Endocrinology and Metabolism

Original Articles

Impact of Antidiabetic Drugs on Clinical Outcomes of COVID-19: A Nationwide Population-Based Study: Han Na Jang, Sun Joon Moon, Jin Hyung Jung, Kyung-Do Han, Eun-Jung Rhee, Won-Young Lee; Received October 16, 2023 Accepted January 3, 2024 Published online January 29, 2024; DOI: https://doi.org/10.3803/EnM.2024.1857 [Epub ahead of print]

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Abstract PDF PubReader ePub: Background
Inconsistent results have been reported regarding the association between the use of antidiabetic drugs and the clinical outcomes of coronavirus disease 2019 (COVID-19). This study aimed to investigate the effect of antidiabetic drugs on COVID-19 outcomes in patients with diabetes using data from the National Health Insurance Service (NHIS) in South Korea.
Methods
We analyzed the NHIS data of patients aged ≥20 years who tested positive for COVID-19 and were taking antidiabetic drugs between December 2019 and June 2020. Multiple logistic regression analysis was performed to analyze the clinical outcomes of COVID-19 based on the use of antidiabetic drugs.
Results
A total of 556 patients taking antidiabetic drugs tested positive for COVID-19, including 271 male (48.7%), most of whom were in their sixties. Of all patients, 433 (77.9%) were hospitalized, 119 (21.4%) received oxygen treatment, 87 (15.6%) were admitted to the intensive care unit, 31 (5.6%) required mechanical ventilation, and 61 (11.0%) died. Metformin was significantly associated with the lower risks of mechanical ventilation (odds ratio [OR], 0.281; 95% confidence interval [CI], 0.109 to 0.720; P=0.008), and death (OR, 0.395; 95% CI, 0.182 to 0.854; P=0.018). Dipeptidylpeptidase-4 inhibitor (DPP-4i) were significantly associated with the lower risks of oxygen treatment (OR, 0.565; 95% CI, 0.356 to 0.895; P=0.015) and death (OR, 0.454; 95% CI, 0.217 to 0.949; P=0.036). Sulfonylurea was significantly associated with the higher risk of mechanical ventilation (OR, 2.579; 95% CI, 1.004 to 6.626; P=0.049).
Conclusion
In patients with diabetes and COVID-19, metformin exhibited reduced risks of mechanical ventilation and death, DPP- 4i was linked with lower risks of oxygen treatment and death, while sulfonylurea was related to the increased risk of mechanical ventilation.

Diabetes, obesity and metabolism
Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION): Byung Wan Lee, KyungWan Min, Eun-Gyoung Hong, Bon Jeong Ku, Jun Goo Kang, Suk Chon, Won-Young Lee, Mi Kyoung Park, Jae Hyeon Kim, Sang Yong Kim, Keeho Song, Soon Jib Yoo; Endocrinol Metab. 2023;38(3):328-337. Published online June 28, 2023; DOI: https://doi.org/10.3803/EnM.2023.1688

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This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin.
Methods
In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks.
Results
The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was –0.66% (0.07) with a 95% confidence interval of –0.80% to –0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted.
Conclusion
Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Diabetes, Obesity and Metabolism Big Data Articles (National Health Insurance Service Database)
Metformin and Cervical Cancer Risk in Patients with Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea: Hyun Min Kim, Min Jin Kang, Sun Ok Song; Endocrinol Metab. 2022;37(6):929-937. Published online December 26, 2022; DOI: https://doi.org/10.3803/EnM.2022.1613; Correction in: Endocrinol Metab 2023;38(1):174

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Background
Cervical cancer is a prevalent malignancy that is a major health problem for women worldwide. The cancer-preventive properties of metformin are well-known, but insufficient data have been reported regarding its relationship to cervical cancer. Therefore, in a nationwide population-based study, we investigated the association between metformin use and cervical cancer incidence in patients with newly diagnosed type 2 diabetes.
Methods
This retrospective cohort study used the Korean National Health Insurance claims database. Individuals newly diagnosed with type 2 diabetes between January 2005 and December 2009 were included. The occurrence of cervical cancer was explored by matching for age, economic status, region of residence, and use of anti-diabetic medication.
Results
In total, 66,013 metformin users and 64,756 non-users were analyzed. Cervical cancer occurred in 219 metformin users (0.33%) and 274 metformin non-users (0.42%) (hazard ratio [HR], 0.783; 95% confidence interval [CI], 0.655 to 0.036; P=0.007). Moreover, cervical cancer risk was considerably reduced in those treated with a high dose (>1,200,000 mg) or for an extended period (≥2,000 days) compared to non-users (HR, 0.151; 95% CI, 0.093 to 0.243; P<0.001; and HR, 0.141; 95% CI, 0.077 to 0.258; P<0.001). The incidence was also significantly lower in metformin users among those over 50 years old (HR, 0.791; 95% CI, 0.650 to 0.961; P<0.001).
Conclusion
Metformin use in patients with newly diagnosed diabetes was associated with a lower risk of cervical cancer in Korea. Furthermore, a significant association was found between the use of metformin and cervical cancer in a dose- and duration-dependent manner and among those over 50 years old.

Citations

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Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp
Mohamad Ali Hijazi, André Gessner, Nahed El-Najjar
Cancers.2023; 15(12): 3199. CrossRef
Network-based drug repurposing for HPV-associated cervical cancer
Faheem Ahmed, Young Jin Yang, Anupama Samantasinghar, Young Woo Kim, Jeong Beom Ko, Kyung Hyun Choi
Computational and Structural Biotechnology Journal.2023; 21: 5186. CrossRef
The Use of Metformin and Postoperative Insulin Pump Were Predictive Factors for Outcomes of Diabetic Colorectal Cancer Patients after Surgery
Xu-Rui Liu, Fei Liu, Zi-Wei Li, Quan Lv, Xin-Peng Shu, Lian-Shuo Li, Yue Tong, Wei Zhang, Dong Peng
Nutrition and Cancer.2023; 75(10): 1926. CrossRef

Review Article

Obesity and Metabolism
Myths about Insulin Resistance: Tribute to Gerald Reaven: Sun H. Kim, Fahim Abbasi; Endocrinol Metab. 2019;34(1):47-52. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.47

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Gerald Reaven was often called the “father of insulin resistance.” On the 1-year anniversary of his death in 2018, we challenge three myths associated with insulin resistance: metformin improves insulin resistance; measurement of waist circumference predicts insulin resistance better than body mass index; and insulin resistance causes weight gain. In this review, we highlight Reaven's relevant research that helped to dispel these myths associated with insulin resistance.

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Assessment of Antidiabetic and Anti-Inflammatory Activities of Carissa carandas Linn Extract: In Vitro and In Vivo Study
Manaschanok Lailerd, Thiri Wai Linn, Narissara Lailerd, Duangporn Amornlerdpison, Arisa Imsumran
Applied Sciences.2023; 13(11): 6454. CrossRef
Association of primary allostatic load mediators and metabolic syndrome (MetS): A systematic review
Francis Osei, Andrea Block, Pia-Maria Wippert
Frontiers in Endocrinology.2022;[Epub] CrossRef
Anthropometric indices and the risk of incident sudden cardiac death among adults with and without diabetes: over 15 years of follow-up in The Tehran Lipid and Glucose Study
Seyyed Saeed Moazzeni, Seyed Saeed Tamehri Zadeh, Samaneh Asgari, Fereidoun Azizi, Farzad Hadaegh
Diabetology & Metabolic Syndrome.2021;[Epub] CrossRef
Metabolic Syndrome or Insulin Resistance: Evolution, Controversies and Association With Cardiovascular Disease Risk
Arun K. Chopra
Indian Journal of Clinical Cardiology.2020; 1(2): 77. CrossRef

Original Articles

Predetermined Anti-Diabetic Drug Regimen Adjustments during Ramadan Fasting: An Observational Study of Safety: Abdallah M. Beano, Mohammad A. Zmaili, Zaid H. Gheith, Ahmad M. Naser, Munther S. Momani, Al-Motassem F. Yousef, Ayman A. Zayed; Endocrinol Metab. 2017;32(2):265-273. Published online June 23, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.2.265

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Background

Many Muslim type 2 diabetes mellitus (T2DM) patients choose to fast the month of Ramadan despite the possible adverse health effects brought about by the change in dietary habits, among other things. Clinical data regarding the safety of multi-drug regimens during fasting are particularly scarce. The aim of the study was to evaluate the safety of a drug protocol devised by the authors to accommodate Ramadan's dietary changes, involving dose adjustments of four anti-diabetic drug regimens in T2DM patients fasting Ramadan.

Methods

In this prospective, observational, open-label study, 301 T2DM patients who wished to fast Ramadan were followed during Ramadan and the preceding month. The incidence of hypoglycemia, diabetic ketoacidosis (DKA) and non-ketotic hyperosmolar state (NKHS) was monitored. Patients were classified into four groups: A group (those taking metformin, sulfonylurea and insulin [n=33]); B group (metformin and sulfonylurea [n=89]); C group (metformin and insulin [n=96]); and D group (premixed 70/30, glargine or regular insulin [n=82]). During Ramadan, drug doses were adjusted as percentages of their pre-Ramadan values: 75% for sulfonylureas, 75% for glargine, 75% for premixed insulin 70/30 in two doses, and 75% for regular insulin. Metformin was adjusted to a twice-daily regimen.

Results

No cases of DKA or NKHS were reported. Hypoglycemia occurred at a lower rate than pre-Ramadan values in groups C, and D; and a similar rate in groups A, and B.

Conclusion

The data suggested that using the above protocol to adjust the doses of anti-diabetic drugs is safe in T2DM patients in regards to hypoglycemia, DKA, and NKHS.

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Replicating human characteristics: A promising animal model of central fatigue
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Evaluation of physicians' approaches for the management of patients with diabetes during Ramadan in Iraq
Majid Alabbood, Rafid Alameri, Yasameen Alsaffar
Diabetes Research and Clinical Practice.2023; 195: 110188. CrossRef
The physiological changing and the recommended management plans for the diabetic patient during Ramadan fasting; A review article
Abeer Alhaj, Omar F Shatnawi
JAP Academy Journal.2023;[Epub] CrossRef
Incidence of diabetic ketoacidosis does not differ in Ramadan compared to other months and seasons: results from a 6-year multicenter study
Fateen Ata, Adeel Ahmad Khan, Ibrahim Khamees, Mohammed Bashir
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Evidence-based risk factors for major complications during Ramadan fasting in people with diabetes grouped under IDF-DAR risk categories
Rahmatullah, Muhammad Yakoob Ahmedani, Abdul Basit, Shagufta Zia, Imran Hasan, Qazi Masroor, Abrar Shaikh, Jehangir Khan, Waheed Iqbal
Diabetes Research and Clinical Practice.2022; 185: 109234. CrossRef
A Systematic Review of Insulin Management Recommendations to Improve Glycemic Control and Reduce Hypoglycemic Events During Ramadan Fasting in Patients With Insulin-Requiring Type 2 Diabetes
Alexander Kieu, Ashley Iles, Moien AB Khan, Linda Östlundh, Duston Boyd, MoezAlIslam Ezzat Faris
Frontiers in Nutrition.2022;[Epub] CrossRef
The DAR 2020 Global survey: Ramadan fasting during COVID 19 pandemic and the impact of older age on fasting among adults with Type 2 diabetes
Mohamed Hassanein, Zanariah Hussein, Inass Shaltout, Wan Juani Wan Seman, Chin Voon Tong, Nurain Mohd Noor, Mehmet Akif Buyukbese, Lobna El Tony, Gamal Mohamed Shaker, Reem M. Alamoudi, Khadija Hafidh, M. Fariduddin, Mohammed A. Batais, Shehla Shaikh, Pr
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Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramaḍān: A Randomized Controlled Trial
Louay Y. Zaghlol, Amir F. Beirat, Justin Z. Amarin, Amro M. Hassoun Al Najar, Yazan Y. Hasan, Abdallah Qtaishat, Michael E. Tierney, Raja Y. Zaghlol, Ayman A. Zayed
Frontiers in Endocrinology.2021;[Epub] CrossRef
Recommendations for management of diabetes during Ramadan: update 2020, applying the principles of the ADA/EASD consensus
Mahmoud Ibrahim, Melanie J Davies, Ehtasham Ahmad, Firas A Annabi, Robert H Eckel, Ebtesam M Ba-Essa, Nuha Ali El Sayed, Amy Hess Fischl, Pamela Houeiss, Hinde Iraqi, Ines Khochtali, Kamlesh Khunti, Shabeen Naz Masood, Safia Mimouni-Zerguini, Samad Shera,
BMJ Open Diabetes Research & Care.2020; 8(1): e001248. CrossRef
Ramadan and Diabetes: A Narrative Review and Practice Update
Syed H. Ahmed, Tahseen A. Chowdhury, Sufyan Hussain, Ateeq Syed, Ali Karamat, Ahmed Helmy, Salman Waqar, Samina Ali, Ammarah Dabhad, Susan T. Seal, Anna Hodgkinson, Shazli Azmi, Nazim Ghouri
Diabetes Therapy.2020; 11(11): 2477. CrossRef
A systematic review on efficacy and safety of the current hypoglycemic agents in patients with diabetes during Ramadan fasting
Fauzia Rashid, Elamin Abdelgadir
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2019; 13(2): 1413. CrossRef
Risk of diabetic ketoacidosis during Ramadan fasting: A critical reappraisal
Salem A. Beshyah, Tahseen A. Chowdhury, Nazim Ghouri, Abdulfattah A. Lakhdar
Diabetes Research and Clinical Practice.2019; 151: 290. CrossRef

Obesity and Metabolism
Metformin-Associated Lactic Acidosis: Predisposing Factors and Outcome: Min Ju Kim, Ju Young Han, Jun Young Shin, Shin Il Kim, Jeong Min Lee, Seongbin Hong, So Hun Kim, Moon Suk Nam, Yong Seong Kim; Endocrinol Metab. 2015;30(1):78-83. Published online March 27, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.1.78

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Background

Metformin is considered the first choice oral treatment for type 2 diabetes patients in the absence of contraindications. Rarely, life-threatening complications associated with metformin treatment are seen in some patients with underlying diseases. The aim of this study was to further investigate the clinical profiles and risk factors for metformin-associated lactic acidosis (MALA) and the treatment modalities according to survival.

Methods

To identify MALA, we performed a retrospective study in seven diabetic patients who were taking metformin and had been diagnosed with lactic acidosis at Inha University Hospital between 1995 and 2012. For each patient, we recorded the age, sex, daily metformin dosage, laboratory test results, admission diagnosis, and risk factors. Also, concurrent conditions, treatment modalities, and outcomes were evaluated.

Results

Six patients had risk factors for lactic acidosis before admission. All patients had renal impairment on admission as a precipitating risk factor. Five patients survived and two patients died despite early renal replacement therapy. Older patients tended to have a poorer prognosis.

Conclusion

Renal function must be monitored in elderly type 2 diabetes mellitus patients with underlying diseases and conditions causing renal impairment who begin metformin treatment. Accurate recognition of MALA and initiation of renal replacement are essential for treatment.

Citations

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Metformin Treatment Reduces the Incidence of Rheumatoid Arthritis: A Two-Sample Mendelian Randomized Study
Jialin Liang, Yuanqing Cai, Jianan Zhang, Zhaopu Jing, Leifeng Lv, Guangyang Zhang, Rupeng Zhang, Ruiyu Liu, Kai Nan, Xiaoqian Dang
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PLGA-based microspheres loaded with metformin hydrochloride: Modified double emulsion method preparation, optimization, characterization, and in vitro evaluation
Priyanka Chauhan, Himanshu Paliwal, Chetan Singh Chauhan, Ankit Paliwal
Annales Pharmaceutiques Françaises.2023; 81(6): 997. CrossRef
Metformin-associated lactic acidosis: underlying multiple myeloma
Clara GOMES, Ana FERREIRA, Neuza SOARES, Vanessa CHAVES, Luís LEMOS, Sofia TAVARES, Marta COUTO
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Obesity and Metabolism
Vav3, a GEF for RhoA, Plays a Critical Role under High Glucose Conditions: Jie Sha, Jungsik Na, Jung Ok Lee, Nami Kim, Soo Kyung Lee, Ji Hae Kim, Ji Wook Moon, Su Jin Kim, Hye Jeong Lee, Jong-Il Choi, Sun Hwa Park, Hyeon Soo Kim; Endocrinol Metab. 2014;29(3):363-370. Published online September 25, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.3.363

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Abstract PDF PubReader

Background

The role of small GTPase molecules is poorly understood under high glucose conditions.

Methods

We analyzed the expression pattern of Vav3 in skeletal muscle C2C12 cells under high glucose culture condition with reverse transcription-polymerase chain reaction and Western blot analysis. We also measured glucose uptake using isotope-labelled glucose.

Results

We showed that expression of Vav3 (a guanine nucleotide exchange factor for RhoA) increased. mRNA and protein levels in skeletal muscle C2C12 cells under high glucose conditions. The AMP-activated protein kinase (AMPK) activator AMPK agonist 5-aminoimidazole-4-carboxy-amide-1-d-ribofuranoside (AICAR) suppressed high glucose-induced Vav3 induction. In addition, exposure of cells to high glucose concentration increased the phosphorylation of PAK-1, a molecule downstream of RhoA. The phosphorylation of paxillin, a downstream molecule of PAK-1, was also increased by exposure to high glucose. Phosphorylation of these molecules was not observed in the presence of AICAR, indicating that AMPK is involved in the RhoA signal pathway under high glucose conditions. Knock down of Vav3 enhances metformin-mediated glucose uptake. Inhibition of AMPK blocked the increases of Vav3 knock down-induced glucose uptake. Metformin-mediated Glut4 translocation was also increased by Vav3 knock-down, suggesting that Vav3 is involved in metformin-mediated glucose uptake.

Conclusion

These results demonstrate that Vav3 is involved in the process of metformin-mediated glucose regulation.

Citations

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