6.36;−4.98 kg). No new safety concerns were identified. Therefore, in routine clinical practice in Spain, OW semaglutide was shown to be associated with statistically significant and clinically relevant reductions in HbA_1c and BW in adults with T2D. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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14 pages, 1891 KiB

Open AccessArticle

Perceptions about the Management of Patients with DM2 and COVID-19 in the Hospital Care Setting

by Ricardo Gómez-Huelgas and Fernando Gómez-Peralta

J. Clin. Med. 2022, 11(15), 4507; https://doi.org/10.3390/jcm11154507 - 2 Aug 2022

Cited by 1 | Viewed by 1492

Abstract

Background: COVID-19 entails a higher rate of complications in subjects with type 2 diabetes mellitus (T2DM). Likewise, COVID-19 infection can cause alterations in glucose metabolism that may lead to worse control. The aim of the study was to analyse the perceptions of a [...] Read more.

Background: COVID-19 entails a higher rate of complications in subjects with type 2 diabetes mellitus (T2DM). Likewise, COVID-19 infection can cause alterations in glucose metabolism that may lead to worse control. The aim of the study was to analyse the perceptions of a large group of Spanish physicians about the relationship between COVID-19 and T2DM, as well as the management, monitoring, and treatment of both diseases. Methods: A cross-sectional multicenter national project was conducted based on a survey which included opinion, attitude, and behavior (OAB) questions. Physicians specialised in internal medicine or endocrinology, whose usual clinical practices included the management of T2DM, responded to the survey between March and April 2021. Results: A total of 112 participants responded to the survey, from which 64.3% believed that COVID-19 entailed a higher risk of glycaemic decompensation irrespective of the presence of previously known T2DM. Obesity was considered a risk factor for poor control of T2DM by 57.7% and for a worse course of COVID-19 by 61.0%. Treatment intensification in not-on-target patients was considered by 57.1% in the presence of COVID-19 and by 73.2% in the absence of COVID-19. No participants considered the suspension of dipeptidyl peptidase 4 inhibitors (DPP-4i) in ambulatory patients, 85.7% declared that this therapeutic approach in hospitalized patients should be kept, and 88.4% supported the option of maintaining DPP-4i when corticosteroids were prescribed. Conclusion: The physicians involved in the management of T2DM and COVID-19 are aware of the bidirectional relationship between both conditions. However, the monitoring and therapeutic management of patients with T2DM who are infected by SARS-CoV-2 needs improvement through the following of the current recommendations and available evidence. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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14 pages, 1569 KiB

Open AccessArticle

Comparing Multiple Linear Regression and Machine Learning in Predicting Diabetic Urine Albumin–Creatinine Ratio in a 4-Year Follow-Up Study

by Li-Ying Huang, Fang-Yu Chen, Mao-Jhen Jhou, Chun-Heng Kuo, Chung-Ze Wu, Chieh-Hua Lu, Yen-Lin Chen, Dee Pei, Yu-Fang Cheng and Chi-Jie Lu

J. Clin. Med. 2022, 11(13), 3661; https://doi.org/10.3390/jcm11133661 - 24 Jun 2022

Cited by 10 | Viewed by 2735

Abstract

The urine albumin–creatinine ratio (uACR) is a warning for the deterioration of renal function in type 2 diabetes (T2D). The early detection of ACR has become an important issue. Multiple linear regression (MLR) has traditionally been used to explore the relationships between risk [...] Read more.

The urine albumin–creatinine ratio (uACR) is a warning for the deterioration of renal function in type 2 diabetes (T2D). The early detection of ACR has become an important issue. Multiple linear regression (MLR) has traditionally been used to explore the relationships between risk factors and endpoints. Recently, machine learning (ML) methods have been widely applied in medicine. In the present study, four ML methods were used to predict the uACR in a T2D cohort. We hypothesized that (1) ML outperforms traditional MLR and (2) different ranks of the importance of the risk factors will be obtained. A total of 1147 patients with T2D were followed up for four years. MLR, classification and regression tree, random forest, stochastic gradient boosting, and eXtreme gradient boosting methods were used. Our findings show that the prediction errors of the ML methods are smaller than those of MLR, which indicates that ML is more accurate. The first six most important factors were baseline creatinine level, systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose. In conclusion, ML might be more accurate in predicting uACR in a T2D cohort than the traditional MLR, and the baseline creatinine level is the most important predictor, which is followed by systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose in Chinese patients with T2D. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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12 pages, 314 KiB

Open AccessArticle

Simple Predictors for Cardiac Fibrosis in Patients with Type 2 Diabetes Mellitus: The Role of Circulating Biomarkers and Pulse Wave Velocity

by Ekaterina B. Luneva, Anastasia A. Vasileva, Elena V. Karelkina, Maria A. Boyarinova, Evgeny N. Mikhaylov, Anton V. Ryzhkov, Alina Y. Babenko, Alexandra O. Konradi and Olga M. Moiseeva

J. Clin. Med. 2022, 11(10), 2843; https://doi.org/10.3390/jcm11102843 - 18 May 2022

Cited by 6 | Viewed by 2472

Abstract

Cardiac fibrosis is the basis of structural and functional disorders in patients with diabetes mellitus (T2DM). A wide range of laboratory and instrumental methods is used for its prediction. The study aimed to identify simple predictors of cardiac fibrosis in patients with T2DM [...] Read more.

Cardiac fibrosis is the basis of structural and functional disorders in patients with diabetes mellitus (T2DM). A wide range of laboratory and instrumental methods is used for its prediction. The study aimed to identify simple predictors of cardiac fibrosis in patients with T2DM based on the analysis of circulating fibrosis biomarkers and arterial stiffness. The study included patients with T2DM (n = 37) and cardiovascular risk factors (RF, n = 27) who underwent ECHO, cardiac magnetic resonance imaging (MRI), pulse wave analysis (PWV), reactive hyperemia (RH), peripheral arterial tonometry, carotid ultrasonography, and assessment of serum fibrosis biomarkers. As a control group, 15 healthy subjects were examined. Left ventricular concentric hypertrophy was accompanied by an increased serum galectin-3 level in T2DM patients. There was a relationship between the PICP and HbA1c levels in both main groups (R2 = 0.309; p = 0.014). A negative correlation between PICP level and the global longitudinal strain (GLS) was found (r = −0.467; p = 0.004). The RH index had a negative correlation with the duration of diabetes (r = −0.356; p = 0.03), the carotid-femoral PWV (r = −0.371; p = 0.024), and the carotid intima-media thickness (r = −0.622; p < 0.001). The late gadolinium-enhanced (LGE) cardiac MRI was detected in 22 (59.5%) T2DM and in 4 (14.85%) RF patients. Diabetes, its baseline treatment with metformin, HbA1c and serum TIMP-1 levels, and left ventricle hypertrophy had moderate positive correlations with LGE findings (p < 0.05). Using the multivariate regression analysis, increased TIMP-1 level was identified as an independent factor associated with cardiac fibrosis. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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16 pages, 2961 KiB

Open AccessArticle

Sex Differences in Cardiovascular Prevention in Type 2: Diabetes in a Real-World Practice Database

by Anna Ramírez-Morros, Josep Franch-Nadal, Jordi Real, Mònica Gratacòs and Didac Mauricio

J. Clin. Med. 2022, 11(8), 2196; https://doi.org/10.3390/jcm11082196 - 14 Apr 2022

Cited by 9 | Viewed by 2160 | Correction

Abstract

Women with type 2 diabetes mellitus (T2DM) have a 40% excess risk of cardiovascular diseases (CVD) compared to men due to the interaction between sex and gender factors in the development, risk, and outcomes of the disease. Our aim was to assess differences [...] Read more.

Women with type 2 diabetes mellitus (T2DM) have a 40% excess risk of cardiovascular diseases (CVD) compared to men due to the interaction between sex and gender factors in the development, risk, and outcomes of the disease. Our aim was to assess differences between women and men with T2DM in the management and degree of control of cardiovascular risk factors (CVRF). This was a matched cross-sectional study including 140,906 T2DM subjects without previous CVD and 39,186 T2DM subjects with prior CVD obtained from the System for the Development of Research in Primary Care (SIDIAP) database. The absolute and relative differences between means or proportions were calculated to assess sex differences. T2DM women without previous CVD showed higher levels of total cholesterol (12.13 mg/dL (0.31 mmol/L); 95% CI = 11.9–12.4) and low-density lipoprotein cholesterol (LDL-c; 5.50 mg/dL (0.14 mmol/L); 95% CI = 5.3–5.7) than men. The recommended LDL-c target was less frequently achieved by women as it was the simultaneous control of different CVRF. In secondary prevention, women showed higher levels of total cholesterol (16.89 mg/dL (0.44 mmol/L); 95% CI = 16.5–17.3), higher levels of LDL-c (8.42 mg/dL (0.22 mmol/L); 95% CI = 8.1–8.8), and higher levels of triglycerides (11.34 mg/dL (0.13 mmol/L); 95% CI = 10.3–12.4) despite similar rates of statin prescription. Recommended targets were less often achieved by women, especially LDL-c < 100 mg/dL (2.59 mmol/L). The composite control was 22% less frequent in women than men. In conclusion, there were substantial sex differences in CVRF management of people with diabetes, with women less likely than men to be on LDL-c target, mainly those in secondary prevention. This could be related to the treatment gap between genders. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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12 pages, 618 KiB

Open AccessArticle

Diabetes Does Not Increase the Risk of Hospitalization Due to COVID-19 in Patients Aged 50 Years or Older in Primary Care—APHOSDIAB—COVID-19 Multicenter Study

by Domingo Orozco-Beltrán, Juan Francisco Merino-Torres, Antonio Pérez, Ana M. Cebrián-Cuenca, Ignacio Párraga-Martínez, Luis Ávila-Lachica, Gemma Rojo-Martínez, Francisco J. Pomares-Gómez, Fernando Álvarez-Guisasola, Manuel Sánchez-Molla, Felix Gutiérrez, Francisco J. Ortega, Manel Mata-Cases, Enrique Carretero-Anibarro, Josep Maria Vilaseca and Jose A. Quesada

J. Clin. Med. 2022, 11(8), 2092; https://doi.org/10.3390/jcm11082092 - 8 Apr 2022

Cited by 3 | Viewed by 2344

Abstract

The purpose of this study was to identify clinical, analytical, and sociodemographic variables associated with the need for hospital admission in people over 50 years infected with SARS-CoV-2 and to assess whether diabetes mellitus conditions the risk of hospitalization. A multicenter case-control study [...] Read more.

The purpose of this study was to identify clinical, analytical, and sociodemographic variables associated with the need for hospital admission in people over 50 years infected with SARS-CoV-2 and to assess whether diabetes mellitus conditions the risk of hospitalization. A multicenter case-control study analyzing electronic medical records in patients with COVID-19 from 1 March 2020 to 30 April 2021 was conducted. We included 790 patients: 295 cases admitted to the hospital and 495 controls. Under half (n = 386, 48.8%) were women, and 8.5% were active smokers. The main comorbidities were hypertension (50.5%), dyslipidemia, obesity, and diabetes (37.5%). Multivariable logistic regression showed that hospital admission was associated with age above 65 years (OR from 2.45 to 3.89, ascending with age group); male sex (OR 2.15, 95% CI 1.47–3.15), fever (OR 4.31, 95% CI 2.87–6.47), cough (OR 1.89, 95% CI 1.28–2.80), asthenia/malaise (OR 2.04, 95% CI 1.38–3.03), dyspnea (4.69, 95% CI 3.00–7.33), confusion (OR 8.87, 95% CI 1.68–46.78), and a history of hypertension (OR 1.61, 95% CI 1.08–2.41) or immunosuppression (OR 4.97, 95% CI 1.45–17.09). Diabetes was not associated with increased risk of hospital admission (OR 1.18, 95% CI 0.80–1.72; p = 0.38). Diabetes did not increase the risk of hospital admission in people over 50 years old, but advanced age, male sex, fever, cough, asthenia, dyspnea/confusion, and hypertension or immunosuppression did. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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9 pages, 605 KiB

Open AccessArticle

Measuring of Advanced Glycation End Products in Acute Stroke Care: Skin Autofluorescence as a Predictor of Ischemic Stroke Outcome in Patients with Diabetes Mellitus

by Alexandra Filipov, Heike Fuchshuber, Josephine Kraus, Anne D. Ebert, Vesile Sandikci and Angelika Alonso

J. Clin. Med. 2022, 11(6), 1625; https://doi.org/10.3390/jcm11061625 - 15 Mar 2022

Cited by 4 | Viewed by 2037

Abstract

Background: Patients with diabetes mellitus (DM) are known to show poor recovery after stroke. This specific burden might be due to acute and chronic hyperglycemic effects. Meanwhile, the underlying mechanisms are a cause of discussion, and the best measure to predict the outcome [...] Read more.

Background: Patients with diabetes mellitus (DM) are known to show poor recovery after stroke. This specific burden might be due to acute and chronic hyperglycemic effects. Meanwhile, the underlying mechanisms are a cause of discussion, and the best measure to predict the outcome is unclear. Skin autofluorescence (SAF) reflects the in-patient load of so-called advanced glycation end products (AGEs) beyond HbA1c and represents a valid and quickly accessible marker of chronic hyperglycemia. We investigated the predictive potential of SAF in comparison to HbA1c and acute hyperglycemia on the functional outcome at 90 days after ischemic stroke in a cohort of patients with DM. Methods: We prospectively included 113 patients with DM type 2 hospitalized for acute ischemic stroke. SAF was measured on each patient’s forearm by a mobile AGE-Reader mu© in arbitrary units. HbA1c and the area under the curve (AUC) of the blood sugar profile after admission were assessed. Functional outcome was assessed via phone interview after 90 days. A poor outcome was defined as a deterioration to a modified Rankin Scale score ≥ 3. A good outcome was defined as a modified Rankin Scale score < 3 or as no deterioration from premorbid level. Results: Patients with a poor outcome presented with higher values of SAF (mean 3.38 (SD 0.55)) than patients with a good outcome (mean 3.13 (SD 0.61), p = 0.023), but did not differ in HbA1c and acute glycemia. In logistic regression analysis, age (p = 0.021, OR 1.24 [1.12–1.37]) and SAF (p = 0.021, OR 2.74 [1.16–6.46]) significantly predicted a poor outcome, whereas HbA1c and acute glycemia did not. Patients with a poor 90-day outcome and higher SAF experienced more infections (4.2% vs. 33.3% (p < 0.01)) and other various in-hospital complications (21.0% vs. 66.7% (p < 0.01)) than patients with a good outcome and lower SAF levels. Conclusions: SAF offers an insight into glycemic memory and appears to be a significant predictor of poor stroke outcomes in patients with DM exceeding HbA1c and acute glycemia. Measuring SAF could be useful to identify specifically vulnerable patients at high risk of complications and poor outcomes. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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19 pages, 1721 KiB

Open AccessArticle

Development of a Complex Intervention for Effective Management of Type 2 Diabetes in a Developing Country

by Tigestu Alemu Desse, Kevin Mc Namara, Helen Yifter and Elizabeth Manias

J. Clin. Med. 2022, 11(5), 1149; https://doi.org/10.3390/jcm11051149 - 22 Feb 2022

Cited by 4 | Viewed by 4455

Abstract

There has been little focus on designing tailored diabetes management strategies in developing countries. The aim of this study is to develop a theory-driven, tailored and context-specific complex intervention for the effective management of type 2 diabetes at a tertiary care setting of [...] Read more.

There has been little focus on designing tailored diabetes management strategies in developing countries. The aim of this study is to develop a theory-driven, tailored and context-specific complex intervention for the effective management of type 2 diabetes at a tertiary care setting of a developing country. We conducted interviews and focus groups with patients, health professionals, and policymakers and undertook thematic analysis to identify gaps in diabetes management. The results of our previously completed systematic review informed data collection. We used the United Kingdom Medical Research Council framework to guide the development of the intervention. Results comprised 48 interviews, two focus groups with 11 participants and three co-design panels with 24 participants. We identified a lack of structured type 2 diabetes education, counselling, and collaborative care of type 2 diabetes. Through triangulation of the evidence obtained from data collection, we developed an intervention called VICKY (patient-centred collaborative care and structured diabetes education and counselling) for effective management of type 2 diabetes. VICKY comprised five components: (1) patient-centred collaborative care; (2) referral system for patients across transitions of care between different health professionals of the diabetes care team; (3) tools for the provision of collaborative care and documentation of care; (4) diabetes education and counselling by trained diabetes educators; and (5) contextualised diabetes education curriculum, educational materials, and documentation tools for diabetes education and counselling. Implementation of the intervention may help to promote evidence-based, patient-centred, and contextualised diabetes care for improved patient outcomes in a developing country. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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23 pages, 2050 KiB

Open AccessArticle

Machine Learning for Screening Microvascular Complications in Type 2 Diabetic Patients Using Demographic, Clinical, and Laboratory Profiles

by Mamunur Rashid, Mohanad Alkhodari, Abdul Mukit, Khawza Iftekhar Uddin Ahmed, Raqibul Mostafa, Sharmin Parveen and Ahsan H. Khandoker

J. Clin. Med. 2022, 11(4), 903; https://doi.org/10.3390/jcm11040903 - 9 Feb 2022

Cited by 12 | Viewed by 3042

Abstract

Microvascular complications are one of the key causes of mortality among type 2 diabetic patients. This study was sought to investigate the use of a novel machine learning approach for predicting these complications using only the patient demographic, clinical, and laboratory profiles. A [...] Read more.

Microvascular complications are one of the key causes of mortality among type 2 diabetic patients. This study was sought to investigate the use of a novel machine learning approach for predicting these complications using only the patient demographic, clinical, and laboratory profiles. A total of 96 Bangladeshi participants with type 2 diabetes were recruited during their routine hospital visits. All patient profiles were assessed by using a chi-squared (χ²) test to statistically determine the most important markers in predicting three microvascular complications: cardiac autonomic neuropathy (CAN), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (RET). A machine learning approach based on logistic regression, random forest (RF), and support vector machine (SVM) algorithms was then developed to ensure automated clinical testing for microvascular complications in diabetic patients. The highest prediction accuracies were obtained by RF using diastolic blood pressure, albumin–creatinine ratio, and gender for CAN testing (98.67%); microalbuminuria, smoking history, and hemoglobin A1C for DPN testing (67.78%); and hemoglobin A1C, microalbuminuria, and smoking history for RET testing (84.38%). This study suggests machine learning as a promising automated tool for predicting microvascular complications in diabetic patients using their profiles, which could help prevent those patients from further microvascular complications leading to early death. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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12 pages, 293 KiB

Open AccessArticle

Fasting Glucose Variability as a Risk Indicator for End-Stage Kidney Disease in Patients with Diabetes: A Nationwide Population-Based Study

by Da Young Lee, Jaeyoung Kim, Sanghyun Park, So Young Park, Ji Hee Yu, Ji A. Seo, Nam Hoon Kim, Hye Jin Yoo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Kyungdo Han and Nan Hee Kim

J. Clin. Med. 2021, 10(24), 5948; https://doi.org/10.3390/jcm10245948 - 18 Dec 2021

Cited by 3 | Viewed by 2663

Abstract

Given the fact that diabetes remains a leading cause of end-stage kidney disease (ESKD), multi-aspect approaches anticipating the risk for ESKD and timely correction are crucial. We investigated whether fasting glucose variability (FGV) could anticipate the development of ESKD and identify the population [...] Read more.

Given the fact that diabetes remains a leading cause of end-stage kidney disease (ESKD), multi-aspect approaches anticipating the risk for ESKD and timely correction are crucial. We investigated whether fasting glucose variability (FGV) could anticipate the development of ESKD and identify the population prone to the harmful effects of GV. We included 777,192 Koreans with diabetes who had undergone health examinations more than three times in 2005–2010. We evaluated the risk of the first diagnosis of ESKD until 2017, according to the quartile of variability independent of the mean (VIM) of FG using multivariate-adjusted Cox proportional hazards analyses. During the 8-year follow-up, a total of 7290 incidents of ESKD were found. Subjects in the FG VIM quartile 4 had a 27% higher risk for ESKD compared to quartile 1, with adjustment for cardiovascular risk factors and the characteristics of diabetes. This effect was more distinct in patients aged < 65 years; those with a long duration of diabetes; the presence of hypertension or dyslipidemia; and prescribed angiotensin-converting enzyme inhibitors, metformin, sulfonylurea, α-glucosidase inhibitors, and insulin. In contrast, the relationship between baseline FG status and ESKD risk showed a U-shaped association. FGV is an independent risk factor for kidney failure regardless of FG. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

11 pages, 960 KiB

Open AccessCommunication

Low Screening Rates Despite a High Prevalence of Significant Liver Fibrosis in People with Diabetes from Primary and Secondary Care

by Laurence J. Dobbie, Mohamed Kassab, Andrew S. Davison, Pete Grace, Daniel J. Cuthbertson and Theresa J. Hydes

J. Clin. Med. 2021, 10(24), 5755; https://doi.org/10.3390/jcm10245755 - 9 Dec 2021

Cited by 12 | Viewed by 3446

Abstract

Diabetes is a driver of non-alcoholic fatty liver disease (NAFLD) and fibrosis. We determine current practices in examining liver fibrosis in people with diabetes and record prevalence levels in primary and secondary care. We extracted HbA_1c results ≥48 mmol/mol to identify people [...] Read more.

Diabetes is a driver of non-alcoholic fatty liver disease (NAFLD) and fibrosis. We determine current practices in examining liver fibrosis in people with diabetes and record prevalence levels in primary and secondary care. We extracted HbA_1c results ≥48 mmol/mol to identify people with diabetes, then examined the proportion who had AST, ALT, and platelets results, facilitating calculation of non-invasive fibrosis tests (NIT), or an enhanced liver fibrosis score. Fibrosis markers were requested in only 1.49% (390/26,090), of which 29.7% (n = 106) had evidence of significant fibrosis via NIT. All patients at risk of fibrosis had undergone transient elastography (TE), biopsy or imaging. TE and biopsy data showed that 80.6% of people with raised fibrosis markers had confirmed significant fibrosis. We also show that fibrosis levels as detected by NIT are marginally lower in patients treated with newer glucose lowering agents (sodium-glucose transporter protein 2 inhibitors, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). In conclusion by utilising a large consecutively recruited dataset we demonstrate that liver fibrosis is infrequently screened for in patients with diabetes despite high prevalence rates of advanced fibrosis. This highlights the need for cost-effectiveness analyses to support the incorporation of widespread screening into national guidelines and the requirement for healthcare practitioners to incorporate NAFLD screening into routine diabetes care. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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18 pages, 3057 KiB

Open AccessArticle

Prediction of Diabetic Sensorimotor Polyneuropathy Using Machine Learning Techniques

by Dae Youp Shin, Bora Lee, Won Sang Yoo, Joo Won Park and Jung Keun Hyun

J. Clin. Med. 2021, 10(19), 4576; https://doi.org/10.3390/jcm10194576 - 2 Oct 2021

Cited by 9 | Viewed by 3330

Abstract

Diabetic sensorimotor polyneuropathy (DSPN) is a major complication in patients with diabetes mellitus (DM), and early detection or prediction of DSPN is important for preventing or managing neuropathic pain and foot ulcer. Our aim is to delineate whether machine learning techniques are more [...] Read more.

Diabetic sensorimotor polyneuropathy (DSPN) is a major complication in patients with diabetes mellitus (DM), and early detection or prediction of DSPN is important for preventing or managing neuropathic pain and foot ulcer. Our aim is to delineate whether machine learning techniques are more useful than traditional statistical methods for predicting DSPN in DM patients. Four hundred seventy DM patients were classified into four groups (normal, possible, probable, and confirmed) based on clinical and electrophysiological findings of suspected DSPN. Three ML methods, XGBoost (XGB), support vector machine (SVM), and random forest (RF), and their combinations were used for analysis. RF showed the best area under the receiver operator characteristic curve (AUC, 0.8250) for differentiating between two categories—criteria by clinical findings (normal, possible, and probable groups) and those by electrophysiological findings (confirmed group)—and the result was superior to that of linear regression analysis (AUC = 0.6620). Average values of serum glucose, International Federation of Clinical Chemistry (IFCC), HbA1c, and albumin levels were identified as the four most important predictors of DSPN. In conclusion, machine learning techniques, especially RF, can predict DSPN in DM patients effectively, and electrophysiological analysis is important for identifying DSPN. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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12 pages, 5018 KiB

Open AccessArticle

Association between Add-On Dipeptidyl Peptidase-4 Inhibitor Therapy and Diabetic Retinopathy Progression

by Eugene Yu-Chuan Kang, Chunya Kang, Wei-Chi Wu, Chi-Chin Sun, Kuan-Jen Chen, Chi-Chun Lai, Tien-Hsing Chen and Yih-Shiou Hwang

J. Clin. Med. 2021, 10(13), 2871; https://doi.org/10.3390/jcm10132871 - 28 Jun 2021

Cited by 12 | Viewed by 2303

Abstract

This study aimed to investigate the association of add-on dipeptidyl peptidase-4 inhibitor (DPP4i) therapy and the progression of diabetic retinopathy (DR). In this retrospective population-based cohort study, we examined Taiwanese patients with type 2 diabetes, preexisting DR, and aged ≥40 years from 2009 [...] Read more.

This study aimed to investigate the association of add-on dipeptidyl peptidase-4 inhibitor (DPP4i) therapy and the progression of diabetic retinopathy (DR). In this retrospective population-based cohort study, we examined Taiwanese patients with type 2 diabetes, preexisting DR, and aged ≥40 years from 2009 to 2013. Prescription of DPP4i was defined as a medication possession ratio of ≥80% during the first 6 months. The outcomes included vitreous hemorrhage (VH), tractional retinal detachment, macular edema, and interventions including retinal laser therapy, intravitreal injection (IVI), and vitrectomy. Of 1,767,640 patients, 62,824 were eligible for analysis. After matching, the DPP4i and non-DPP4i groups each contained 20,444 patients. The risks of VH (p = 0.013) and macular edema (p = 0.035) were higher in the DPP4i group. The DPP4i group also had higher risks of receiving surgical interventions (retinal laser therapy (p < 0.001), IVI (p = 0.049), vitrectomy (p < 0.001), and any surgical intervention (p < 0.001)). More patients in the DPP4i group received retinal laser therapy (p < 0.001) and IVI (p = 0.001) than in the non-DPP4i group. No between-group differences in cardiovascular outcomes were noted. In the real-world database study, add-on DPP4i therapy may be associated with the progression of DR in patients with type 2 diabetes. No additional cardiovascular risks were found. The early progression of DR in rapid glycemic control was inconclusive in our study. The possible effect of add-on DPP4i therapy in the progression of DR in patients with type 2 diabetes requires further research. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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Review

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14 pages, 1651 KiB

Open AccessReview

Pneumatosis Intestinalis Induced by Alpha-Glucosidase Inhibitors in Patients with Diabetes Mellitus

by Blake J. McKinley, Mariangela Santiago, Christi Pak, Nataly Nguyen and Qing Zhong

J. Clin. Med. 2022, 11(19), 5918; https://doi.org/10.3390/jcm11195918 - 7 Oct 2022

Cited by 5 | Viewed by 2231

Abstract

Alpha-glucosidase inhibitor (αGIs)-induced pneumatosis intestinalis (PI) has been narrated in case reports but never systematically investigated. This study aimed to investigate the concurrency of PI and αGIs. A literature search was performed in PubMed, Google Scholar, WorldCat, and the Directory of Open-Access Journals [...] Read more.

Alpha-glucosidase inhibitor (αGIs)-induced pneumatosis intestinalis (PI) has been narrated in case reports but never systematically investigated. This study aimed to investigate the concurrency of PI and αGIs. A literature search was performed in PubMed, Google Scholar, WorldCat, and the Directory of Open-Access Journals (DOAJ) by using the keywords “pneumatosis intestinalis”, “alpha-glucosidase inhibitors”, and “diabetes”. In total, 29 cases of αGIs-induced PI in 28 articles were included. There were 11 men, 17 women, and one undefined sex, with a median age of 67. The most used αGI was voglibose (44.8%), followed by acarbose (41.4%) and miglitol (6.8%). Nine (31%) patients reported concomitant use of prednisone/prednisolone with or without immunosuppressants. The main symptoms were abdominal pain (54.5%) and distention (50%). The ascending colon (55.2%) and the ileum (34.5%) were the most affected. Nineteen (65.5%) patients had comorbidities. Patients with comorbidities had higher rates of air in body cavities, the portal vein, extraintestinal tissues, and the wall of the small intestine. Only one patient was found to have non-occlusive mesenteric ischemia. Twenty-five patients were treated with conservative therapy alone, and two patients received surgical intervention. All patients recovered. In conclusion, comorbidities, glucocorticoids, and immunosuppressants aggravate αGIs-induced PI. Conservative therapy is recommended when treating αGIs-induced PI. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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14 pages, 868 KiB

Open AccessReview

Evaluation of Quality and Bone Microstructure Alterations in Patients with Type 2 Diabetes: A Narrative Review

by José Ignacio Martínez-Montoro, Beatriz García-Fontana, Cristina García-Fontana and Manuel Muñoz-Torres

J. Clin. Med. 2022, 11(8), 2206; https://doi.org/10.3390/jcm11082206 - 14 Apr 2022

Cited by 11 | Viewed by 2830

Abstract

Bone fragility is a common complication in subjects with type 2 diabetes mellitus (T2DM). However, traditional techniques for the evaluation of bone fragility, such as dual-energy X-ray absorptiometry (DXA), do not perform well in this population. Moreover, the Fracture Risk Assessment Tool [...] Read more.

Bone fragility is a common complication in subjects with type 2 diabetes mellitus (T2DM). However, traditional techniques for the evaluation of bone fragility, such as dual-energy X-ray absorptiometry (DXA), do not perform well in this population. Moreover, the Fracture Risk Assessment Tool (FRAX) usually underestimates fracture risk in T2DM. Importantly, novel technologies for the assessment of one microarchitecture in patients with T2DM, such as the trabecular bone score (TBS), high-resolution peripheral quantitative computed tomography (HR-pQCT), and microindentation, are emerging. Furthermore, different serum and urine bone biomarkers may also be useful for the evaluation of bone quality in T2DM. Hence, in this article, we summarize the limitations of conventional tools for the evaluation of bone fragility and review the current evidence on novel approaches for the assessment of quality and bone microstructure alterations in patients with T2DM. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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15 pages, 869 KiB

Open AccessReview

Non-Alcoholic Fatty Liver Disease and Risk of Macro- and Microvascular Complications in Patients with Type 2 Diabetes

by Alessandro Mantovani, Andrea Dalbeni, Giorgia Beatrice, Davide Cappelli and Fernando Gomez-Peralta

J. Clin. Med. 2022, 11(4), 968; https://doi.org/10.3390/jcm11040968 - 12 Feb 2022

Cited by 26 | Viewed by 6571

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. To date, NAFLD is the most frequent chronic liver disease seen day by day in clinical practice across most high-income countries, affecting nearly 25–30% of adults in the general population [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. To date, NAFLD is the most frequent chronic liver disease seen day by day in clinical practice across most high-income countries, affecting nearly 25–30% of adults in the general population and up to 70% of patients with T2DM. Over the last few decades, it clearly emerged that NAFLD is a “multisystemic disease” and that the leading cause of death among patients with NAFLD is cardiovascular disease (CVD). Indeed, several observational studies and some meta-analyses have documented that NAFLD, especially its advanced forms, is strongly associated with fatal and non-fatal cardiovascular events, as well as with specific cardiac complications, including sub-clinical myocardial alteration and dysfunction, heart valve diseases and cardiac arrhythmias. Importantly, across various studies, these associations remained significant after adjustment for established cardiovascular risk factors and other confounders. Additionally, several observational studies and some meta-analyses have also reported that NAFLD is independently associated with specific microvascular conditions, such as chronic kidney disease and distal or autonomic neuropathy. Conversely, data regarding a potential association between NAFLD and retinopathy are scarce and often conflicting. This narrative review will describe the current evidence about the association between NAFLD and the risk of macro- and microvascular manifestations of CVD, especially in patients with T2DM. We will also briefly discuss the biological mechanisms underpinning the association between NAFLD and its advanced forms and macro- and microvascular CVD. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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16 pages, 696 KiB

Open AccessReview

COVID-19 and Diabetes

by Virginia Bellido and Antonio Pérez

J. Clin. Med. 2021, 10(22), 5341; https://doi.org/10.3390/jcm10225341 - 16 Nov 2021

Cited by 18 | Viewed by 3880

Abstract

Diabetes mellitus (DM) is one of the most common comorbid conditions in persons with COVID-19 and a risk factor for poor prognosis. The reasons why COVID-19 is more severe in persons with DM are currently unknown although the scarce data available on patients [...] Read more.

Diabetes mellitus (DM) is one of the most common comorbid conditions in persons with COVID-19 and a risk factor for poor prognosis. The reasons why COVID-19 is more severe in persons with DM are currently unknown although the scarce data available on patients with DM hospitalized because of COVID-19 show that glycemic control is inadequate. The fact that patients with COVID-19 are usually cared for by health professionals with limited experience in the management of diabetes and the need to prevent exposure to the virus may also be obstacles to glycemic control in patients with COVID-19. Effective clinical care should consider various aspects, including screening for the disease in at-risk persons, education, and monitoring of control and complications. We examine the effect of COVID-19 on DM in terms of glycemic control and the restrictions arising from the pandemic and assess management of diabetes and drug therapy in various scenarios, taking into account factors such as physical exercise, diet, blood glucose monitoring, and pharmacological treatment. Specific attention is given to patients who have been admitted to hospital and critically ill patients. Finally, we consider the role of telemedicine in the management of DM patients with COVID-19 during the pandemic and in the future. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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Other

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13 pages, 1481 KiB

Open AccessSystematic Review

Efficacy of Liraglutide in Non-Diabetic Obese Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Joshuan J. Barboza, Mariella R. Huamán, Beatriz Melgar, Carlos Diaz-Arocutipa, German Valenzuela-Rodriguez and Adrian V. Hernandez

J. Clin. Med. 2022, 11(11), 2998; https://doi.org/10.3390/jcm11112998 - 25 May 2022

Cited by 14 | Viewed by 4707

Abstract

Objective: We systematically assessed the efficacy of liraglutide in non-diabetic obese adults. Methods: Six databases were searched up to July 2021 for randomized controlled trials (RCTs) assessing liraglutide versus placebo in obese adults. Primary outcomes were body weight and body mass index (BMI). [...] Read more.

Objective: We systematically assessed the efficacy of liraglutide in non-diabetic obese adults. Methods: Six databases were searched up to July 2021 for randomized controlled trials (RCTs) assessing liraglutide versus placebo in obese adults. Primary outcomes were body weight and body mass index (BMI). Secondary outcomes were treatment-emergent adverse events (TEAEs), hypoglycemic episodes, HbA1c, and blood pressure. Effect measures were risk ratio (RR) or mean difference (MD) with their confidence interval (95%CI). Random-effects models and inverse variance meta-analyses were used. Quality of evidence was assessed using GRADE. Results: Twelve RCTs (n = 8249) were included. In comparison to placebo, liraglutide reduced body weight (MD −3.35 kg; 95%CI −4.65 to −2.05; p < 0.0001), and BMI (MD −1.45 kg/m²; 95%CI −1.98 to −0.91; p < 0.0001). Liraglutide did not reduce TEAEs (RR 1.08; 95%CI 0.92 to 1.27; p = 0.25), and Hb1Ac (MD −0.76%; 95%CI −2.24 to 0.72; p = 0.31). Furthermore, it did not increase hypoglycemic episodes (RR 2.01; 95%CI 0.37 to 11.02; p = 0.28). Finally, liraglutide reduced systolic blood pressure (MD −3.07 mmHg; 95%CI −3.66 to −2.48; p < 0.0001) and diastolic blood pressure (MD −1.01 mmHg; 95%CI −1.55 to −0.47; p = 0.0003). Seven RCTs had a high risk of bias. Subgroup analyses by length of treatment and doses had effects similar to the overall analyses. Quality of evidence was low or very low for most outcomes. Conclusions: In non-diabetic obese adults, liraglutide reduced body weight, BMI and blood pressure in comparison to placebo. Adverse events, Hb1Ac levels and hypoglycemic episodes were not different than placebo. Full article

(This article belongs to the Special Issue Clinical Research on Type 2 Diabetes and Its Complications)

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