The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

A 52-week efficacy and safety study of enavogliflozin versus dapagliflozin as an add-on to metformin in patients with type 2 diabetes mellitus: ENHANCE-M extension study.

AIM: To evaluate the long-term safety and efficacy of enavogliflozin 0.3 mg/day added to metformin in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: After 24 weeks of a randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 101) or dapagliflozin 10 mg/day (n = 99) added to metformin, all patients received enavogliflozin 0.3 mg/day plus metformin for an additional 28 weeks during the open-label extension period. RESULTS: Eighty-two patients continued enavogliflozin (maintenance group), and 77 were switched from dapagliflozin to enavogliflozin (switch group). All adverse drug reactions (ADR) were mild in severity. In the maintenance group, ADRs (cystitis and vaginal infection) were reported in two patients (2.44%) during 52 weeks. In the switch group, ADR (hypoglycaemia) was reported in one patient (1.30%) during a 28-week open-label extension period. At week 52, glycated haemoglobin and fasting plasma glucose were significantly lower than at the baseline, by 0.85% and 29.08 mg/dl, respectively, in the maintenance group (p < .0001 for both), and by 0.81% and 32.77 mg/dl, respectively, in the switch group (p < .0001 for both). At week 52, 68.92% of patients from the maintenance group and 64.29% from the switch group achieved glycated haemoglobin <7%. A significant increase in the urine glucose-creatinine ratio was observed at week 52, by 58.81 g/g and 63.77 g/g in the maintenance and switch groups, respectively (p < .0001). CONCLUSIONS: Enavogliflozin added to metformin was tolerated well for up to 52 weeks and provided continual glycaemic control in type 2 diabetes mellitus, along with a significant increase in the urine glucose-creatinine ratio.

Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study.

BACKGRUOUND: To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM). METHODS: This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c ), fasting plasma glucose, and body weight. RESULTS: Data were collected from 3,067 subjects, and 3,022 subjects who received ≥1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg). CONCLUSION: Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population.

Age at Mortality in Patients with Type 2 Diabetes Who Underwent Kidney Transplantation: An Analysis of Data from the Korean National Health Insurance and Statistical Information Service, 2006 to 2018.

BACKGROUND: Although the clinical outcomes of diabetes have improved, diabetes remains the principal cause of end-stage renal disease. The aim of the study is to investigate whether mortality trends in individuals with type 2 diabetes and kidney transplantation (KT) have changed. METHODS: This study analyzed data from the National Health Insurance Service claims database linked to death records from the National Statistical Information Service in Korea. Information from a total of 2521 deaths of KT recipients was collected from 2006 to 2018. RESULTS: The age at death of KT recipients increased from 57.4 years in 2006 to 65.2 years in 2018, with a mean change of +0.65 years/year (p < 0.001). The overall age at death increased by 0.55 and 0.66 years/year in the type 2 diabetes and non-diabetes populations, respectively. The age at death was significantly higher in the type 2 diabetes group, and was maintained during the study period. The proportion of death due to malignancy and cerebrovascular and heart disease was maintained, that due to type 2 diabetes decreased and that due to pneumonia increased. Neither diabetes nor hypertension determined the age at death, and the age at KT was the most prominent factor affecting age at death in KT recipients. CONCLUSIONS: The age at death in KT recipients increased over the 12 years between 2006 and 2018, with similar trends in the type 2 diabetes and non-diabetes groups. The age at KT was higher in patients with type 2 diabetes, and was the main contributor to the age at death in KT recipients.

Tolerability and Effectiveness of Switching to Dulaglutide in Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy.

Aims: Glucagon-like peptide 1 (GLP-1) receptor agonists have demonstrated strong glycemic control. However, few studies have investigated the effects of switching from insulin to GLP-1 receptor agonists. We aimed to investigate, using real-world data, whether switching to dulaglutide improves glycemic control in patients with type 2 diabetes mellitus (T2D) inadequately controlled with conventional insulin treatment. Materials and methods: We retrospectively evaluated 138 patients with T2D who were switched from insulin to dulaglutide therapy. We excluded 20 patients who dropped out during the follow-up period. The participants were divided into two groups according to whether they resumed insulin treatment at 6 months after switching to a GLP-1 receptor agonist (group I) or not (group II). A multiple logistic regression analysis was performed to evaluate the parameters associated with the risk of resuming insulin after replacement with dulaglutide. Results: Of 118 patients initiated on the GLP-1 receptor agonist, 62 (53%) resumed insulin treatment (group I), and 53 (47%) continued with GLP-1 receptor agonists or switched to oral anti-hypoglycemic agents (group II). Older age, a higher insulin dose, and lower postprandial glucose levels while switching to the GLP-1 receptor agonist were associated with failure to switch to the GLP-1 receptor agonist from insulin. Conclusions: A considerable proportion of patients with T2D inadequately controlled with insulin treatment successfully switched to the GLP-1 receptor agonist. Younger age, a lower dose of insulin, and a higher baseline postprandial glucose level may be significant predictors of successful switching from insulin to GLP-1 receptor agonist therapy.

Improvement in Age at Mortality and Changes in Causes of Death in the Population with Diabetes: An Analysis of Data from the Korean National Health Insurance and Statistical Information Service, 2006 to 2018.

BACKGRUOUND: Diabetes is a leading cause of death that is responsible for 1.6 million annual deaths worldwide. However, the life expectancy and age at death of people with diabetes have been a matter of debate. METHODS: The National Health Insurance Service claims database, merged with death records from the National Statistical Information Service in Korea from 2006 to 2018, was analyzed. RESULTS: In total, 1,432,567 deaths were collected. The overall age at death increased by 0.44 and 0.26 year/year in the diabetes and control populations, respectively. The disparity in the mean age at death between the diabetes and control populations narrowed from 5.2 years in 2006 to 3.0 years in 2018 (p<0.001). In a subgroup analysis according to the presence of comorbid diseases, the number and proportion of deaths remained steady in the group with diabetes only, but steadily increased in the groups with diabetes combined with dyslipidemia and/or hypertension. Compared to the control population, the increase in the mean death age was higher in the population with diabetes. This trend was more prominent in the groups with dyslipidemia and/or hypertension than in the diabetes only group. Deaths from vascular disease and diabetes decreased, whereas deaths from cancer and pneumonia increased. The decline in the proportion of deaths from vascular disease was greater in the diabetes groups with hypertension and/or dyslipidemia than in the control population. CONCLUSION: The age at death in the population with diabetes increased more steeply and reached a comparable level to those without diabetes.

Short Term Isocaloric Ketogenic Diet Modulates NLRP3 Inflammasome Via B-hydroxybutyrate and Fibroblast Growth Factor 21.

A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum ß-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1ß (IL-1ß) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. In ex-vivo experiments with macrophages, both FGF21 and BHB further reduced IL-1ß secretion compared to either BHB or FGF21 alone. The inhibitory effect of FGF21 on IL-1ß secretion was blunted with bafilomycin treatment, which blocked autophagy flux. In conclusion, isocaloric KD for 3 days is a promising approach to improve metabolic and inflammatory status. Clinical Trial Registration: clinicaltrials.gov (NCT02964572).

Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study).

BACKGROUND: The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change. RESULTS: Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104). CONCLUSIONS: Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).

Dipeptidyl peptidase-4 inhibitor protects against non-alcoholic steatohepatitis in mice by targeting TRAIL receptor-mediated lipoapoptosis via modulating hepatic dipeptidyl peptidase-4 expression.

Dipeptidyl peptidase-4 inhibitors (DPP4i) are antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP4). DPP4 is ubiquitously expressed, and its hepatic DPP4 expression is upregulated under non-alcoholic steatohepatitis (NASH) conditions. We investigated the effect of DPP4i treatment on NASH pathogenesis, as well as its potential underlying molecular mechanisms. Mice were randomly divided into three groups: Group 1, chow-fed mice treated with vehicle for 20 weeks; Group 2, high-fat, high-fructose, and high-cholesterol Amylin liver NASH (AMLN) diet-fed mice treated with vehicle for 20 weeks; Group 3, AMLN diet-fed mice treated with vehicle for the first 10 weeks, followed by the DPP4i teneligliptin (20 mg/kg/day) for additional 10 weeks. DPP4i administration reduced serum liver enzyme and hepatic triglyceride levels and markedly improved hepatic steatosis and fibrosis in the AMLN diet-induced NASH model. In vivo, NASH alleviation significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and downregulated hepatic DPP4 expression. In vitro, DPP4i treatment significantly decreased the markers of TRAIL receptor-mediated lipoapoptosis and suppressed DPP4 expression in palmitate-treated hepatocytes. In conclusion, DPP4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly by modulating hepatic DPP4 expression.

Metformin and Gastrointestinal Cancer Development in Newly Diagnosed Type 2 Diabetes: A Population-Based Study in Korea.

INTRODUCTION: Clinical studies have produced conflicting results on the effects of metformin on gastrointestinal cancer development. We aimed to investigate the association between metformin use and stomach, colon, liver, and pancreatic cancer development among patients with newly diagnosed, drug-naïve type 2 diabetes. METHODS: This retrospective study evaluated propensity score-matched patients with newly diagnosed type 2 diabetes from the Korean National Health Insurance Service database. Metformin users were categorized into tertiles according to the cumulative dose or duration of metformin treatment, and the risks of gastrointestinal cancers were compared. RESULTS: Metformin users had reduced risks of developing stomach cancer (hazard ratio [HR]: 0.841, 95% confidence interval [CI]: 0.797-0.887), colon cancer (HR: 0.865, 95% CI: 0.822-0.91), and liver cancer (HR: 0.709, 95% CI: 0.675-0.746; P < 0.001). However, metformin users did not have a reduced overall risk of pancreatic cancer (HR: 1.335, 95% CI: 1.209-1.475; P < 0.001). The risks tended to decrease at higher cumulative doses and durations of metformin use, with significantly reduced risks of all 4 cancers at the highest cumulative dose (≥1,200,000 mg) and the longest duration (≥2,000 days) of metformin use. DISCUSSION: This population-based data suggest that metformin could be associated with reductions in the risks of stomach, colon, and liver cancers, as well a reduced risk of pancreatic cancer in some subgroups. Metformin has benefit as a first-line treatment for type 2 diabetes mellitus. A further role in cancer risk reduction could be studied in controlled trials.

Data Configuration and Publication Trends for the Korean National Health Insurance and Health Insurance Review & Assessment Database.

Background: Big data reports related to diseases and health care for the Korean population have been published since the National Health Insurance Service (NHIS) and the Health Insurance Review & Assessment (HIRA) Service provided limited open access to their databases. Here, we reviewed the structure, content, and means of using data from the National Health Insurance (NHI) system for the benefit of Korean researchers and presented the latest publication trends in Korean healthcare data procured from the NHI and HIRA databases. METHODS: Since 2013, researchers have been able to obtain nationwide population-based studies using the NHI and HIRA databases of the insured. We searched publications using the NHI and the HIRA databases between 2013 and 2019 retrieved from PubMed. RESULTS: The NHI and HIRA databases provide nationwide population-based data. The total number of publications from 2014 to 2019 using NHI and HIRA databases is 2,541 and 655, respectively. A total of 5,465 endocrinology-related studies were performed during 2014 to 2019. CONCLUSION: The NHIS and HIRA databases have provided tools for guidelines to approach world-leading population-based epidemiology and disease research.

Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti-diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first-line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD.

SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1ß release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1ß secretion compared to sulfonylurea accompanied by increased serum ß-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association.

This clinical practice position statement, a product of the Fatty Liver Research Group of the Korean Diabetes Association, proposes recommendations for the diagnosis, progression and/or severity assessment, management, and follow-up of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NAFLD have an increased risk of non-alcoholic steatohepatitis (NASH) and fibrosis and a higher risk of cardiovascular diseases and diabetic complications compared to those without NAFLD. With regards to the evaluation of patients with T2DM and NAFLD, ultrasonography-based stepwise approaches using noninvasive biomarker models such as fibrosis-4 or the NAFLD fibrosis score as well as imaging studies such as vibration-controlled transient elastography with controlled attenuation parameter or magnetic resonance imaging-proton density fat fraction are recommended. After the diagnosis of NAFLD, the stage of fibrosis needs to be assessed appropriately. For management, weight reduction achieved by lifestyle modification has proven beneficial and is recommended in combination with antidiabetic agent(s). Evidence that some antidiabetic agents improve NAFLD/NASH with fibrosis in patients with T2DM is emerging. However, there are currently no definite pharmacologic treatments for NAFLD in patients with T2DM. For specific cases, bariatric surgery may be an option if indicated.

Gamma glutamyltransferase and risk of dementia in prediabetes and diabetes.

Diabetes is associated with cognitive impairment and greater risk for dementia, but the role of gamma-glutamyltransferase (γ-GT) in dementia has not been elucidated. We determined incident dementia including Alzheimer's disease and vascular dementia, analyzing data from participants aged 40 years or older in the National Health Insurance Database, collected by the National Health Insurance Service in Korea, from January 2009 to December 2015. During a median follow-up of 7.6 years, 272,657 participants were diagnosed as having dementia. Higher serum γ-GT was associated with increased risk of dementia (HR = 1.22, 95% CI = 1.20-1.24), and had a strong positive association with early onset dementia (HR = 1.32, 95% CI = 1.24-1.40). An additive impact of higher γ-GT on dementia was observed regardless of glycemic status, and prevalent diabetes with the highest γ-GT quartile had a 1.8-fold increased dementia risk (HR = 1.82, 95% CI = 1.78-1.85). This effect of γ-GT concentration in diabetes was more prominent in individuals with vascular dementia (HR = 1.94, 95% CI = 1.84-2.04). In subgroup analysis, young age, male sex, and relatively healthy subjects with a higher γ-GT quartile had more increased dementia risk. In conclusion, γ-GT concentration as well as glycemic status could be a future risk factor for dementia in the general population.

Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors.

PURPOSE: Targeted therapy using phosphatidylinositol 3-kinase (PI3K) inhibitors is used to treat cancer such as lymphoma. In animal studies, its use raised concern about alteration of glucose metabolism. To date, clinical data are inconclusive; therefore, we investigated the incidence and clinical manifestations of diabetes in cancer patients treated with PI3K inhibitors. METHODS: In a retrospective review of diabetes-free patients with advanced solid tumors treated with PI3K inhibitor, we performed Cox regression to identify independent predictors for the development of diabetes. RESULTS: Of 38 patients (mean age: 54.5 years, 23.7% female) having a mean duration of follow-up of 238.5 days who initiated PI3K inhibitors, 55.3% developed diabetes during treatment (mean 29.1 days); among these, 28.6% experienced remission of diabetes after discontinuing PI3K inhibitors (mean 72.1 days). Patients with incident diabetes had higher anti-hypertensive medication use, higher HbA1c levels and fasting glucose at baseline, and longer duration of PI3K inhibitor use (P = 0.024, P = 0.005, P = 0.008, and P = 0.023, respectively). Previous steroid use and lower baseline HbA1c level were significantly associated with development of diabetes (HR = 8.41, 95% CI 1.89-37.33; HR = 2.16, 95% CI 1.09-4.25, respectively). Patients whose diabetes remitted after discontinuing PI3K inhibitors were younger (P = 0.035) and had lower fasting glucose levels during PI3K inhibitor treatment (P = 0.001) compared to those non-remitters. CONCLUSIONS: Previous steroid use and lower baseline HbA1c level may be important predictors for developing diabetes in patients with advanced solid tumors treated with PI3K inhibitors, warranting close observation and careful intervention.

Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders that are often comorbid conditions. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone; pharmacological treatments are helpful in this regard. Although many drugs have been investigated, pioglitazone could be a first-line therapy in patients with NAFLD and diabetes. Many more drugs are currently being developed and investigated, and it is likely that combination strategies will be used for future treatment of NAFLD and diabetes. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.

Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis.

Nonalcoholic fatty liver disease (NAFLD) and diabetes are common metabolic disorders whose prevalence rates are expected to rise worldwide, corresponding to aging and increasingly obese populations. Compared to the general population (around 25%), 50% to 70% of people with diabetes have NAFLD, and NAFLD severity (including fibrosis) tends to be worsened by the presence of diabetes. NAFLD is considered an emerging risk factor for type 2 diabetes mellitus and a contributor to the development of chronic diabetes-related complications. This reciprocal relationship demonstrates the importance of confirming suspected NAFLD in patients with diabetes. Due to the invasive nature of liver biopsy to assess NAFLD status, various alternative non-invasive modalities have been developed and validated. Here, we summarized the epidemiology of NAFLD in patients with diabetes and reviewed currently available imaging modalities and biomarker-based prediction models for their ability to detect liver steatosis and/or fibrosis.

Characteristics of Dapagliflozin Responders: A Longitudinal, Prospective, Nationwide Dapagliflozin Surveillance Study in Korea.

INTRODUCTION: Sodium glucose co-transporter 2 (SGLT2) inhibitors, such as dapagliflozin, have demonstrated favorable effects in patients with type 2 diabetes (T2D). However, there are limited reports in the literature regarding the glucose-lowering effects of SGLT2 inhibitors in actual clinical settings. METHODS: The post-marketing surveillance data from a longitudinal prospective study of 2007 patients with T2D who were prescribed dapagliflozin (10 mg/day) were analyzed (ClinicalTrials.gov, NCT02252224). RESULTS: After 12 weeks of dapagliflozin treatment, glycated hemoglobin (HbA1c) and body mass index were significantly decreased (P < 0.001) from 8.1 ± 1.3% to 7.5 ± 1.2% and from 28.1 ± 4.4 to 27.6 ± 4.2 kg/m2, respectively. Both body weight and HbA1c were reduced in 67.7% of patients, and HbA1c was lowered in 75.1%. Younger age, male sex, shorter diabetes duration, higher baseline HbA1c and estimated glomerular filtration rate (eGFR), and having dapagliflozin as add-on therapy were associated with stronger HbA1c reductions after dapagliflozin use (all P < 0.05). Moreover, subgroup analysis of eGFR of subjects with renal hyperfiltration (eGFR ≥ 120 ml/min/1.73 m2) showed the largest reduction in glucose level (% change, - 9.5; 95% CI - 6.8 to - 12.3 for HbA1c; P < 0.001). Multivariable logistic regression analysis showed that recent T2D diagnosis and higher HbA1c at baseline in patients who received an add-on regimen of dapagliflozin were statistically significantly associated with a dapagliflozin response (all P < 0.05). CONCLUSIONS: Dapagliflozin provides benefits for glycemic control and body weight. Patients in a relatively early stage of the course of diabetes with renal hyperfiltration might be more suitable for and gain maximal benefit from dapagliflozin treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02252224. FUNDING: AstraZeneca.

Protective Effect of Metformin Against Thyroid Cancer Development: A Population-Based Study in Korea.

BACKGROUND: Metformin, the most widely used drug for type 2 diabetes, has recently attracted attention with regard to its antitumor activity. However, clinical studies have yielded conflicting results regarding the association between metformin and thyroid cancer development, despite its antitumor effect in preclinical studies. METHODS: This is a retrospective cohort study using the Korean National Health Insurance claim database. Matched populations of 128,453 metformin users and 128,453 non-users were analyzed for thyroid cancer incidence. Metformin users were categorized into lowest, middle, and highest tertiles according to cumulative dose or duration of metformin therapy. RESULTS: Thyroid cancer developed in 340 (0.26%) metformin users and 487 (0.38%) non-users during a mean follow-up of 7.2 years (hazard ratio = 0.69 [confidence interval 0.60-0.79]; p < 0.001). The incidence of thyroid cancer per 105 person-years was 51.6 in metformin non-users. For metformin users, the incidence was 84.5 for <529,000 mg, 20.6 for 529,000-1,007,799 mg, and 6.3 for >1,007,799 mg; 86.3 for <1085 days, 20.3 for 1085-2094 days, and 4.7 for >2094 days for duration of therapy. The hazard ratio for thyroid cancer decreased significantly in metformin users as a function of dose and duration of metformin therapy. CONCLUSIONS: Metformin appears to be associated with a preventive effect on thyroid cancer development in a nationwide population-based study, but is not effective in the early phase of treatment. Considering the increasing prevalence of obesity and the role of insulin resistance in the development of cancer, metformin might be the preferred treatment for its dual anti-diabetic and antitumor effects.