Continuous glucose monitoring with structured education in adults with type 2 diabetes managed by multiple daily insulin injections: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to compare the effectiveness of stand-alone intermittently scanned continuous glucose monitoring (isCGM) with or without a structured education programme and blood glucose monitoring (BGM) in adults with type 2 diabetes on multiple daily insulin injections (MDI). METHODS: In this 24 week randomised open-label multicentre trial, adults with type 2 diabetes on intensive insulin therapy with HbA1c levels of 58-108 mmol/mol (7.5-12.0%) were randomly assigned in a 1:1:1 ratio to isCGM with a structured education programme on adjusting insulin dose and timing according to graphical patterns in CGM (intervention group), isCGM with conventional education (control group 1) or BGM with conventional education (control group 2). Block randomisation was conducted by an independent statistician. Due to the nature of the intervention, blinding of participants and investigators was not possible. The primary outcome was change in HbA1c from baseline at 24 weeks, assessed using ANCOVA with the baseline value as a covariate. RESULTS: A total of 159 individuals were randomised (n=53 for each group); 148 were included in the full analysis set, with 52 in the intervention group, 49 in control group 1 and 47 in control group 2. The mean (± SD) HbA1c level at baseline was 68.19±10.94 mmol/mol (8.39±1.00%). The least squares mean change (± SEM) from baseline HbA1c at 24 weeks was -10.96±1.35 mmol/mol (-1.00±0.12%) in the intervention group, -6.87±1.39 mmol/mol (-0.63±0.13%) in control group 1 (p=0.0367 vs intervention group) and -6.32±1.42 mmol/mol (-0.58±0.13%) in control group 2 (p=0.0193 vs intervention group). Adverse events occurred in 28.85% (15/52) of individuals in the intervention group, 26.42% (14/53) in control group 1 and 48.08% (25/52) in control group 2. CONCLUSIONS/INTERPRETATION: Stand-alone isCGM offers a greater reduction in HbA1c in adults with type 2 diabetes on MDI when education on the interpretation of graphical patterns in CGM is provided. TRIAL REGISTRATION: ClinicalTrials.gov NCT04926623. FUNDING: This study was supported by Daewoong Pharmaceutical Co., Ltd.

Comparison between a tubeless, on-body automated insulin delivery system and a tubeless, on-body sensor-augmented pump in type 1 diabetes: a multicentre randomised controlled trial.

AIMS/HYPOTHESIS: This study compares the efficacy and safety of a tubeless, on-body automated insulin delivery (AID) system with that of a tubeless, on-body sensor-augmented pump (SAP). METHODS: This multicentre, parallel-group, RCT was conducted at 13 tertiary medical centres in South Korea. Adults aged 19-69 years with type 1 diabetes who had HbA1c levels of <85.8 mmol/mol (<10.0%) were eligible. The participants were assigned at a 1:1 ratio to receive a tubeless, on-body AID system (intervention group) or a tubeless, on-body SAP (control group) for 12 weeks. Stratified block randomisation was conducted by an independent statistician. Blinding was not possible due to the nature of the intervention. The primary outcome was the percentage of time in range (TIR), blood glucose between 3.9 and 10.0 mmol/l, as measured by continuous glucose monitoring. ANCOVAs were conducted with baseline values and study centres as covariates. RESULTS: A total of 104 participants underwent randomisation, with 53 in the intervention group and 51 in the control group. The mean (±SD) age of the participants was 40±11 years. The mean (±SD) TIR increased from 62.1±17.1% at baseline to 71.5±10.7% over the 12 week trial period in the intervention group and from 64.7±17.0% to 66.9±15.0% in the control group (difference between the adjusted means: 6.5% [95% CI 3.6%, 9.4%], p<0.001). Time below range, time above range, CV and mean glucose levels were also significantly better in the intervention group compared with the control group. HbA1c decreased from 50.9±9.9 mmol/mol (6.8±0.9%) at baseline to 45.9±7.4 mmol/mol (6.4±0.7%) after 12 weeks in the intervention group and from 48.7±9.1 mmol/mol (6.6±0.8%) to 45.7±7.5 mmol/mol (6.3±0.7%) in the control group (difference between the adjusted means: -0.7 mmol/mol [95% CI -2.0, 0.8 mmol/mol] (-0.1% [95% CI -0.2%, 0.1%]), p=0.366). No diabetic ketoacidosis or severe hypoglycaemia events occurred in either group. CONCLUSIONS/INTERPRETATION: The use of a tubeless, on-body AID system was safe and associated with superior glycaemic profiles, including TIR, time below range, time above range and CV, than the use of a tubeless, on-body SAP. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0008398 FUNDING: The study was funded by a grant from the Korea Medical Device Development Fund supported by the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare; and the Ministry of Food and Drug Safety (grant number: RS-2020-KD000056).

MAFLD might be better in identifying subjects with sarcopenia or cardiovascular risk than NAFLD: A nationwide study.

BACKGROUND AND AIM: Clinical features of non-alcoholic fatty liver disease (NAFLD), but not fulfilling the diagnostic criteria of metabolic dysfunction-associated fatty liver disease (MAFLD), remain unclear. We investigated the risk of sarcopenia and cardiovascular disease (CVD) in MAFLD and non-metabolic risk (MR) NAFLD. METHODS: Subjects were selected from the Korean National Health and Nutrition Examination Surveys 2008-2011. Liver steatosis was assessed using fatty liver index. Significant liver fibrosis was defined using fibrosis-4 index, categorized by age cut-offs. Sarcopenia was defined as the lowest quintile sarcopenia index. Atherosclerotic CVD (ASCVD) risk score > 10% was defined as high probability. RESULTS: A total of 7248 subjects had fatty liver (137 with non-MR NAFLD, 1752 with MAFLD/non-NAFLD, and 5359 with overlapping MAFLD and NAFLD). In non-MR NAFLD group 28 (20.4%) had significant fibrosis. The risk of sarcopenia (adjusted odds ratio [aOR] = 2.71, 95% confidence index [CI] = 1.27-5.78) and high probability of ASCVD (aOR = 2.79, 95% CI = 1.23-6.35) was significantly higher in MAFLD/non-NAFLD group than in non-MR NAFLD group (all P < 0.05). The risk of sarcopenia and high probability of ASCVD was similar between subjects with and without significant fibrosis in non-MR NAFLD group (all P > 0.05). However, the risk was significantly higher in MAFLD group than in non-MR NAFLD group (aOR = 3.38 for sarcopenia and 3.73 for ASCVD; all P < 0.05). CONCLUSIONS: The risks of sarcopenia and CVD were significantly higher in MAFLD group but did not differ according to fibrotic burden in non-MR NAFLD group. The MAFLD criteria might be better for identifying high-risk fatty liver disease than the NAFLD criteria.

Prognostic value of resting heart rate in predicting undiagnosed diabetes in adults: Korean National Health and Nutrition Examination Survey 2008-2018.

BACKGROUND AND AIM: Although resting heart rate (RHR) is associated with prevalence and incidence of diabetes, whether it is associated with undiagnosed diabetes is still unclear. We aimed to investigate whether the RHR is associated with the prevalence of undiagnosed diabetes in a large Korean national dataset. METHODS AND RESULTS: The Korean National Health and Nutrition Examination Survey data from 2008 to 2018 were used. After screening, 51,637 participants were included in this study. The odds ratios and 95% confidence intervals (CIs) for undiagnosed diabetes were calculated using multivariable-adjusted logistic regression analyses. Analyses showed that participants with a RHR of ≥90 bpm showed a 4.00- (95% CI: 2.77-5.77) and 3.21-times (95% CI: 2.01-5.14) higher prevalence of undiagnosed diabetes for men and women, respectively, than those with a RHR of <60 bpm. The linear dose-response analyses showed that each 10-bpm increment in RHR was associated with a 1.39- (95% CI: 1.32-1.48) and 1.28-times (95% CI: 1.19-1.37) higher prevalence of undiagnosed diabetes for men and women, respectively. In the stratified analyses, the positive association between RHR and the prevalence of undiagnosed diabetes was tended to be stronger among those who were younger (age: <40 years) and lean (BMI: <23 kg/m2). CONCLUSIONS: Elevated RHR was significantly associated with a higher prevalence of undiagnosed diabetes in Korean men and women, independent of demographic, lifestyle, and medical factors. Accordingly, the value of RHR as a clinical indicator and health marker, especially in reducing the prevalence of undiagnosed diabetes, is suggestible.

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 ).

Safety and effectiveness of linagliptin in Korean patients with type 2 diabetes: A postmarketing surveillance study.

We designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was -0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.

Nonalcoholic fatty liver disease, diastolic dysfunction, and impaired myocardial glucose uptake in patients with type 2 diabetes.

AIMS: To investigate whether degree of nonalcoholic fatty liver disease (NAFLD) is associated with myocardial dysfunction related to impaired myocardial glucose uptake in patients with type 2 diabetes. MATERIALS AND METHODS: In total, 131 patients with type 2 diabetes from a tertiary care hospital were included in this study. Myocardial glucose uptake was assessed using [18 F]-fluorodeoxyglucose-positron emission tomography. Hepatic steatosis and fibrosis were determined using transient liver elastography. Echocardiography was performed to evaluate cardiac structure and function. RESULTS: Patients with NAFLD had cardiac diastolic dysfunction with higher left ventricular filling pressure (E/e' ratio) and left atrial (LA) volume index than patients without NAFLD (all P < 0.05). Hepatic steatosis correlated with E/e' ratio and LA volume index, and hepatic fibrosis also correlated with E/e' ratio (all P < 0.05). Even after adjusting for confounding factors, a higher degree of hepatic steatosis (r2 = 0.409, P = 0.041) and a higher degree of fibrosis (r2 = 0.423, P = 0.009) were independent contributing factors to a higher E/e' ratio. Decreased myocardial glucose uptake was associated with a higher degree of steatosis (P for trend = 0.084) and fibrosis (P for trend = 0.012). At the same time, decreased myocardial glucose uptake was an independent contributing factor for a higher E/e' ratio (r2 = 0.409; P = 0.040). CONCLUSIONS: Hepatic steatosis and fibrosis were significantly associated with diastolic heart dysfunction in patients with type 2 diabetes coupled with impaired myocardial glucose uptake.

Nonalcoholic Fatty Liver Disease and Sarcopenia Are Independently Associated With Cardiovascular Risk.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) and sarcopenia have a close association with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study investigated the influence of NAFLD and sarcopenia on ASCVD risk. METHODS: Data from the 2008-2011 Korean National Health and Nutrition Examination Surveys database were analyzed (n = 7,191). The sarcopenia index was calculated using dual-energy x-ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cutoffs = 0.882 for men and 0.582 for women). NAFLD was defined as a comprehensive NAFLD score ≥40. Liver fibrosis was assessed using the fibrosis-4 (FIB-4) index. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk >10%. RESULTS: The prevalence rates of NAFLD and sarcopenia were 31.2% (n = 2,241) and 19.5% (n = 1,400), respectively. The quartile-stratified ASCVD risk scores were positively associated with NAFLD and sarcopenia (all P for trend < 0.001). Subjects with both NAFLD and sarcopenia had a higher risk for high probability of ASCVD (odds ratio = 1.83, P = 0.014) compared with controls without NAFLD and sarcopenia. Among subjects with NAFLD, FIB-4-defined significant liver fibrosis and sarcopenia additively raised the risk for high probability of ASCVD (odds ratio = 3.56, P < 0.001) compared with controls without FIB-4-defined significant liver fibrosis or sarcopenia. DISCUSSION: NAFLD and sarcopenia were significantly associated with an increased risk of ASCVD in the general population. In addition, NAFLD with significant liver fibrosis and sarcopenia were significantly associated with an increased risk of ASCVD in subjects with NAFLD.

Non-alcoholic steatohepatitis and progression of carotid atherosclerosis in patients with type 2 diabetes: a Korean cohort study.

BACKGROUND: There is increasing concern regarding cardiovascular risk in individuals with non-alcoholic fatty liver disease. This study was conducted to evaluate whether hepatic steatosis with or without fibrosis is associated with the progression of carotid atherosclerosis in patients with type 2 diabetes. METHODS: From a longitudinal cohort, we enrolled 1120 patients with type 2 diabetes who underwent repeated carotid artery ultrasonography every 1-2 years. Ultrasonographic findings at baseline and after 6-8 years were compared. Presence of hepatic steatosis was mainly assessed by abdominal ultrasonography; patients with hepatic steatosis were further evaluated for hepatic fibrosis according to fibrosis-4 index. We investigated the association between liver status and atherosclerosis progression. RESULTS: Of 1120 patients, 636 (56.8%) were classified as having hepatic steatosis at baseline. After 6-8 years, 431 (38.5%) showed atherosclerosis progression. Hepatic steatosis was significantly associated with atherosclerosis progression (adjusted odds ratio[AOR]: 1.370, 95% CI 1.025-1.832; p < 0.05). Among patients with hepatic steatosis, only individuals with fibrosis showed significant association with atherosclerosis progression (AOR: 1.615, 95% CI 1.005-2.598; p < 0.05). The association between hepatic fibrosis and atherosclerosis progression was significant in all metabolic subgroups regardless of age, body mass index, presence of metabolic syndrome, or insulin sensitivity (all p < 0.05). Furthermore, subjects with hepatic steatosis & fibrosis and ≥ 4 components of metabolic syndrome criteria showed markedly increased risk of atherosclerosis progression (AOR: 2.430, 95% CI 1.087-5.458; p < 0.05). CONCLUSIONS: Hepatic steatosis with fibrosis is independently associated with the progression of carotid atherosclerosis in patients with type 2 diabetes.

Effect of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on gluconeogenesis in proximal renal tubules.

AIMS: To investigate the effect of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on renal gluconeogenesis in vitro, ex vivo and in vivo. MATERIALS AND METHODS: We treated HK-2 cells (human renal proximal tubule cells) and mouse primary renal proximal tubule cells with dapagliflozin, and evaluated the process of renal gluconeogenesis. We also examined the effect of dapagliflozin on renal gluconeogenesis in normoglycaemic and hyperglycaemic mice. RESULTS: Dapagliflozin enhanced renal gluconeogenesis in vitro, ex vivo and in vivo. It increased phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), peroxisome proliferative activated receptor-gamma co-activator 1α (PGC-1α) and phosphorylated cyclic-AMP response element binding protein (CREB) expression and decreased phosphorylated Forkhead Box O1 (FOXO1) expression in HK-2 cells, mouse primary renal proximal tubule cells, and the mouse renal cortex. Glutamine enhanced the gluconeogenic effect of dapagliflozin in HK-2 cells. Also, dapagliflozin increased 14 C-glutamine utilization in HK-2 cells. Glucagon did not affect dapagliflozin-induced enhancement in renal gluconeogenesis in HK-2 cells. SGLT2 gene knockdown with siRNA resulted in an increase of gluconeogenic gene expression and associated transcription factors in HK-2 cells. Dapagliflozin reduced fasting plasma glucose levels and improved oral glucose tolerance and insulin tolerance in high-fat diet-fed hyperglycaemic mice, although renal gluconeogenesis was enhanced. CONCLUSIONS: Dapagliflozin increased levels of gluconeogenic enzyme in the renal cortex and consequently increased renal gluconeogenesis, which is mediated by SGLT2 inhibition.

Efficacy and safety of insulin glargine 300 U/mL versus insulin glargine 100 U/mL in Asia Pacific insulin-naïve people with type 2 diabetes: The EDITION AP randomized controlled trial.

AIM: To compare the efficacy and safety of Gla-300 versus Gla-100 in insulin-naïve people with type 2 diabetes in Asia Pacific. MATERIALS AND METHODS: In this open-label, randomized, active-controlled, 26-week study, insulin-naïve participants with type 2 diabetes inadequately controlled with non-insulin antihyperglycaemic drugs were randomized (2:1) to Gla-300 or Gla-100. The initial daily dose of basal insulin was 0.2 U/kg and was adjusted at least weekly for 8-12 weeks to a target fasting self-monitored plasma glucose (SMPG) of 4.4-5.6 mmol/L. RESULTS: Of the 604 participants randomized, 570 (Gla-300, n = 375; Gla-100, n = 195) completed the study. Non-inferiority of Gla-300 versus Gla-100 in HbA1c reduction from baseline to week 26 was confirmed. In the Gla-300 and Gla-100 groups, 51.1% and 52.2% of participants achieved the HbA1c target of <7.0% (rate ratio [95% CI]: 0.98 [0.84 to 1.14]) and 19.1% and 21.9% achieved the target without hypoglycaemia during the last 12 weeks of treatment (rate ratio [95% CI]: 0.87 [0.63 to 1.20]). Changes in fasting plasma glucose and 24-hour average eight-point SMPG were comparable between groups. Incidence of hypoglycaemia at any time of day was similar between treatment groups at week 26, but incidence of any nocturnal hypoglycaemia was numerically lower with Gla-300 than Gla-100 over the initial 12-week titration period and 26-week on-treatment period. Rates of adverse events were similar between groups and low for serious adverse events. CONCLUSIONS: Glycaemic control of Gla-300 is non-inferior to Gla-100 with a similar or lower incidence and proportion of hypoglycaemia in people with type 2 diabetes in Asia Pacific, reinforcing the results in the global EDITION programme.

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).

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.

Prevention of Hepatocellular Carcinoma by Statins: Clinical Evidence and Plausible Mechanisms.

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used to treat hypercholesterolemia for primary and secondary prevention of cardiovascular disease. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and modulate the downstream signaling of the mevalonate pathway. In addition to the primary effect, the antitumor effect of statins can be associated with mevalonate pathway-mediated and nonmevalonate pathway-mediated mechanisms, which improve endothelial function and lead to proapoptotic, antiproliferative, antiinflammatory, and antifibrotic properties. Statins are implicated in the improvement of metabolic status. Statins are orally available and safely and widely used for long-term treatment; they represent a novel approach for the prevention and treatment for hepatocellular carcinoma (HCC). Although several observational studies and experimental studies have revealed the preventive and therapeutic potential of statins for HCC treatment, further prospective interventional studies and randomized control trials are warranted to confirm these observations.

Spontaneous ketonuria and risk of incident diabetes: a 12 year prospective study.

AIMS/HYPOTHESIS: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic variables in a large population-based observational study. METHODS: We analysed 8703 individuals free of diabetes at baseline enrolled in the Korean Genome and Epidemiology Study, a community-based 12 year prospective study. Individuals with (n = 195) or without fasting ketonuria were matched 1:4 by propensity score. Incident diabetes was defined as fasting plasma glucose ≥7.0 mmol/l, post-load 2 h glucose ≥11.1 mmol/l on biennial OGTTs, or current use of glucose-lowering medication. Using Cox regression models, HRs for developing diabetes associated with the presence of ketonuria at baseline were analysed. RESULTS: Over 12 years, of the 925 participants in the propensity score-matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in participants with spontaneous ketonuria compared with those without ketonuria (HR 0.63; 95% CI 0.41, 0.97). Results were virtually identical when participants with fasting ketonuria were compared against all participants without ketonuria (after multivariate adjustment, HR 0.66; 95% CI 0.45, 0.96). During follow-up, participants with baseline ketonuria maintained lower post-load 1 h and 2 h glucose levels and a higher insulinogenic index despite comparable baseline values. CONCLUSIONS/INTERPRETATION: The presence of spontaneous fasting ketonuria was significantly associated with a reduced risk of diabetes, independently of metabolic variables. Our findings suggest that spontaneous fasting ketonuria may have a potential preventive role in the development of diabetes.

Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk.

AIM: To investigate sodium-glucose cotransporter 2 inhibitor (SGLT2i)-induced changes in ketogenic enzymes and transporters in normal and diabetic mice models. MATERIALS AND METHODS: Normal mice were randomly assigned to receive either vehicle or SGLT2i (25 mg/kg/d by oral gavage) for 7 days. Diabetic mice were treated with vehicle, insulin (4.5 units/kg/d by subcutaneous injection) or SGLT2i (25 mg/kg/d by intra-peritoneal injection) for 5 weeks. Serum and tissues of ketogenic organs were analysed. RESULTS: In both normal and diabetic mice, SGLT2i increased beta-hydroxybutyrate (BHB) content in liver, kidney and colon tissue, as well as in serum and urine. In these organs, SGLT2i upregulated mRNA expression of ketogenic enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 and 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Similar patterns were observed in the kidney, ileum and colon for mRNA and protein expression of sodium-dependent monocarboxylate transporters (SMCTs), which mediate the cellular uptake of BHB and butyrate, an important substrate for intestinal ketogenesis. In diabetic mice under euglycaemic conditions, SGLT2i increased major ketogenic enzymes and SMCTs, while insulin suppressed ketogenesis. CONCLUSIONS: SGLT2i increased systemic and tissue BHB levels by upregulating ketogenic enzymes and transporters in the liver, kidney and intestine, suggesting the integrated physiological consequences for ketone body metabolism of SGLT2i administration.

Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double-blind, non-inferiority trial.

AIM: To assess the efficacy and safety of add-on therapy with the dipeptidyl peptidase-4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately controlled with metformin and glimepiride. MATERIALS AND METHODS: This was a phase 3, randomized, double-blind, non-inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c. RESULTS: At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, -1.03% ± 0.10% [P < 0.0001]; sitagliptin, -1.02% ± 0.10% [P < 0.0001]). The inter-group difference was -0.01% (95% confidence interval [CI]: -0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non-inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 [61.76%]; sitagliptin, n = 61 [62.24%]; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 [31.37%]; sitagliptin, n = 28 [28.57%]; P = 0.6656) were similar. CONCLUSION: Teneligliptin was non-inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.

Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study.

BACKGROUND & AIMS: Statins are widely used to treat hypercholesterolemia. Statins may prevent hepatocellular carcinoma (HCC), but have not yet been fully studied, particularly in patients at high risk. Therefore, we investigated the risk of HCC after statin use in the whole general population and evaluated the effects of preexisting diabetes mellitus (DM) and liver cirrhosis (LC) on that risk. METHODS: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort 2002-2013 in the Republic of Korea. Individuals diagnosed with HCC were matched to controls based on the time of the follow-up, sex, and age at index date. Odds ratios (ORs) and 95% confidence intervals (CIs) for HCC associated with statin use were analyzed by multivariable conditional logistic regression analyses. In total, 1,642 HCC cases were matched to 8,210 control individuals from 514,866 participants. RESULTS: Statin use was associated with reduced risk of HCC development (adjusted OR [AOR] 0.44; 95% CI 0.33-0.58) compared with nonusers. The reduction in risk was significant in the presence (AOR 0.28; 95% CI 0.17-0.46) and absence of DM (AOR 0.53; 95% CI 0.39-0.73) and in the presence (AOR 0.39; 95% CI 0.26-0.60) and absence of LC (AOR 0.42; 95% CI 0.32-0.57). Statin use also significantly reduced the risk of HCC among patients with DM, without chronic complications (AOR 0.19; 95% CI 0.08-0.46) or with chronic complications (AOR 0.34; 95% CI 0.19-0.64), compared to nonusers. CONCLUSIONS: Statin use may have a beneficial inhibitory effect on HCC development, particularly in patients with DM or LC, at high risk of HCC. LAY SUMMARY: In this longitudinal nationwide population-based nested case-control study, the association between statin use and the risk of HCC was investigated in Asian populations. Herein, we noted a beneficial effect of statin use on the development of HCC in the general population and individuals at high risk of HCC (i.e. those with diabetes or liver cirrhosis).

Association of non-alcoholic steatohepatitis with subclinical myocardial dysfunction in non-cirrhotic patients.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk. Among categories of NAFLD, hepatic fibrosis is most likely to affect mortality. Myocardial function and its energy metabolism are tightly linked, which might be altered by an insulin resistant condition such as NAFLD. We investigated whether hepatic steatosis and fibrosis were associated with myocardial dysfunction relative to myocardial glucose uptake. METHODS: A total of 308 patients (190 without NAFLD, 118 with NAFLD) were studied in a tertiary care hospital. Myocardial glucose uptake was evaluated at fasted state using [18F]-fluorodeoxyglucose-positron emission tomography (18FDG-PET). Hepatic steatosis and fibrosis were assessed by transient liver elastography (Fibroscan®) with controlled attenuation parameter, which quantifies hepatic fat and by surrogate indices (fatty liver index and NAFLD fibrosis score). Cardiac structure and function were examined by echocardiogram. RESULTS: Compared to those without NAFLD, patients with NAFLD had alterations in cardiac remodeling, manifested by increased left ventricular mass index, left ventricular end-diastolic diameter, and left atrial volume index (all p <0.05). Hepatic steatosis was significantly associated with left ventricular filling pressure (E/e' ratio), which reflects diastolic dysfunction (p for trend <0.05). Those without NAFLD were more likely to have higher myocardial glucose uptake compared to those with NAFLD. Significant hepatic fibrosis was also correlated with diastolic dysfunction and impaired myocardial glucose uptake. Using multivariable linear regression, E/e' ratio was independently associated with hepatic fibrosis (standardized ß = 0.12 to 0.27; all p <0.05). Association between hepatic steatosis and E/e' ratio was also significant (standardized ß = 0.10 to 0.15; all p <0.05 excluding the model adjusted for adiposity). CONCLUSIONS: Hepatic steatosis and fibrosis are significantly associated with diastolic heart dysfunction. This association is linked with myocardial glucose uptake evaluated by 18FDG-PET. LAY SUMMARY: Non-alcoholic fatty liver disease is associated with an increased risk of cardiovascular disease. More severe forms of non-alcoholic fatty liver disease, where hepatic fibrosis occurs, are linked to increased mortality. In this study, we have shown that hepatic steatosis and fibrosis are associated with subclinical myocardial dysfunction. This association is linked to altered myocardial glucose uptake.

Waist-to-calf circumstance ratio is an independent predictor of hepatic steatosis and fibrosis in patients with type 2 diabetes.

BACKGROUND AND AIM: Although a combination of central obesity and decreased skeletal muscle mass has been associated with various cardiometabolic disorders, its influence on the presence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D) is unclear. We investigated whether waist-to-calf circumference ratio (WCR) predicts NAFLD or hepatic fibrosis in T2D. METHODS: Patients with T2D (n = 5507) were enrolled in this study. Hepatic steatosis was diagnosed using abdominal ultrasound and predicting score. NAFLD was defined as 'hepatic steatosis absent other causes of chronic liver disease,' such as virus or alcoholism. Degree of hepatic fibrosis was calculated using non-invasive serum biomarker-based models. Insulin resistance was assessed by short insulin tolerance test. RESULTS: The prevalence of NAFLD and obesity (BMI ≥ 25 kg/m2 , Asian definition) were 46.4% and 38.9%, respectively. NAFLD prevalence was higher with increasing WCR tertiles: lowest tertile (36% in men, 28% in women) versus highest tertile (53.8% in men, 58.2% in women, both P < 0.001 after stratification by insulin resistance status. Increasing WCR tertiles were independently associated with presence of NAFLD: odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.22-1.68 and OR = 1.56, 95% CI = 1.31-1.86, in the middle and highest tertiles, respectively. Furthermore, patients with NAFLD and the highest WCR tertile had significant fibrosis (OR = 8.62, 95% CI = 1.39-53.36, P = 0.021). Also, WCR was correlated with risk of sarcopenia (OR = 3.18, 95% CI = 2.50-4.05, P < 0.001, highest tertile). CONCLUSIONS: Higher WCR is associated with increased risk of NAFLD and hepatic fibrosis independent of insulin resistance. This suggests that WCR may be a useful index to predict high risk of hepatic steatosis in T2D.