Diabetes & Metabolism Journal

Original Articles

Drug Regimen
Efficacy and Safety of Evogliptin Add-on Therapy to Dapagliflozin/Metformin Combinations in Patients with Poorly Controlled Type 2 Diabetes Mellitus: A 24-Week Multicenter Randomized Placebo-Controlled Parallel-Design Phase-3 Trial with a 28-Week Extension: Jun Sung Moon, Il Rae Park, Hae Jin Kim, Choon Hee Chung, Kyu Chang Won, Kyung Ah Han, Cheol-Young Park, Jong Chul Won, Dong Jun Kim, Gwan Pyo Koh, Eun Sook Kim, Jae Myung Yu, Eun-Gyoung Hong, Chang Beom Lee, Kun-Ho Yoon; Diabetes Metab J. 2023;47(6):808-817. Published online September 26, 2023; DOI: https://doi.org/10.4093/dmj.2022.0387

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Abstract PDF Supplementary Material PubReader ePub: Background
This study investigates the long-term efficacy and safety of evogliptin add-on therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM) previously received dapagliflozin and metformin (DAPA/MET) combination.
Methods
In this multicenter randomized placebo-controlled phase 3 trial, patients with glycosylated hemoglobin (HbA1c) levels 7.0% to 10.5% (n=283) previously used DAPA 10 mg plus MET (≥1,000 mg) were randomly assigned to the evogliptin 5 mg once daily or placebo group (1:1). The primary endpoint was the difference in the HbA1c level from baseline at week 24, and exploratory endpoints included the efficacy and safety of evogliptin over 52 weeks (trial registration: ClinicalTrials.gov NCT04170998).
Results
Evogliptin add-on to DAPA/MET therapy was superior in HbA1c reduction compared to placebo at weeks 24 and 52 (least square [LS] mean difference, –0.65% and –0.55%; 95% confidence interval [CI], –0.79 to –0.51 and –0.71 to –0.39; P<0.0001). The proportion of patients achieving HbA1c <7% was higher in the triple combination group at week 52 (32.14% vs. 8.51% in placebo; odds ratio, 5.62; P<0.0001). Evogliptin significantly reduced the fasting glucose levels and mean daily glucose levels with improvement in homeostatic model assessment of β-cell function (LS mean difference, 9.04; 95% CI, 1.86 to 16.21; P=0.0138). Adverse events were similar between the groups, and no serious adverse drug reactions were reported in the evogliptin group.
Conclusion
Long-term triple combination with evogliptin added to DAPA/MET showed superior HbA1c reduction and glycemic control compared to placebo at 52 weeks and was well tolerated.

Drug/Regimen
Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial: Ji Eun Jun, In-Kyung Jeong, Jae Myung Yu, Sung Rae Kim, In Kye Lee, Kyung-Ah Han, Sung Hee Choi, Soo-Kyung Kim, Hyeong Kyu Park, Ji-Oh Mok, Yong-ho Lee, Hyuk-Sang Kwon, So Hun Kim, Ho-Cheol Kang, Sang Ah Lee, Chang Beom Lee, Kyung Mook Choi, Sung-Ho Her, Won Yong Shin, Mi-Seung Shin, Hyo-Suk Ahn, Seung Ho Kang, Jin-Man Cho, Sang-Ho Jo, Tae-Joon Cha, Seok Yeon Kim, Kyung Heon Won, Dong-Bin Kim, Jae Hyuk Lee, Moon-Kyu Lee; Diabetes Metab J. 2020;44(1):78-90. Published online June 20, 2019; DOI: https://doi.org/10.4093/dmj.2018.0265

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Abstract PDF Supplementary Material PubReader

Background

Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia.

Methods

This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment.

Results

After 8 weeks of treatment, the percent changes from baseline in TG (−29.8% vs. 3.6%, P<0.001) and non-HDL-C (−10.1% vs. 4.9%, P<0.001) levels were significantly greater in the ATOMEGA group (n=97) than in the atorvastatin group (n=103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P<0.001). The incidence of adverse events did not differ between the two groups.

Conclusion

The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia.

Citations

Citations to this article as recorded by

Association Between Omega‐3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose–Response Meta‐Analysis of Randomized Controlled Trials
Tianjiao Wang, Xin Zhang, Na Zhou, Yuxuan Shen, Biao Li, Bingshu E. Chen, Xinzhi Li
Journal of the American Heart Association.2023;[Epub] CrossRef
Nutraceutical support in the prevention and treatment of cardiovascular diseases
E. V. Gracheva, E. A. Starovoytova, E. S. Kulikov, N. A. Kirillova, S. V. Fedosenko, M. A. Balaganskaya, D. V. Kromka
Rational Pharmacotherapy in Cardiology.2023; 19(3): 298. CrossRef
Effect of coadministration of omega-3 fatty acids with glimepiride on glycemic control, lipid profile, irisin, and sirtuin-1 in type 2 diabetes mellitus patients: a randomized controlled trial
Rehab H. Werida, Aalaa Ramzy, Youssri Nassief Ebrahim, Maged Wasfy Helmy
BMC Endocrine Disorders.2023;[Epub] CrossRef
The Effect of Dietary Interventions on Hypertriglyceridemia: From Public Health to Molecular Nutrition Evidence
Karla Paulina Luna-Castillo, Xochitl Citlalli Olivares-Ochoa, Rocío Guadalupe Hernández-Ruiz, Iris Monserrat Llamas-Covarrubias, Saraí Citlalic Rodríguez-Reyes, Alejandra Betancourt-Núñez, Barbara Vizmanos, Erika Martínez-López, José Francisco Muñoz-Valle
Nutrients.2022; 14(5): 1104. CrossRef
The effect of omega-3 fatty acids and its combination with statins on lipid profile in patients with hypertriglyceridemia: A systematic review and meta-analysis of randomized controlled trials
Yunjiao Yang, Wen Deng, Yanmei Wang, Tongyi Li, Yiding Chen, Cong Long, Qing Wen, Yue Wu, Qiu Chen
Frontiers in Nutrition.2022;[Epub] CrossRef
Comparison of the Efficacy and Safety of Atorvastatin 40 mg/ω-3 Fatty Acids 4 g Fixed-dose Combination and Atorvastatin 40 mg Monotherapy in Hypertriglyceridemic Patients who Poorly Respond to Atorvastatin 40 mg Monotherapy: An 8-week, Multicenter, Random
Jong Shin Woo, Soon Jun Hong, Dong Hoon Cha, Kee Sik Kim, Moo Hyun Kim, Jun-Won Lee, Myung Ho Jeong, Jin-Ok Jeong, Jun-Hee Lee, Doo Soo Jeon, Eun Joo Cho, Soon Kil Kim, Jun Kwan, Chang Gyu Park, Hae Young Lee, Taek Jong Hong, Jinho Shin, Ho Joong Youn, Do
Clinical Therapeutics.2021; 43(8): 1419. CrossRef
All-Cause Mortality and Cardiovascular Death between Statins and Omega-3 Supplementation: A Meta-Analysis and Network Meta-Analysis from 55 Randomized Controlled Trials
Jeongseon Kim, Tung Hoang, Ji-Myung Kim, So Young Bu, Jeong-Hwa Choi, Eunju Park, Seung-Min Lee, Eunmi Park, Ji Yeon Min, In Seok Lee, So Young Youn, Jee-Young Yeon
Nutrients.2020; 12(10): 3203. CrossRef

Brief Report

Epidemiology
Glycosylated Hemoglobin Threshold for Predicting Diabetes and Prediabetes from the Fifth Korea National Health and Nutrition Examination Survey: Sangmo Hong, Jun Goo Kang, Chul Sik Kim, Seong Jin Lee, Cheol-Young Park, Chang Beom Lee, Sung-Hee Ihm; Diabetes Metab J. 2016;40(2):167-170. Published online April 5, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.2.167

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We aimed to estimate the threshold level of glycosylated hemoglobin (HbA1c) for the fasting plasma glucose of 100 and 126 mg/dL in the Korean adult population, using the 2011 Korea National Health and Nutrition Examination Survey. A total of 4,481 participants over 19 years of age without diabetic medications and conditions to influence the interpretation of HbA1c levels, such as anemia, renal insufficiency, liver cirrhosis, and cancers, were analyzed. A point-wise area under the receiver operating characteristic curve was used to estimate the optimal HbA1c cutoff value. A HbA1c threshold of 6.35% was optimal for predicting diabetes with a sensitivity of 86.9% and a specificity of 99.1%. Furthermore, the threshold of HbA1c was 5.65% for prediabetes, with a sensitivity of 69.3% and a specificity of 71%. Further prospective studies are needed to evaluate the HbA1c cutoff point for diagnosing prediabetes and diabetes in the Korean population.

Citations

Citations to this article as recorded by

The Cutoff Value of HbA1c in Predicting Diabetes and Impaired Fasting Glucose
Seyoung Kwon, Youngak Na
The Korean Journal of Clinical Laboratory Science.2017; 49(2): 114. CrossRef
Cutoff Point of HbA1c for Diagnosis of Diabetes Mellitus in Chinese Individuals
Bing Wang, Ming-Chuan Liu, Xin-Yu Li, Xu-Han Liu, Qiu-Xia Feng, Lu Lu, Zhu Zhu, Ying-Shu Liu, Wei Zhao, Zheng-Nan Gao, Noel Christopher Barengo
PLOS ONE.2016; 11(11): e0166597. CrossRef

Original Article

Serum Adiponectin and Type 2 Diabetes: A 6-Year Follow-Up Cohort Study: Sun Ha Jee, Chul Woo Ahn, Jong Suk Park, Chang Gyu Park, Hyon-Suk Kim, Sang-Hak Lee, Sungha Park, Myoungsook Lee, Chang Beom Lee, Hye Soon Park, Heejin Kimm, Sung Hee Choi, Jidong Sung, Seungjoon Oh, Hyojee Joung, Sung Rae Kim, Ho-Joong Youn, Sun Mi Kim, Hong Soo Lee, Yejin Mok, Eunmi Choi, Young Duk Yun, Soo-Jin Baek, Jaeseong Jo, Kap Bum Huh; Diabetes Metab J. 2013;37(4):252-261. Published online August 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.4.252

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Abstract PDF PubReader

Background

Studies on factors which may predict the risk of diabetes are scarce. This prospective cohort study was conducted to determine the association between adiponectin and type 2 diabetes among Korean men and women.

Methods

A total of 42,845 participants who visited one of seven health examination centers located in Seoul and Gyeonggi province, Republic of Korea between 2004 and 2008 were included in this study. The incidence rates of diabetes were determined through December 2011. To evaluate the effects of adiponectin on type 2 diabetes, the Cox proportional hazard model was used.

Results

Of the 40,005 participants, 959 developed type 2 diabetes during a 6-year follow-up. After the adjustment for age, body mass index (BMI), and waist circumference, the risks for type 2 diabetes in participants with normoglycemia had a 1.70-fold (95% confidence interval [CI], 1.21 to 2.38) increase in men and a 1.83-fold (95% CI, 1.17 to 2.86) increase in women with the lowest tertile of adiponectin when compared to the highest tertile of adiponectin. For participants with impaired fasting glucose (IFG), the risk for type 2 diabetes had a 1.46-fold (95% CI, 1.17 to 1.83) increase in men and a 2.52-fold (95% CI, 1.57 to 4.06) increase in women with the lowest tertile of adiponectin. Except for female participants with normoglycemia, all the risks remained significant after the adjustment for fasting glucose and other confounding variables. Surprisingly, BMI and waist circumference were not predictors of type 2 diabetes in men or women with IFG after adjustment for fasting glucose and other confounders.

Conclusion

A strong association between adiponectin and diabetes was observed. The use of adiponectin as a predictor of type 2 diabetes is considered to be useful.

Citations

Citations to this article as recorded by

Adiponectin and metabolic cardiovascular diseases: Therapeutic opportunities and challenges
Xiaotian Lei, Sheng Qiu, Gangyi Yang, Qinan Wu
Genes & Diseases.2023; 10(4): 1525. CrossRef
Low levels of total and high-molecular-weight adiponectin may predict non-alcoholic fatty liver in Korean adults
Young-Sang Kim, Soo-Hyun Lee, Seung Geon Park, Bo Youn Won, Hyejin Chun, Doo-Yeoun Cho, Moon-Jong Kim, Ji Eun Lee, Ji-Hee Haam, Kunhee Han
Metabolism.2020; 103: 154026. CrossRef
Anti-inflammatory effects of sucrose-derived oligosaccharides produced by a constitutive mutant L. mesenteroides B-512FMCM dextransucrase in high fat diet-fed mice
Min-Gyung Kang, Hee Jae Lee, Jae-Young Cho, Kanghwa Kim, Soo Jin Yang, Doman Kim
Biochemical and Biophysical Research Communications.2016; 477(3): 350. CrossRef
Adiponectin as a Protective Factor Against the Progression Toward Type 2 Diabetes Mellitus in Postmenopausal Women
Hossein Darabi, Alireza Raeisi, Mohammad Reza Kalantarhormozi, Afshin Ostovar, Majid Assadi, Kamyar Asadipooya, Katayoun Vahdat, Sina Dobaradaran, Iraj Nabipour
Medicine.2015; 94(33): e1347. CrossRef
Effect of ketotifen in obese patients with type 2 diabetes mellitus
Sahar M. El-Haggar, Wael F. Farrag, Fedaa A. Kotkata
Journal of Diabetes and its Complications.2015; 29(3): 427. CrossRef
Smoking and Diabetes: Is the Association Mediated by Adiponectin, Leptin, or C-reactive Protein?
Esayas Haregot Hilawe, Hiroshi Yatsuya, Yuanying Li, Mayu Uemura, Chaochen Wang, Chifa Chiang, Hideaki Toyoshima, Koji Tamakoshi, Yan Zhang, Nobuo Kawazoe, Atsuko Aoyama
Journal of Epidemiology.2015; 25(2): 99. CrossRef
Association between the level of circulating adiponectin and prediabetes: A meta‐analysis
Huasheng Lai, Nie Lin, Zhenzhen Xing, Huanhuan Weng, Hua Zhang
Journal of Diabetes Investigation.2015; 6(4): 416. CrossRef
Adiponectin as a Biomarker of Osteoporosis in Postmenopausal Women: Controversies
Anna Lubkowska, Aleksandra Dobek, Jan Mieszkowski, Wojciech Garczynski, Dariusz Chlubek
Disease Markers.2014; 2014: 1. CrossRef
Modulation of adiponectin as a potential therapeutic strategy
Soo Lim, Michael J. Quon, Kwang Kon Koh
Atherosclerosis.2014; 233(2): 721. CrossRef

Randomized Controlled Trial

Effects of Adding omega-3 Fatty Acids to Simvastatin on Lipids, Lipoprotein Size and Subspecies in Type 2 Diabetes Mellitus with Hypertriglyceridemia.: Won Jun Kim, Chang Beom Lee, Cheol Young Park, Se Eun Park, Eun Jung Rhee, Won Young Lee, Ki Won Oh, Sung Woo Park, Dae Jung Kim, Hae Jin Kim, Seung Jin Han, Hong Keum Cho; Korean Diabetes J. 2009;33(6):494-502. Published online December 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.6.494

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Abstract PDF: BACKGROUND
omega-3 fatty acids are known to improve lipid profiles, the distribution of lipoprotein subclasses, and secondary prevention against post-myocardial infarction. Rare reports have emerged of synergistic results of omega-3 fatty acids with simvastatin in cases of type 2 diabetes mellitus with hypertriglyceridemia. The purpose of this study was to determine the combined relationship of omega-3 fatty acids plus simvastatin on lipid, lipoprotein size and the types of subspecies. METHODS: This randomized, multi-center, comparison study evaluated eight weeks of combination therapy (omega-3 fatty acids (Omacor) 4 g/day plus simvastatin 20 mg/day) or monotherapy (simvastatin 20 mg/day) for at least six weeks in 62 diabetic patients. Subjects with a triglyceride concentration of more than 200 mg/dL were eligible for inclusion. RESULTS: No significant differences for omega-3 fatty acids + simvastatin versus simvastatin alone were observed for triglycerides (-22.7% vs. -14.3%, P = 0.292), HDL peak particle size (+2.8% vs. -0.4%, P = 0.076), LDL mean particle size (+0.4% vs -0.1%, P = 0.376) or LDL subspecies types, although the combination therapy showed a tendency toward lower triglycerides, larger HDL, and LDL particle sizes than did the monotherapy. There were no significant differences between the two groups in regard to HDL-C, LDL-C, or HbA1c levels. There were no serious adverse events and no abnormalities in the laboratory values associated with this study. CONCLUSION: omega-3 fatty acids were a safeform of treatment in hypertriglyceridemic patients with type 2 diabetes mellitus. But, regarding efficacy, a much larger sample size and longer-term follow-up may be needed to distinguish between the effects of combination therapy and monotherapy.

Original Articles

Fetal Organogenesis in a Pregestational Diabetic Mother Who has Taking an Oral Hypoglycemic Agent in Early Pregnancy.: Chang Beom Lee, Seung Yong Kim; Korean Diabetes J. 2004;28(6):530-537. Published online December 1, 2004

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Abstract PDF: BACKGROUND
Women with diabetes mellitus are not treated with oral hypoglycemic agents because of the concerns about teratogenicity and neonate complication. There is not enough information about the safety of these drugs and especially during the first trimester of pregnancy. METHODS: Eight type 2 diabetic pregnant women with accidental exposure to an oral hypoglycemic agent during embryogenesis and twenty type 2 diabetic pregnant women who were matched for age, weight, and glycemic control, but they were not exposed to an oral hypoglycemic agent, were compared retrospectively. RESULTS: 1) Three out of the eight neonates (38%) in the oral hypoglycemic agent group had congenital malformations and stillbirth compared with five out of twenty (25%) in the control group (Odds ratio 1.8; range: 0.2~13.8, P >0.05). 2) In the control group, the mean HbA1c of the 5 mothers with anomalistic neonates and stillbirths was higher than that of 15 mothers with normal neonates (8.8% vs. 6.2 %, P = 0.1). The anomalies included three congenital heart diseases (1 ventricular septal defect, 2 patent ductus arteriosus) and one renal agenesis. 3) In the oral hypoglycemic agent group, the mean HbA1c of the 3 mothers with anomalistic neonates and stillbirth was higher than that of the 5 mothers with normal neonates (9.0% vs. 6.3%, P = 0.4). The anomalies included one urachal sinus and one facial palsy that have not been commonly described for diabetic embryopathy. 4) In both groups, the mean HbA1c of 8 mothers with complicated neonates and the 20 mothers with normal neonates was 8.1% and 6.8%, respectively, (P =0.09). CONCLUSION: We found no obvious indication for therapeutic abortions in patients who have accidentally been treated with an oral hypoglycemic agent during embryogenesis. On the contrary, it seems reasonable to reassure these women with respect to their risk of having a malformed baby, and then to stop treatment with an oral hypoglycemic agent and initiate insulin treatment.

The Role of Chromium as an Insulin Sensitizer in Rats Receivieng Corticosteroid.: Dong Sun Kim, Chang Beom Lee, Yong Soo Park, You Hern Ahn, Tae Wha Kim, Ho Soon Choi, Il Kyu Park, Hyun Jin Shin, Ju Seop Kang; Korean Diabetes J. 2001;25(3):211-217. Published online June 1, 2001

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Abstract PDF: BACKGROUND
Chromium (Cr) has been known to be essential for the regulation of insulin action. Recently it has been reported that corticosteroid increases urinary loss of Cr, and that Cr supplementation recovers steroid induced diabetes mellitus. METHODS: Rats were daily treated with dexamethasone (0.2 mg/kg, ip) for first 7 days and were further treated daily with dexamethasone plus either chromium picolinate (30 mg/kg) or a placebo for a period of 14 days. RESULTS: At the end of experiment (Day 21), the control rats treated only with dexamethasone weighed 320 gram (80% of initial weight) in average, but the Cr treated rats weighed 364 gram (91% of initial weight. p<0.05). An insulin sensitivity test [subcutaneous injection of insulin (5 U/kg) plus intraperitoneal injection of glucose (30 minutes after insulin injection)] were conducted. During the insulin sensitivity tests, the area under curves (AUC(0->120 min)) of the time-glucose concentrations curves in the Cr-treated group were decreased compared to those in the control group (5250 vs 15883 mg-min/dL, p<0.01). Fasting serum insulin levels in the Cr-treated rats were clearly decreased by 46.9% compared to those in the control group (2.98 vs 5.60 ng/mL, p<0.05). CONCLUSIONS: We conclude that chromium supplementation reverse a catabolic state, and increase insulin sensitivity in dexamethasone treated rats.

The Effect of Cyclosporine on Insulin Sensitivity in Streptozotocin Induced Diabetic Rats.: Ju Seop Kang, Dong Sun Kim, Chang Beom Lee, Yong Soo Park, Woong Hwan Choi, Tae Wha Kim, Mok Hyun Kim; Korean Diabetes J. 1999;23(2):142-146. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Cyclosporine (CsA), being used as a immunosuppressant is known to have deleterious effects on the liver and kidney, but the harmful effect on glucose tolerance has not been clearly elucidated. This study was undertaken to determine whether the CsA affected peripheral insulin sensitivity in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats. METHODS: After the daily treatment of CsA (10mg/kg, i.p.) for 2 weeks, glucose tolerance tests were carried out by the intraperitoneal administration of glucose alone or in conjunction with insulin (5 U/kg, s.c.). The glucose tolerance and peripheral insulin sensitivity were determined by measuring the deremental area under the time-lasma glucose concentration curve (AUC; mg-min/mL) according to the trapezoidal rule. The plasma glucose levels (mg/dL) were measured by a glucose analyzer at 0, 10, 30, 60, 90 and 120min after glucose load (2 g/kg). The STZ-diabetic rats were divided into thre groups (GLU- as control, INS+GLU- and CsA+INS+GLU-treated group, n 7 in each groups). RESULTS: In STZ-diabetic rats, the AUC 0-120 of the CsA+INS+GLU-treated group was significantly (p<0.01) lower than those of the control group (48.6% of control), but significantly (p<0.03) higher thain those of the INS+GLUtreated group (28.1% of control). CONCLUSIONS: These results suggest that intraperitoneal injection of CsA gives rise to a deterioration of glucose etabolism which is probably due to a decrease of insulin sensitivity of peripheral tissue in STZ-diabetic rats.

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