Publications by authors named "Young Min Cho"

199 Publications

Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes.

Cell Rep 2021 Jul;36(4):109447

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea. Electronic address:

Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. In this study, we found that MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) prevented autoimmune β cell destruction by targeting T cells in non-obese diabetic (NOD) mice. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-severe combined immunodeficiency (SCID) mice. Metabolic and genomic analyses revealed that MOTS-c modulated T cell phenotype and function by regulating T cell receptor (TCR)/mTOR complex 1 (mTORC1) signaling. Type 1 diabetes (T1D) patients had a lower serum MOTS-c level than did healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients, suggesting therapeutic potential. Our findings indicate that MOTS-c regulates the T cell phenotype and suppresses autoimmune diabetes.
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http://dx.doi.org/10.1016/j.celrep.2021.109447DOI Listing
July 2021

Sodium-glucose cotransporter-2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation.

Diabetes Obes Metab 2021 Jul 28. Epub 2021 Jul 28.

Department of Translational Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Aims: To evaluate whether sodium-glucose cotransporter-2 (SGLT2) inhibition reduces cellular senescence in the kidney and to investigate the molecular pathways involved in the renoprotective effect.

Materials And Methods: Dapagliflozin (1 mg/kg), glimepiride (2.5 mg/kg) or vehicle was administered daily via oral gavage for 8 weeks in db/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real-time RT-PCR, immunohistochemistry, and Western blot analysis. For in vitro analysis, HK-2 cells, a human renal tubular epithelial cell line, were pretreated with H O to induce cellular senescence, and the levels of ageing markers were measured after treatment with β-hydroxybutyrate (β-HB) or NRF2-specific siRNA.

Results: Expression levels of ageing marker genes (p21, p16 and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db + vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db + SGLT2 inhibitor) group, but not in the glimepiride-treated db/db (db/db + sulphonylurea [SU]) group. In the kidneys of mice in the db/db + SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db/db + vehicle and db/db + SU groups. Dapagliflozin increased plasma β-HB, which reduced H O -induced DNA damage and senescence in HK-2 cells. β-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways.

Conclusions: Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation.
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http://dx.doi.org/10.1111/dom.14503DOI Listing
July 2021

Pneumatosis Intestinalis in the Setting of COVID-19: A Single Center Case Series From New York.

Front Med (Lausanne) 2021 4;8:638075. Epub 2021 Jun 4.

Department of Surgery, North Shore University Hospital, Manhasset, NY, United States.

This case series reviews four critically ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARSCoV2) [coronavirus disease 2019 (COVID-19)] suffering from pneumatosis intestinalis (PI) during their hospital admission. All patients received the biological agent tocilizumab (TCZ), an interleukin (IL)-6 antagonist, as an experimental treatment for COVID-19 before developing PI. COVID-19 and TCZ have been independently linked to PI risk, yet the cause of this relationship is unknown and under speculation. PI is a rare condition, defined as the presence of gas in the intestinal wall, and although its pathogenesis is poorly understood, intestinal ischemia is one of its causative agents. Based on COVID-19's association with vasculopathic and ischemic insults, and IL-6's protective role in intestinal epithelial ischemia-reperfusion injury, an adverse synergistic association of COVID-19 and TCZ can be proposed in the setting of PI. To our knowledge, this is the first published, single center, case series of pneumatosis intestinalis in COVID-19 patients who received tocilizumab therapy.
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http://dx.doi.org/10.3389/fmed.2021.638075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212022PMC
June 2021

Efficacy and Safety of Self-Titration Algorithms of Insulin Glargine 300 units/mL in Individuals with Uncontrolled Type 2 Diabetes Mellitus (The Korean TITRATION Study): A Randomized Controlled Trial.

Diabetes Metab J 2021 Jun 16. Epub 2021 Jun 16.

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: To compare the efficacy and safety of two insulin self-titration algorithms, Implementing New Strategies with Insulin Glargine for Hyperglycemia Treatment (INSIGHT) and EDITION, for insulin glargine 300 units/mL (Gla-300) in Korean individuals with uncontrolled type 2 diabetes mellitus (T2DM).

Methods: In a 12-week, randomized, open-label trial, individuals with uncontrolled T2DM requiring basal insulin were randomized to either the INSIGHT (adjusted by 1 unit/day) or EDITION (adjusted by 3 units/week) algorithm to achieve a fasting self-monitoring of blood glucose (SMBG) in the range of 4.4 to 5.6 mmol/L. The primary outcome was the proportion of individuals achieving a fasting SMBG ≤5.6 mmol/L without noct urnal hypoglycemia at week 12.

Results: Of 129 individuals (age, 64.1±9.5 years; 66 [51.2%] women), 65 and 64 were randomized to the INSIGHT and EDITION algorithms, respectively. The primary outcome of achievement was comparable between the two groups (24.6% vs. 23.4%, P=0.876). Compared with the EDITION group, the INSIGHT group had a greater reduction in 7-point SMBG but a similar decrease in fasting plasma glucose and glycosylated hemoglobin. The increment of total daily insulin dose was significantly higher in the INSIGHT group than in the EDITION group (between-group difference: 5.8±2.7 units/day, P=0.033). However, body weight was significantly increased only in the EDITION group (0.6±2.4 kg, P=0.038). There was no difference in the occurrence of hypoglycemia between the two groups. Patient satisfaction was significantly increased in the INSIGHT group (P=0.014).

Conclusion: The self-titration of Gla-300 using the INSIGHT algorithm was effective and safe compared with that using the EDITION algorithm in Korean individuals with uncontrolled T2DM (ClinicalTrials.gov number: NCT03406663).
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http://dx.doi.org/10.4093/dmj.2020.0274DOI Listing
June 2021

In Memoriam: Remembering Professor Hun-Ki Min (1928-2021).

Authors:
Young Min Cho

Endocrinol Metab (Seoul) 2021 Apr 20;36(2):207-208. Epub 2021 Apr 20.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3803/EnM.2021.204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090469PMC
April 2021

Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists.

Endocrinol Metab (Seoul) 2021 Feb 24;36(1):22-29. Epub 2021 Feb 24.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.
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http://dx.doi.org/10.3803/EnM.2021.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937847PMC
February 2021

Predictive value of cardio-ankle vascular index for the risk of end-stage renal disease.

Clin Kidney J 2021 Jan 28;14(1):255-260. Epub 2020 Jul 28.

Division of Nephrology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: Arterial stiffness is associated with increased cardiovascular morbidity and mortality. However, the predictive value of the cardio-ankle vascular index (CAVI), one of the indicators for arterial stiffness, for the risk of end-stage renal disease (ESRD) remains unknown.

Methods: A total of 8701 patients with documented CAVI measurements by pulse wave velocity (PWV) were included in the study. Patients were divided according to the quartiles of CAVI. The hazard ratio (HR) of ESRD was calculated using the Cox model, after adjustment for multiple variables or death.

Results: During the median follow-up period of 7 years (maximum 12 years), ESRD and mortality occurred in 203 and 1071 patients, respectively. The median value of CAVI was 8.5 (interquartile range 7.7-9.3). The risk of ESRD was higher in the fourth-quartile group than the first-quartile group [adjusted HR 2.46 (IQR 1.62-3.71), P<0.001]. When a death-adjusted risk analysis was performed, the fourth quartile of CAVI had a higher risk of ESRD than the first quartile [adjusted HR 2.35 (IQR 1.58-3.49), P<0.001].

Conclusions: The measurement of CAVI by PWV may be needed to predict the risk of ESRD.
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http://dx.doi.org/10.1093/ckj/sfaa116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857790PMC
January 2021

Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism.

Cell Metab 2021 02;33(2):334-349.e6

Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul 05505, Korea. Electronic address:

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPR) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPR and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.
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http://dx.doi.org/10.1016/j.cmet.2021.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959183PMC
February 2021

Vertical sleeve gastrectomy induces distinctive transcriptomic responses in liver, fat and muscle.

Sci Rep 2021 01 27;11(1):2310. Epub 2021 Jan 27.

Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Vertical sleeve gastrectomy (VSG) is the most commonly performed bariatric/metabolic surgery, exhibiting a high rate of diabetes remission in humans. To elucidate the molecular mechanisms of VSG, we performed transcriptomic analysis of the liver, fat, and muscle in VSG mice. C57BL/6 mice fed a high-fat diet were randomly assigned to sham or VSG surgery. The sham-operated mice were fed ad libitum (sham group) or pair-fed (sham-PF group) matching their food intake to the VSG-operated mice. Comparative transcriptomic analysis of the liver, fat, and muscle using RNA sequencing was performed. VSG reduced body weight and improved glucose tolerance compared to the sham group, but not more than the sham-PF group. Improvement in fatty liver and adipose tissue inflammation was comparable between VSG and sham-PF. However, global gene expression profiles showed distinctive changes in the liver, fat, and muscle of the VSG group compared to both the sham or sham-PF groups. The liver showed the most prominent gene expression changes. Immune response-related pathways were commonly upregulated in the three organs of the VSG group compared to the sham or sham-PF. VSG induces organ-specific gene expression changes in the liver, fat, and muscle, which may play critical roles in metabolic improvements after VSG.
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http://dx.doi.org/10.1038/s41598-021-81866-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840766PMC
January 2021

Thermal Properties of Ethanol Organosolv Lignin Depending on Its Structure.

ACS Omega 2021 Jan 7;6(2):1534-1546. Epub 2021 Jan 7.

Department of Agriculture, Forestry, and Bioresources, Seoul National University, 1, Gwanak-ro, Seoul 08826, Republic of Korea.

In general, lignin exhibits unpredictable and nonuniform thermal properties due to the structural variations caused by the extraction processes. Therefore, a systematic understanding of the correlation between the extraction conditions, structural characteristics, and properties is indispensable for the commercial utilization of lignin. In this study, the effect of extraction conditions on the structural characteristics of ethanol organosolv lignin (EOL) was investigated by response surface methodology. The structural characteristics of EOL (molecular weight, hydroxyl content, and intramolecular coupling structure) were significantly affected by the extraction conditions (temperature, sulfuric acid concentration, and ethanol concentration). In addition, the correlation between the structural characteristics and thermal properties of the extracted EOLs was estimated. The relevant correlations between the structural characteristics and thermal properties were determined. In particular, EOLs that had a low molecular weight, high phenolic hydroxyl content, and low aryl-ether linkage content exhibited prominent thermal properties in terms of their initial decomposition rate and a high glass transition temperature, . Correspondingly, EOL-PLA blends prepared using three EOL types exhibited improved thermal properties (starting point of thermal decomposition and maximum decomposition temperature) compared to neat PLA and had thermal decomposition behaviors coincident with the thermal properties of the constituent EOLs.
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http://dx.doi.org/10.1021/acsomega.0c05234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818625PMC
January 2021

Bariatric Surgery for Cowden Syndrome with PTEN Mutation: a Case Report.

Obes Surg 2021 May 22;31(5):2316-2318. Epub 2021 Jan 22.

Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1007/s11695-021-05231-1DOI Listing
May 2021

Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial.

BMJ Open Diabetes Res Care 2020 12;8(2)

Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.

Introduction: The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide.

Research Design And Methods: A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA and body weight.

Results: In the durability part, mean (SD) changes in HbA and body weight from week 0 were -1.5% (0.8) and -1.3% (1.0) and -2.8 kg (3.8) and -3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA from week 52 to week 104 were -0.2% for oral semaglutide and 0.1% for sitagliptin (difference -0.3% (95% CI -0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were -2.4 kg and -0.9 kg (difference -1.5 kg (95% CI -2.8 to -0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide.

Conclusions: Long-term oral semaglutide with flexible dose adjustment maintained HbA reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA reductions, helped more patients achieve HbA targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight.

Trial Registration Number: NCT02849080.
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http://dx.doi.org/10.1136/bmjdrc-2020-001649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737050PMC
December 2020

Effect of Changes in Patient's Self-management Strategies on Clinical Outcomes: Evidence from a Cohort Study of Patients with Diabetes, Hypertension, and Hyperlipidemia.

Int J Behav Med 2021 Aug 10;28(4):479-487. Epub 2020 Nov 10.

Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul, 03080, Korea.

Background: Self-management has become the dominant care model for chronic disease management. This study aimed to investigate the effect of changes in self-management strategies on the clinical outcomes of chronic diseases.

Methods: Two hundred ninety-seven patients with one or more chronic disease (diabetes, dyslipidemia, or hypertension) were registered and followed in this prospective cohort study. We compared differences in the changes in clinical outcomes from baseline to 6 months according to the improvement of self-management strategies by analysis of covariance.

Results: Diabetic patients with improved self-management strategies showed a significantly greater change in HbA1c levels compared to patients without improvement of self-management strategies (group difference in HbA1c = 0.51%). In hypertensive patients, systolic and diastolic blood pressure (BP) showed a significant decline in the patients with improved self-management strategies (group difference in systolic BP = 6.2 mmHg and in diastolic BP = 5.5 mmHg). Clinical outcomes improved significantly when self-management strategies improved in people with a poor self-management strategy at baseline.

Conclusions: This study suggests that improvements in self-management strategies are associated with an improvement in clinical outcomes among patients with chronic diseases, especially for those with an initially poor self-management strategy.
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http://dx.doi.org/10.1007/s12529-020-09937-xDOI Listing
August 2021

Development of a clinical risk score for incident diabetes: A 10-year prospective cohort study.

J Diabetes Investig 2021 Apr 9;12(4):610-618. Epub 2020 Sep 9.

Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Korea.

Aims/introduction: We developed a self-assessable Korean Diabetes Risk score using the data of the Korean Genome and Epidemiology Study.

Materials And Methods: A total of 8,740 participants without diabetes at baseline were followed up biannually over a period of 10 years. We included variables that were significantly different between participants who developed diabetes mellitus and those who did not in the development cohort at baseline. We assigned a maximum score of 100 to the selected variable in each gender group. Next, the 10-year probability of incident diabetes was calculated and validated in the validation cohort. Finally, we compared the predictive power of Korean Diabetes Risk score with models including fasting plasma glucose or glycated hemoglobin and other cohort models of Atherosclerosis Risk in Communities and Korea National Health and Nutrition Examination Survey.

Results: During a median follow-up period of 9.7 years, 22.7% of the participants progressed to diabetes. The Korean Diabetes Risk score included age, living location (urban or rural area), waist circumference, hypertension, family history of diabetes and smoking history. The developed risk score yielded acceptable discrimination for incident diabetes (area under the curve 0.657) and the predictive power was improved when the model included fasting plasma glucose (area under the curve 0.690) or glycated hemoglobin (area under the curve 0.746). In addition, our model predicted incident diabetes more accurately than previous Western or Korean models.

Conclusions: This newly developed self-assessable diabetes risk score is easily applicable to predict the future risk of diabetes even without the necessity for laboratory tests. This score is useful for the Korean diabetes prevention program, because high-risk individuals can be easily screened.
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http://dx.doi.org/10.1111/jdi.13382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015827PMC
April 2021

Invincible β-cells in type 1 diabetes.

J Diabetes Investig 2021 Feb 12;12(2):137-139. Epub 2020 Aug 12.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1111/jdi.13362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858098PMC
February 2021

Magnetically-driven implantable pump for on-demand bolus infusion of short-acting glucagon-like peptide-1 receptor agonist.

J Control Release 2020 09 30;325:111-120. Epub 2020 Jun 30.

Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University, Seoul 03080, Republic of Korea; Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, Seoul 08826, Republic of Korea; Department of Biomedical Engineering, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address:

For type 2 diabetic patients, short acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) is often prescribed with frequent needled injections. Long-acting GLP-1 RA for less frequent injections do not mimic physiologic secretion of GLP-1. Therefore, an implantable pump is proposed in this work, which can deliver a short-acting GLP-1 RA, exenatide, without needles and batteries. The implanted pump can infuse an accurate amount of exenatide bolus only when a noninvasive magnetic force is applied from outside the body. The pump includes a safety feature of patterned magnets for actuation to prevent accidental infusion possibly caused by a general household magnet. The reservoir for exenatide is made of a flexible biomaterial and thus, a negative pressure build-up in the reservoir can be prevented even after multiple actuations and almost all drug consumption (~ 94%). This allows a reproducible drug dose for a longer period after implantation, hence less frequent replenishment procedures. The pump is also equipped with an intermediate container with two distinct check-valves and thus, the reservoir of exenatide can be further separated and better prevented from infiltration of the bodily fluid surrounding the implanted pump. When tested in Goto-Kakizaki rats, the pump demonstrates the efficacy of exenatide similar to conventional subcutaneous injections. Therefore, the pump can be promising for patient-friendly, optimal delivery of short-acting GLP-1 RA that better follows the physiologic secretion profile of GLP-1.
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http://dx.doi.org/10.1016/j.jconrel.2020.06.022DOI Listing
September 2020

Prognosis of Patients with Colorectal Cancer with Diabetes According to Medication Adherence: A Population-Based Cohort Study.

Cancer Epidemiol Biomarkers Prev 2020 06;29(6):1120-1127

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea (South).

Background: Diabetes mellitus is known to have a negative effect on colorectal cancer survival due to hyperinsulinemia or hyperglycemia, and medications such as metformin, which targets insulin resistance and hyperinsulinemia, have a preventive effect on the risk of death. The aim of this study was to compare the risk of death among patients with colorectal cancer with diabetes with different levels of adherence to oral antidiabetics.

Methods: National Health Information Database was used, which has all claims data for those who are registered for national health insurance in Korea, from 2002 to 2016, for conducting a retrospective cohort study. Newly diagnosed patients with colorectal cancer among diabetics were followed up from the date of diagnosis until death or December 31, 2016. The medication adherence was calculated as the proportion of days covered (PDC). The HR and 95% confidence interval (CI) for death were estimated using the low-adherence patients as a reference.

Results: A total of 33,841 diabetic patients with newly diagnosed colorectal cancer were followed for an average of 4.7 years. Patients with colorectal cancer with good adherence (PDC ≥ 80%) showed a reduced risk of death [HR (95% CI), 0.82 (0.78-0.86)] compared with those with poor adherence (PDC < 80%). A reduced risk of death was observed for all cancer subsites.

Conclusions: The maintenance of good medication adherence for diabetes mellitus was related to a favorable prognosis of colorectal cancer.

Impact: This study provides evidence that patients with colorectal cancer who are adherent to their diabetes medication will have better survival than patients who are not adherent.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1455DOI Listing
June 2020

Economic benefit of prescribing an adjusted renal dose of dipeptidyl peptidase IV inhibitors in type 2 diabetes patients with chronic kidney disease.

J Diabetes 2020 Sep 25;12(9):645-648. Epub 2020 Jun 25.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

Highlights Based on nationwide insurance data in Korea, the use of dipeptidyl peptidase IV inhibitors (DPP-IVi) not requiring renal dose adjustment (NRDA DPP-IVi) is widespread in the type 2 diabetes chronic kidney disease (T2D CKD) population. Instead of prescribing NRDA DPP-IVi, the use of DPP-IVi requiring renal dose adjustment with appropriate renal dose adjustments in T2D CKD patients can achieve a considerable annual cost saving of up to 7.8%.
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http://dx.doi.org/10.1111/1753-0407.13067DOI Listing
September 2020

Effects of MOTS-c on the mitochondrial function of cells harboring 3243 A to G mutant mitochondrial DNA.

Mol Biol Rep 2020 May 11;47(5):4029-4035. Epub 2020 Apr 11.

Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Mitochondrial derived peptides (MDPs) are a class of peptide encoded in small open reading frames of mitochondrial DNA (mtDNA). MOTS-c, a recently discovered MDP, participates in retrograde signaling from the mitochondria to the nucleus to control cellular metabolism. Humanin, another MDP, has cytoprotective properties and enhances mitochondrial function. However, it has not yet been tested whether MOTS-c can affect mitochondrial function. We investigated the effect of exogenous and endogenous MOTS-c on mitochondrial function in a cybrid cell harboring 3243 A to G mutant mtDNA, which causes significant mitochondrial dysfunction. To test the effects of endogenous MOTS-c, the cybrid cell was transfected with a MOTS-c EGFP expression vector. Exogenous (synthetic) MOTS-c did not show a significant effect on the ATP content or the mRNA and protein levels of the mitochondrial complex in the mutant cybrid cells. Basal and stimulated mitochondrial respiration were also not affected by exogenous MOTS-c. The mutant cybrid cells transfected with the MOTS-c EGFP expression vector stably expressed MOTS-c, but ATP production and mRNA and protein levels of the mitochondrial complex were not affected. In contrast to other MDPs, MOTS-c does not improve mitochondrial dysfunction in cybrid cells with mutant mtDNA, which suggests the heterogeneous nature of MDPs.
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http://dx.doi.org/10.1007/s11033-020-05429-zDOI Listing
May 2020

Efficacy of an Electronic Health Management Program for Patients With Cardiovascular Risk: Randomized Controlled Trial.

J Med Internet Res 2020 01 22;22(1):e15057. Epub 2020 Jan 22.

Seoul National University College of Medicine, Cancer Research Institute, Seoul, Republic of Korea.

Background: In addition to medication, health behavior management is crucial in patients with multiple risks of cardiovascular mortality.

Objective: This study aimed to examine the efficacy of a 3-month Smart Management Strategy for Health-based electronic program (Smart Healthing).

Methods: A 2-arm randomized controlled trial was conducted to assess the efficacy of Smart Healthing in 106 patients with at least one indicator of poor disease control and who had hypertension, diabetes, or hypercholesterolemia. The intervention group (n=53) took part in the electronic program, which was available in the form of a mobile app and a Web-based PC application. The program covered 4 areas: self-assessment, self-planning, self-learning, and self-monitoring by automatic feedback. The control group (n=53) received basic educational material concerning disease control. The primary outcome was the percentage of participants who achieved their clinical indicator goal after 12 weeks into the program: glycated hemoglobin (HbA) <7.0%, systolic blood pressure (SBP) <140 mmHg, or low-density lipoprotein cholesterol <130 mg/dL.

Results: The intervention group showed a significantly higher success rate (in comparison with the control group) for achieving each of 3 clinical indicators at the targeted goal levels (P<.05). Only the patients with hypertension showed a significant improvement in SBP from the baseline as compared with the control group (72.7% vs 35.7%; P<.05). There was a significant reduction in HbA in the intervention group compared with the control group (difference=0.54%; P≤.05). In the intervention group, 20% of patients with diabetes exhibited a ≥1% decrease in HbA (vs 0% among controls; P≤.05).

Conclusions: A short-term self-management strategy-based electronic program intervention may improve clinical outcomes among patients with cardiovascular risks.

Trial Registration: ClinicalTrials.gov NCT03294044; https://clinicaltrials.gov/ct2/show/NCT03294044.
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http://dx.doi.org/10.2196/15057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003122PMC
January 2020

Ileal Transposition Increases Pancreatic β Cell Mass and Decreases β Cell Senescence in Diet-Induced Obese Rats.

Obes Surg 2020 05;30(5):1849-1858

Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Background: Ileal transposition (IT) is a surgical procedure to investigate the role of the distal small intestine in metabolic improvements induced by bariatric/metabolic surgery, which has been applied to some human cases. We performed IT in diet-induced obese rats to investigate the effect of IT on glucose metabolism and β cell senescence.

Methods: Sprague-Dawley rats were fed high-fat diet (60% of total calories from fat) for 12 weeks and randomized into either IT or sham surgery. In the IT group, the distal ileal segment located between 5 and 15 cm proximal to the ileocecal valve was transposed 10 cm distal to the Treitz ligament isoperistaltically. In the sham surgery group, 3 corresponding transections of the intestine were made at the same locations as in IT and reattached in situ. β cell senescence was examined by the expression of two markers in vivo, p53BP1 and p16.

Results: IT did not have a significant effect on body weight and insulin sensitivity, but postprandial insulin secretion was significantly increased. Glucagon-like peptide-1 (GLP-1) and peptide YY secretion were also increased after IT. The histology of the transposed ileum showed distinct hypertrophy with increased GLP-1 positive enteroendocrine cells. Pancreatic β cell area was significantly increased in the IT group. The percentage of p16 or p53BP1 positive senescent β cells was significantly lower in the IT group versus the sham group.

Conclusions: IT improved glucose tolerance in diet-induced obese rats mainly through augmented insulin secretion. This improvement was associated with attenuated β cell senescence.
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http://dx.doi.org/10.1007/s11695-020-04406-6DOI Listing
May 2020

Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus.

Diabetes Metab J 2020 04 4;44(2):248-259. Epub 2019 Nov 4.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: To investigate the effects of a glucagon-like peptide-1 receptor agonist on functional brain activation in lean and obese individuals with type 2 diabetes mellitus (T2DM) in response to visual food cues.

Methods: In a randomized, single-blinded, crossover study, 15 lean and 14 obese individuals with T2DM were administered lixisenatide or normal saline subcutaneously with a 1-week washout period. We evaluated brain activation in response to pictures of high-calorie food, low-calorie food, and nonfood using functional magnetic resonance imaging and measured appetite and caloric intake in participants who were given access to an buffet.

Results: Obese individuals with T2DM showed significantly greater activation of the hypothalamus, pineal gland, parietal cortex (high-calorie food vs. low-calorie food, <0.05), orbitofrontal cortex (high-calorie food vs. nonfood, <0.05), and visual cortex (food vs. nonfood, <0.05) than lean individuals with T2DM. Lixisenatide injection significantly reduced the functional activation of the fusiform gyrus and lateral ventricle in obese individuals with T2DM compared with that in lean individuals with T2DM (nonfood vs. high-calorie food, <0.05). In addition, in individuals who decreased their caloric intake after lixisenatide injection, there were significant interaction effects between group and treatment in the posterior cingulate, medial frontal cortex (high-calorie food vs. low-calorie food, <0.05), hypothalamus, orbitofrontal cortex, and temporal lobe (food vs. nonfood, <0.05).

Conclusion: Brain responses to visual food cues were different in lean and obese individuals with T2DM. In addition, acute administration of lixisenatide differentially affected functional brain activation in these individuals, especially in those who decreased their caloric intake after lixisenatide injection.
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http://dx.doi.org/10.4093/dmj.2019.0018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188972PMC
April 2020

Efficacy and safety of gemigliptin as add-on therapy to insulin, with or without metformin, in patients with type 2 diabetes mellitus (ZEUS II study).

Diabetes Obes Metab 2020 01 8;22(1):123-127. Epub 2019 Oct 8.

Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

The objective of this study was to evaluate the efficacy and safety of gemigliptin added to a stable dose of insulin alone or of insulin in combination with metformin in patients with type 2 diabetes mellitus. After a two-week run-in period, patients were randomized 2:1 to receive gemigliptin 50 mg or placebo once daily as add-on to background therapy with insulin or insulin plus metformin for 24 weeks. The primary endpoint was change in haemoglobin A1c (HbA1c) from baseline at Week 24. Baseline characteristics were similar between the gemigliptin (n = 188) and placebo (n = 95) groups in terms of HbA1c (8.1%). At Week 24, the gemigliptin group showed a statistically significant reduction in mean HbA1c from baseline as compared with placebo (between-group mean difference, -0.7% [95% CI, -0.9% to -0.4%]; P-value < 0.0001). The incidence of overall adverse events and the number of hypoglycaemic adverse events were similar between the study groups. Gemigliptin added to insulin alone or to insulin in combination with metformin resulted in superior glycaemic control compared to that in the placebo group and was well tolerated for 24 weeks in patients with type 2 diabetes mellitus, without causing weight gain or increasing the incidence of hypoglycaemia.
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http://dx.doi.org/10.1111/dom.13873DOI Listing
January 2020

Premeal Consumption of a Protein-Enriched, Dietary Fiber-Fortified Bar Decreases Total Energy Intake in Healthy Individuals.

Diabetes Metab J 2019 12 25;43(6):879-892. Epub 2019 Jun 25.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: A premeal load of protein can increase satiety and reduce energy intake. Dietary fiber also conveys metabolic benefits by modulating energy intake. We made a protein-enriched, dietary fiber-fortified bar (PFB) and aimed to investigate its effects on food intake and gut hormone secretion in healthy individuals.

Methods: Twenty subjects with normal glucose tolerance were enrolled. On three separate visits, the subjects received, in a randomized order, one of the following: a PFB containing 73 kcal with 10.7 g of protein and 12.7 g of dietary fiber; a usual bar (UB) containing the same calories as the PFB but only 0.9 g of protein and no dietary fiber; or water (control). After 15 minutes, the subjects had intake of a test meal. Food consumption, appetite, and plasma gut hormone levels were measured.

Results: Total energy intake, including the bar and the test meal, was significantly reduced with the PFB preload compared to the water (904.4±534.9 kcal vs. 1,075.0±508.0 kcal, =0.016). With the UB preload, only the intake of the test meal was reduced (=0.044) but not the total energy intake (=0.471) than the water. Fullness was also significantly increased after the PFB. In addition, postprandial glucose levels decreased and glucagon-like peptide-1 levels increased with the PFB compared with both the UB and water.

Conclusion: In healthy individuals, a premeal supplementation of PFB reduced total energy intake and decreased postprandial glucose excursion. This finding necessitates long-term studies regarding clinical use in obesity.
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http://dx.doi.org/10.4093/dmj.2018.0202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943273PMC
December 2019

Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea.

Diabetes Metab J 2019 08 19;43(4):432-446. Epub 2019 Jun 19.

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM).

Methods: This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia.

Results: The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. -0.9±6.0 kg, =0.011).

Conclusion: The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.
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http://dx.doi.org/10.4093/dmj.2018.0092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712234PMC
August 2019

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial.

Lancet Diabetes Endocrinol 2019 07 9;7(7):528-539. Epub 2019 Jun 9.

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg.

Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing.

Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p<0·0001; and trial product estimand: 5·54, 3·54-8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: -2·6 kg [SE 0·3] vs -0·7 kg [SE 0·2], estimated treatment difference [ETD] -1·9 kg, 95% CI -2·6 to -1·2; p<0·0001; and trial product estimand: -2·9 kg [SE 0·3] vs -0·8 kg [SE 0·3], ETD -2·2 kg, -2·9 to -1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial.

Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists.

Funding: Novo Nordisk A/S.
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http://dx.doi.org/10.1016/S2213-8587(19)30194-9DOI Listing
July 2019

Lilly Insulin Glargine Versus Lantus in Type 2 Diabetes Mellitus Patients: India and East Asia Subpopulation Analyses of the ELEMENT 5 Study.

Clin Drug Investig 2019 Aug;39(8):745-756

Eli Lilly Deutschland GmbH, Bad Homburg, Germany.

Background And Objectives: Lilly insulin glargine (LY IGlar; Basaglar) and the reference insulin glargine product (IGlar; Lantus) are basal insulin glargine analogs with identical amino acid sequence and similar pharmacological profiles. ELEMENT 5, a Phase 3, prospective, randomized, multinational, two-arm, active-controlled, open-label, parallel-design study in type 2 diabetes mellitus (T2DM) patients (N = 493) showed similar efficacy and safety profiles with LY IGlar and IGlar. This study reports results from India (N = 100) and East Asia (N = 134) subpopulations.

Methods: Patients from India and East Asia (Korea and Taiwan) with T2DM who were insulin naïve (glycated hemoglobin (HbA1c) ≥ 7.0% and ≤ 11.0%) or on basal insulin (HbA1c ≤ 11.0%) were randomized to receive LY IGlar or IGlar along with oral antihyperglycemic medications (OAMs) for 24 weeks. Patients were instructed to self-titrate from the starting dose by 1 unit/day until fasting blood glucose (FBG) ≤ 5.6 mmol/L (100 mg/dL) was achieved. The key outcome was HbA1c change from baseline to Week 24.

Results: Within-group least-squares mean (LSM) decrease (baseline to Week 24) in HbA1c was similar between treatments. The upper limit of confidence interval (CI) for treatment difference was below the defined 0.4% noninferiority margin in India (LY IGlar: - 0.83%; IGlar: - 0.62%; difference [95% CI] - 0.21 [- 0.70, 0.28]) and East Asia (LY IGlar: - 1.28%; IGlar: - 1.26%; difference [95% CI] - 0.02 [- 0.34, 0.30]) subpopulations. Results of other efficacy and safety endpoints at Week 24 were similar between treatments in both subpopulations. LSM self-monitored FBG levels were similar between treatments at all visits in both subpopulations except at Week 24 in the India subpopulation (LY IGlar: 5.65 [0.10] mmol/L or 101.8 [1.86] mg/dL; IGlar: 5.18 [0.10] mmol/L or 93.3 [1.75] mg/dL; p = 0.002).

Conclusion: Efficacy and safety profiles of LY IGlar and IGlar, in combination with OAMs, were similar in India and East Asia subpopulations. This was consistent with the ELEMENT 5 total population.

Clinical Trial Registration: NCT02302716.
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http://dx.doi.org/10.1007/s40261-019-00798-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656918PMC
August 2019
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