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Aim: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D)., Materials and Methods: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104., Results: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT., Conclusions: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Backgruound: Recent diabetes management guidelines recommend that sodium-glucose cotransporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) with proven cardiovascular benefits should be prioritized for combination therapy in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD). This study was aimed at evaluating SGLT2i or GLP-1RA usage rates and various related factors in patients with T2DM and established CVD., Methods: We enrolled adults with T2DM aged ≥30 years who were hospitalized due to established CVD from January 2019 to May 2020 at 13 secondary and tertiary hospitals in Korea in this retrospective observational study., Results: Overall, 2,050 patients were eligible for analysis among 2,107 enrolled patients. The mean patient age, diabetes duration, and glycosylated hemoglobin level were 70.0 years, 12.0 years, and 7.5%, respectively. During the mean follow-up duration of 9.7 months, 25.7% of the patients were prescribed SGLT2is after CVD events. However, only 1.8% were prescribed GLP-1RAs. Compared with SGLT2i non-users, SGLT2i users were more frequently male and obese. Furthermore, they had a shorter diabetes duration but showed worse glycemic control and better renal function at the time of the event. GLP-1RA users had a longer duration of diabetes and worse glycemic control at the time of the event than GLP-1RA non-users., Conclusion: The SGLT2i or GLP-1RA prescription rates were suboptimal in patients with T2DM and established CVD. Sex, body mass index, diabetes duration, glycemic control, and renal function were associated with the use of these agents.

Type 2 diabetes (T2D) is a progressive disease in which it is challenging to achieve long-term durable glycemic control. However, intensive glycemic control is crucial for preventing diabetes-related complications. Previous studies showed that monotherapy with a stepwise add-on approach was seldom effective for long-term durable glycemic control. Combination therapy, which refers to the use of two or more drugs to control hyperglycemia, has multiple benefits, including the ability to target a variety of pathophysiological processes underlying hyperglycemia. In clinical trials, initial combination therapy showed better glycemic control than monotherapy or a stepwise approach. Emerging evidence indicates that initial combination therapy is associated with preserved β-cell function and fewer complications in T2D. However, cost-effectiveness and adverse events with combination therapy are issues that should be considered. Therefore, initial combination therapy is an important option for patients with T2D that clinicians should consider with a view toward balancing benefits and potential harms. In this review, we summarize the literature addressing initial combination therapy in T2D, and we suggest optimal strategies based on clinical situations and patient characteristics.

Novel strategies are required to reduce the risk of developing diabetes and/or clinical outcomes and complications of diabetes. In this regard, the role of the circadian system may be a potential candidate for the prevention of diabetes. We reviewed evidence from animal, clinical, and epidemiological studies linking the circadian system to various aspects of the pathophysiology and clinical outcomes of diabetes. The circadian clock governs genetic, metabolic, hormonal, and behavioral signals in anticipation of cyclic 24-hour events through interactions between a "central clock" in the suprachiasmatic nucleus and "peripheral clocks" in the whole body. Currently, circadian rhythmicity in humans can be subjectively or objectively assessed by measuring melatonin and glucocorticoid levels, core body temperature, peripheral blood, oral mucosa, hair follicles, rest-activity cycles, sleep diaries, and circadian chronotypes. In this review, we summarized various circadian misalignments, such as altered light-dark, sleep-wake, rest-activity, fasting-feeding, shift work, evening chronotype, and social jetlag, as well as mutations in clock genes that could contribute to the development of diabetes and poor glycemic status in patients with diabetes. Targeting critical components of the circadian system could deliver potential candidates for the treatment and prevention of type 2 diabetes mellitus in the future.

Backgruound: A substantial cardiovascular disease risk remains even after optimal statin therapy. Comparative predictiveness of major lipid and lipoprotein parameters for cardiovascular events in patients with type 2 diabetes mellitus (T2DM) who are treated with statins is not well documented., Methods: From the Korean Nationwide Cohort, 11,900 patients with T2DM (≥40 years of age) without a history of cardiovascular disease and receiving moderate- or high-intensity statins were included. The primary outcome was the first occurrence of major adverse cardiovascular events (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death. The risk of MACE was estimated according to on-statin levels of low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), highdensity lipoprotein cholesterol (HDL-C), and non-HDL-C., Results: MACE occurred in 712 patients during a median follow-up period of 37.9 months (interquartile range, 21.7 to 54.9). Among patients achieving LDL-C levels less than 100 mg/dL, the hazard ratios for MACE per 1-standard deviation change in ontreatment values were 1.25 (95% confidence interval [CI], 1.07 to 1.47) for LDL-C, 1.31 (95% CI, 1.09 to 1.57) for non-HDL-C, 1.05 (95% CI, 0.91 to 1.21) for TG, and 1.16 (95% CI, 0.98 to 1.37) for HDL-C, after adjusting for potential confounders and lipid parameters mutually. The predictive ability of on-statin LDL-C and non-HDL-C for MACE was prominent in patients at high cardiovascular risk or those with LDL-C ≥70 mg/dL., Conclusion: On-statin LDL-C and non-HDL-C levels are better predictors of the first cardiovascular event than TG or HDL-C in patients with T2DM.

Backgruound: To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic cardiovascular disease (ASCVD) risk patients with type 2 diabetes mellitus (T2DM)., Methods: This study was a randomized, multicenter, open, parallel phase 4 study, and enrolled T2DM subjects with an estimated 10-year ASCVD risk ≥7.5%. The primary endpoint was the low-density lipoprotein cholesterol (LDL-C) change rate after 24-week rosuvastatin 10 mg/ezetimibe 10 mg treatment was non-inferior to that of rosuvastatin 20 mg. The achievement proportion of 10-year ASCVD risk <7.5% or comprehensive lipid target (LDL-C <70 mg/dL, non-high-density lipoprotein cholesterol <100 mg/dL, and apolipoprotein B <80 mg/dL) without discontinuation, and several metabolic parameters were explored as secondary endpoints., Results: A hundred and six participants were assigned to each group. Both groups showed significant reduction in % change of LDL-C from baseline at week 24 (-63.90±6.89 vs. -55.44±6.85, combination vs. monotherapy, p=0.0378; respectively), but the combination treatment was superior to high-intensity monotherapy in LDL-C change (%) from baseline (least square [LS] mean difference, -8.47; 95% confidence interval, -16.44 to -0.49; p=0.0378). The combination treatment showed a higher proportion of achieved comprehensive lipid targets rather than monotherapy (85.36% vs. 62.22% in monotherapy, p=0.015). The ezetimibe combination significantly improved homeostasis model assessment of β-cell function even without A1c changes (LS mean difference, 17.13; p=0.0185)., Conclusion: In high ASCVD risk patients with T2DM, the combination of moderate-intensity rosuvastatin and ezetimibe was not only non-inferior but also superior to improving dyslipidemia with additional benefits compared to high-intensity rosuvastatin monotherapy.

Backgruound: There was limited evidence to evaluate the association between lifestyle habits and continuous glucose monitoring (CGM) metrics. Thus, we aimed to depict the behavioral and metabolic determinants of CGM metrics in insulin-treated patients with type 2 diabetes mellitus (T2DM)., Methods: This is a prospective observational study. We analyzed data from 122 insulin-treated patients with T2DM. Participants wore Dexcom G6 and Fitbit, and diet information was identified for 10 days. Multivariate-adjusted logistic regression analysis was performed for the simultaneous achievement of CGM-based targets, defined by the percentage of time in terms of hyper, hypoglycemia and glycemic variability (GV). Intake of macronutrients and fiber, step counts, sleep, postprandial C-peptide-to-glucose ratio (PCGR), information about glucose lowering medications and metabolic factors were added to the analyses. Additionally, we evaluated the impact of the distribution of energy and macronutrient during a day, and snack consumption on CGM metrics., Results: Logistic regression analysis revealed that female, participants with high PCGR, low glycosylated hemoglobin (HbA1c) and daytime step count had a higher probability of achieving all targets based on CGM (odds ratios [95% confidence intervals] which were 0.24 [0.09 to 0.65], 1.34 [1.03 to 1.25], 0.95 [0.9 to 0.99], and 1.15 [1.03 to 1.29], respectively). And participants who ate snacks showed a shorter period of hyperglycemia and less GV compared to those without., Conclusion: We confirmed that residual insulin secretion, daytime step count, HbA1c, and women were the most relevant determinants of adequate glycemic control in insulin-treated patients with T2DM. In addition, individuals with snack consumption were exposed to lower times of hyperglycemia and GV.

Aim: This study aimed to determine the association between fenofibrate added to statin therapy and diabetic retinopathy progression., Methods: In this propensity-matched study using the Korean National Health Insurance Service cohort (2002-2019), patients with type 2 diabetes and metabolic syndrome (≥ 30 years) receiving statin therapy were matched 1:2 by propensity score into the statin plus fenofibrate group (n = 22,395) and statin-only group (n = 43,191). The primary outcome was a composite of diabetic retinopathy progression including vitreous hemorrhage, vitrectomy, laser photocoagulation, intravitreous injection therapy and retinal detachment., Results: The median (quartiles) follow-up duration was 44.0 (27.6-70.6) months. For the primary outcome, the incidence rate per 1,000 person-years was 9.66 in the statin-only group and 8.68 in the statin-plus-fenofibrate group. The risk of the primary outcome was significantly lower (hazard ratio [HR]=0.88; 95% confidence interval [0.81;0.96] P = 0.005) in the statin-plus-fenofibrate group than in the statin-only group. Only patients with pre-existing retinopathy showed benefits from fenofibrate treatment (HR=0.83 [0.73;0.95] P = 0.006). In addition, the statin plus fenofibrate group exhibited significantly lower risks of vitreous hemorrhage (HR= 0.86 [0.75;0.995] P = 0.042), laser photocoagulation (HR=0.86 [0.77;0.96] P = 0.009) and intravitreous injection therapy (HR=0.73 [0.59;0.90] P = 0.003) than those in the statin-only group. There was no significant interaction between the different characteristics at baseline and the treatment effect., Conclusion: The addition of fenofibrate to statins was associated with significantly lower risk of diabetic retinopathy progression than statin therapy alone in patients with type 2 diabetes and metabolic syndrome., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Aim: To investigate the longitudinal changes in brain volume and cognitive function associated with diabetes at midlife, and to examine whether long-term hyperglycaemia, insulin resistance or secretory function is associated with brain atrophy and cognitive decline., Materials and Methods: We used data from 2377 participants with both baseline and 4-year follow-up brain magnetic resonance images and neuropsychological measures from the Ansan cohort of the Korean Genome Epidemiology Study. Time-weighted mean glycaemic values were calculated using all measurements over an average duration of 10.6 years from cohort initiation to baseline visits., Results: Type 2 diabetes was associated with greater white matter volume reduction (adjusted volume difference = -1.96 ml, 95% CI: -3.73, -0.18) and executive function decline (adjusted Z score difference = -0.14, 95% CI: -0.23, -0.05) during the follow-up period of 4.2 years. Decline of verbal and visual memory or verbal fluency was not associated with diabetes. Greater executive function decline was associated with higher time-weighted mean HbA1c level over the preceding 10.6 years (P < .001), but not with insulin resistance markers in the diabetes group. Participants with diabetes, whose time-weighted average HbA1c level was maintained above 6.5% over the previous decade, showed greater decline in executive function and global cognition than the normal glucose group., Conclusions: Long-term hyperglycaemia was a major independent factor associated with rapid cognitive decline in middle-aged adults with diabetes. Maintaining ideal glucose levels in diabetes at midlife might prevent later rapid cognitive decline., (© 2022 John Wiley & Sons Ltd.)

Backgruound: We aimed to investigate the moderating effects of obesity, age, and sex on the association between sleep duration and the development of diabetes in Asians., Methods: We analyzed data from a cohort of the Korean Genome and Epidemiology Study conducted from 2001 to 2020. After excluding shift workers and those with diabetes at baseline, 7,407 participants were stratified into three groups according to sleep duration: ≤5 hours/night, >5 to 7 hours/night (reference), and >7 hours/night. The Cox proportional hazards analyses were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes mellitus (T2DM). Subgroup analyses were performed according to obesity, age, and sex., Results: During 16 years of follow-up, 2,024 cases of T2DM were identified. Individuals who slept ≤5 h/night had a higher risk of incident diabetes than the reference group (HR, 1.17; 95% CI, 1.02 to 1.33). The subgroup analysis observed a valid interaction with sleep duration only for obesity. A higher risk of T2DM was observed in the ≤5 hours/night group in non-obese individuals, men, and those aged <60 years, and in the >7 hours/night group in obese individuals (HRs were 1.34 [95% CI, 1.11 to 1.61], 1.22 [95% CI, 1 to 1.49], and 1.18 [95% CI, 1.01 to 1.39], respectively)., Conclusion: This study confirmed the effect of sleep deprivation on the risk of T2DM throughout the 16-year follow-up period. This impact was confined to non-obese or young individuals and men. We observed a significant interaction between sleep duration and obesity.

Background: To evaluate the safety and effectiveness of empagliflozin in routine clinical settings, we collected and assessed the clinical profiles of Korean patients with type 2 diabetes mellitus., Methods: This was a post-marketing surveillance study of empagliflozin 10 and 25 mg. Information on adverse events and adverse drug reactions (ADRs) was collected as safety data sets. Available effectiveness outcomes, including glycosylated hemoglobin (HbA1c) level, fasting plasma glucose, body weight, and blood pressure, were assessed., Results: The incidence rate of ADRs was 5.14% in the safety dataset (n=3,231). Pollakiuria, pruritis genital, and weight loss were the most common ADRs. ADRs of special interest accounted for only 1.18%, and there were no serious events that led to mortality or hospitalization. In the effectiveness data set (n=2,567), empagliflozin significantly reduced the mean HbA1c level and body weight during the study period by -0.68%±1.39% and -1.91±3.37 kg (both P<0.0001), respectively. In addition, shorter disease duration, absence of dyslipidemia, and higher baseline HbA1c levels were identified as the clinical features characteristic of a "responder" to empagliflozin therapy., Conclusion: Empagliflozin is a safe and potent glucose-lowering drug in routine use among Korean patients with type 2 diabetes mellitus. It is expected to have better glycemic efficacy in Korean patients with poorly controlled type 2 diabetes mellitus.

Diabetic kidney disease (DKD) is a prevalent renal complication of diabetes mellitus that ultimately develops into end-stage kidney disease (ESKD) when not managed appropriately. Substantial risk of ESKD remains even with intensive management of hyperglycemia and risk factors of DKD and timely use of renin-angiotensin-aldosterone inhibitors. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce hyperglycemia primarily by inhibiting glucose and sodium reabsorption in the renal proximal tubule. Currently, their effects expand to prevent or delay cardiovascular and renal adverse events, even in those without diabetes. In dedicated renal outcome trials, SGLT2 inhibitors significantly reduced the risk of composite renal adverse events, including the development of ESKD or renal replacement therapy, which led to the positioning of SGLT2 inhibitors as the mainstay of chronic kidney disease management. Multiple mechanisms of action of SGLT2 inhibitors, including hemodynamic, metabolic, and anti-inflammatory effects, have been proposed. Restoration of tubuloglomerular feedback is a plausible explanation for the alteration in renal hemodynamics induced by SGLT2 inhibition and for the associated renal benefit. This review discusses the clinical rationale and mechanism related to the protection SGLT2 inhibitors exert on the kidney, focusing on renal hemodynamic effects.

Lifestyle is a critical aspect of diabetes management. We aimed to define a healthy lifestyle using objectively measured parameters obtained from a wearable activity tracker (Fitbit) in patients with type 2 diabetes. This prospective observational study included 24 patients (mean age, 46.8 years) with type 2 diabetes. Expectation-maximization clustering analysis produced two groups: A (n=9) and B (n=15). Group A had a higher daily step count, lower resting heart rate, longer sleep duration, and lower mean time differences in going to sleep and waking up than group B. A Shapley additive explanation summary analysis indicated that sleep-related factors were key elements for clustering. The mean hemoglobin A1c level was 0.3 percentage points lower at the end of follow-up in group A than in group B. Factors related to regular sleep patterns could be possible determinants of lifestyle clustering in patients with type 2 diabetes.

Background: Current guidelines recommend life-long use of statin for patients with type 2 diabetes (T2D), however, a number of patients discontinue statin therapy in clinical practice. We aimed to estimate the optimal statin therapy including statin therapy duration, statin intensity, and low-density lipoprotein cholesterol (LDL-C) level among patients with T2D in a real-world setting., Methods: From Korean National Health Insurance Service Cohort (2007-2015), 8937 patients with T2D (≥ 40 years of age) who received statin therapy for at least 90 days were included. Risk of major adverse cardiovascular event (MACE) including ischemic heart disease, ischemic stroke, and cardiovascular death was estimated according to statin intensity, achieved serum LDL-C level, and statin therapy duration, respectively. The relative contributions of these factors to MACE risk were quantified by calculating the proportion of log-likelihood explained by each factor., Results: The hazard ratio (HR) of MACE was lower in patients receiving moderate- or high-intensity statins than in those receiving low-intensity statins (HR, 0.72; p = 0.027). Among patients who received moderate- or high-intensity statins, lower achieved LDL-C level was associated with lower cardiovascular risk. Notably, the longer the patients received statins, the lower was the risk of MACE; the HR of MACE was significantly reduced after at least 18 months (adjusted HR, 0.70; p = 0.009) as a reference to 3-6 months of therapy. The proportion of explainable log-likelihood for MACE was greatest for statin duration (2.55), followed by achieved LDL-C level (2.18), and statin intensity (0.95)., Conclusions: Statin therapy duration is as important as or more crucial than statin intensity or achieved LDL-C level for the reduction of cardiovascular risk in T2D patients. The concept of "longer is better" regarding statin therapy should be considered in clinical practice., (© 2022. The Author(s).)

Background: Although type 2 diabetes (T2D) remission after gastric cancer surgery has been reported, little is known about the predictors of postoperative T2D remission., Methods: This study used data from a nationwide cohort provided by the National Health Insurance Service in Korea. We developed a diabetes prediction (DP) score, which predicted postoperative T2D remissions using a logistic regression model based on preoperative variables. We applied machine-learning algorithms [random forest, XGboost, and least absolute shrinkage and selection operator (LASSO) regression] and compared their predictive performances with those of the DP score., Results: The DP score comprised five parameters: baseline body mass index (< 25 or ≥ 25 kg/m 2 ), surgical procedures (subtotal or total gastrectomy), age (< 65 or ≥ 65 years), fasting plasma glucose levels (≤ 130 or > 130 mg/dL), and antidiabetic medications (combination therapy including sulfonylureas, combination therapy not including sulfonylureas, single sulfonylurea, or single non-sulfonylurea]). The DP score showed a clinically useful predictive performance for T2D remission at 3 years after surgery [training cohort: area under the receiver operating characteristics (AUROC) 0.73, 95% confidence interval (CI), 0.71-0.75; validation cohort: AUROC 0.72, 95% CI 0.69-0.75], which was comparable to that of the machine-learning models (random forest: AUROC 0.71, 95% CI 0.68-0.74; XGboost: AUROC 0.70, 95% CI 0.67-0.73; LASSO regression: AUROC 0.75, 95% CI 0.73-0.78 in the validation cohort). It also predicted the T2D remission at 6 and 9 years after surgery., Conclusions: The DP score is a useful scoring system for predicting T2D remission after gastric cancer surgery., (© 2021. The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

The prevalence of young-onset (diagnosis at age < 40 years) type 2 diabetes mellitus (T2DM) is increasing globally. Young-onset T2DM has a common pathophysiology of glucose dysregulation as in late-onset T2DM. However, it presents a greater association with obesity and a more rapid decline in β-cell function than late-onset T2DM. Accumulating evidence indicates that disease progression in young-onset T2DM is rapid, resulting in early and frequent development of microvascular and macrovascular complications, as well as premature death. Improper management and low adherence to medical therapy are important issues in young-onset T2DM. This review discusses the epidemiology, disease entity, and clinical issues associated with young-onset T2DM. We also present the prevalence and clinical characteristics of patients with young-onset T2DM in South Korea.

Background: To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes., Methods: We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes., Results: Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors., Conclusion: SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.

This study was conducted to investigate the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual renal outcomes in patients with type 2 diabetes. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to September 2017 to identify randomized controlled trials comparing SGLT2 inhibitors with placebo or antidiabetic drugs and reporting any renal outcomes in patients with type 2 diabetes. Additionally, we identified 4 articles which were published after the predefined period to include relevant data. A meta-analysis was performed to calculate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) for each renal outcome. We included 48 studies involving 58,165 patients in the analysis. SGLT2 inhibitors significantly lowered urine albumin-to-creatinine ratio (UACR) (WMD, -14.64 mg/g; 95% CI, -25.15 to -4.12; P = 0.006) compared with controls. The UACR-lowering effects of SGLT2 inhibitors were greater with a higher baseline UACR. Overall changes in estimated glomerular filtration rate (eGFR) were comparable between two groups (WMD, 0.19 mL/min/1.73 m 2 ; 95% CI, -0.44 to 0.82; P = 0.552). However, SGLT2 inhibitors significantly slowed eGFR decline in patients with a higher baseline eGFR and a longer duration of treatment. Compared with controls, SGLT2 inhibitors significantly reduced the risk of microalbuminuria (RR, 0.69; 95% CI, 0.49 to 0.97; P = 0.032), macroalbuminuria (RR, 0.49; 95% CI, 0.33 to 0.73; P < 0.001), and worsening nephropathy (RR, 0.73; 95% CI, 0.58 to 0.93; P = 0.012). In addition, the risk of end-stage renal disease was significantly lower in SGLT2 inhibitors than in controls (RR, 0.70; 95% CI, 0.57 to 0.87; P = 0.001). In conclusion, SGLT2 inhibitors had beneficial renal effects by lowering the risk of albuminuria development or progression and reducing the risk of end-stage renal disease compared with placebo or other antidiabetic drugs.

Background: To determine the impact of dipeptidyl peptidase-4 inhibitor (DPP4i) on the risk of major cardiocerebrovascular and renal outcomes compared with sulfonylurea (SU) combined with metformin in patients with type 2 diabetes from a population-based cohort., Methods: From a nationwide cohort in Korea (2008-2013), 23,674 patients with type 2 diabetes treated with DPP4i plus metformin or SU plus metformin were selected and matched by propensity score. Composite cardiocerebrovascular events including incident ischemic heart disease (IHD), ischemic stroke (IS), hospitalization for heart failure (HHF), and cardiocerebrovascular death, as well as renal events including incident end-stage renal disease or initiation of renal-replacement therapy were assessed by Cox proportional-hazards models., Results: During a median follow-up of 19.6 months (interquartile range 7.2-36.4), 762 composite cardiocerebrovascular events and 17 end-stage renal events occurred. There was no significant difference in the risk of IHD (hazard ratio [HR], 1.00; 95% CI 0.81-1.23), IS (HR, 0.95; 95% CI 0.74-1.23), or cardiocerebrovascular death (HR, 0.74; 95% CI 0.46-1.18) in the DPP4i group compared to that in the SU group. Likewise, DPP4i therapy was not associated with the risk of end-stage renal outcomes (HR, 1.23; 95% CI 0.41-3.62). However, the risk of HHF was significantly higher in the DPP4i group than in the SU group (HR, 1.47; 95% CI 1.07-2.04)., Conclusions: This real-world database analysis showed that DPP4i therapy did not increase the overall risk of major cardiovascular and renal outcomes compared to SU therapy. However, the DPP4i-associated risk of HHF remained significant.

Background: To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes., Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome., Results: We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls ( P =0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P =0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P =0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P <0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, -1.11 mL/min/1.73 m²; 95% CI, -1.78 to -0.44; P =0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P =0.475)., Conclusion: DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019 Korean Endocrine Society.)

Background: Sarcopenic obesity (SO) is a serious public health concern, few studies have examined the clinical implications of SO in newly-diagnosed type 2 diabetes mellitus (T2DM) patients. We evaluated the prevalence of the newly diagnosed, drug-naïve T2DM patients with low muscle mass with abdominal obesity and its association with insulin resistance and other diabetic complications., Methods: We classified 233 drug-naïve T2DM subjects into four groups according to abdominal obesity (waist circumference ≥90 cm in men and ≥85 cm in women) and low muscle mass status (appendicular skeletal muscle <7.0 kg/m² for men and <5.4 kg/m² for women)., Results: The proportion of the subjects with low muscle mass and abdominal obesity among the newly diagnosed, drug-naïve T2DM patients was 8.2%. Homeostasis model assessment of insulin resistance (HOMA-IR) increased linearly according to body composition group from normal to abdominal obesity to both low muscle mass and abdominal obesity. The multiple logistic regression analysis indicated that subjects with low muscle mass and abdominal obesity (odds ratio [OR], 9.39; 95% confidence interval [CI], 2.41 to 36.56) showed a higher risk for insulin resistance, defined as HOMA-IR ≥3, than those with abdominal obesity (OR, 5.36; 95% CI, 2.46 to 11.69), even after adjusting for other covariates. However, there were no differences in lipid profiles, microalbuminuria, or various surrogate markers for atherosclerosis among the four groups., Conclusion: Subjects with both low muscle mass and abdominal obesity had a higher risk of insulin resistance than those with low muscle mass or abdominal obesity only., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2018 Korean Diabetes Association.)

Objective: Although increasing evidence suggests the association between short-term variability of fasting plasma glucose (FPG) and diabetic complications or mortality, the impact of visit-to-visit variability of FPG on the development of type 2 diabetes (T2D) has not been evaluated., Research Design and Methods: Our analysis included 131,744 Korean men and women without diabetes using the Korean National Health Insurance System cohort with periodic health examination program. FPG variability was calculated using the coefficient of variation (FPG-CV), SD (FPG-SD), and variability independent of the mean (FPG-VIM)., Results: During the median follow-up time of 8.3 years, Kaplan-Meier curves demonstrated lower disease-free probability in the higher FPG variability group compared with the lower FPG variability group. Multivariable Cox proportional hazards analysis exhibited that the hazard ratio for incident T2D was 1.67 (95% CI 1.58-1.77, P < 0.001) in the highest quartile of FPG-CV compared with the lowest quartile of FPG-CV after adjusting for confounding variables, including mean FPG. The association between FPG variability and the risk of T2D was consistent when modeling using FPG-SD and FPG-VIM in both normal and impaired fasting glucose groups. A 1 SD increase in the FPG-CV was associated with a 24% increased risk of T2D in the fully adjusted model., Conclusions: Increased variability of FPG is associated with the development of T2D independently of diverse risk factors., (© 2018 by the American Diabetes Association.)

Aims: Previous in-vitro and in-vivo experimental studies have shown that Sestrin2 attenuates oxidative stress and the pro-inflammatory pathway, resulting in improving metabolic homeostasis. However, the relationship between circulating Sestrin2 concentration and cardiometabolic risks in humans has not been explored., Methods: Sestrin2 concentration was measured in 240 subjects (46 without diabetes and 194 with diabetes), and the associations between Sestrin2 level and various cardiometabolic risk factors including body composition, insulin resistance, and atherosclerosis was assessed., Results: Sestrin2 concentration showed a trend of increasing in subjects with metabolic syndrome. After adjustment for age and gender, Sestrin2 level had a positive relationship with serum triglyceride, alanine aminotransferase (ALT), and creatinine levels, but no association with carotid atherosclerosis. Especially, in subjects with type 2 diabetes Sestrin2 concentration exhibited a significant positive correlation with body mass index (P = 0.015), waist circumference (P = 0.020), high-sensitivity C-reactive protein (P = 0.008), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (P = 0.041), percentage body fat (P = 0.001), and truncal fat mass (P = 0.005) after adjusting age and gender. Multiple stepwise regression analysis identified age, serum ALT and creatinine levels, and percentage body fat as independent determining factors for Sestrin2 concentration in patients with type 2 diabetes (R 2  = 0.173)., Conclusions: This study is the first to demonstrate a trend for increased Sestrin2 level in subjects with metabolic syndrome. In particular, in subjects with type 2 diabetes, Sestrin2 was significantly related to insulin resistance and percentage body fat, suggesting its potential as a novel modulatory factor for metabolic disorders in humans., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Patients with type 2 diabetes are at risk of microvascular and macrovascular complications. Intensive glycaemic control, especially in patients with short duration of diabetes, is the mainstay of management of type 2 diabetes to lower the risk of complications. However, despite the improvement in the understanding of the pathophysiology of type 2 diabetes and development of novel glucose-lowering agents, long-term durable glycaemic control remains a difficult goal to achieve. Several challenging clinical trials proved that an early combination therapy with a variety of glucose-lowering agents had a more favourable effect than conventional stepwise therapy in terms of glycaemic control. We aim to evaluate the efficacy and tolerability of a novel, initial triple combination therapy with metformin, sodium glucose cotransporter 2 inhibitor (dapagliflozin) and dipeptidyl peptidase-4 inhibitor (saxagliptin) compared with conventional stepwise add-on therapy in drug-naïve patients with recent-onset type 2 diabetes., Methods and Analysis: This study is a multicentre, prospective, randomised, open-label, parallel group, comparator-controlled trial. A total of 104 eligible participants will be randomised to either the initial combination therapy group or the conventional stepwise add-on therapy group for 104 weeks. The primary endpoint is the proportion of patients who achieved haemoglobin A1c level<6.5% without hypoglycaemia, weight gain or discontinuation due to adverse events at 104 weeks. This trial will determine whether a novel triple combination therapy with metformin, dapagliflozin and saxagliptin has a beneficial effect on durable glycaemic control compared with conventional therapy in drug-naïve patients with type 2 diabetes., Ethics and Dissemination: This study protocol was approved by the local institutional review boards and independent ethics committees over the recruitment sites. Results of this study will be disseminated in scientific journals and scientific conferences., Trial Registration Number: NCT02946632; Pre-results., Competing Interests: Competing interests: SGK has received funds for research, honoraria for speaking at meetings and has served on Advisory Boards for Astra Zeneca. NHK has received honoraria for speaking at meetings from Astra Zeneca., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Meteorin-like (Metrnl) was recently identified as a novel adipomyokine induced by exercise and cold exposure. Metrnl improves glucose tolerance, increases systemic energy expenditure, induces white adipose browning, and promotes anti-inflammatory gene programs in obese/diabetic mice. However, the relationship of Metrnl with diabetes and cardiometabolic risk variables in humans has not been explored., Methods: In 800 subjects (400 patients with type 2 diabetes and 400 non-diabetes), Metrnl concentration was measured with an enzyme-linked immunosorbent assay, and the correlations of Metrnl level with anthropometric parameters, lifestyle factors, body composition values, and laboratory measurements were assessed., Results: Metrnl concentration was significantly higher in patients with diabetes than in those without diabetes [median (inter-quartile range); diabetes: 1219.9 (1020.6, 1535.6), non-diabetes: 1131.2 (993.1, 1313.6) pg/ml, P < .001]. After adjustment for age and sex, Metrnl level was significantly associated with fasting plasma glucose, blood pressure, lipid profile, and eGFR, but not with BMI or percent body fat. Multiple stepwise regression analysis exhibited that Metrnl level was independently associated with diabetes status (P < .001), eGFR (P < .001), and total cholesterol (P = .026) (R 2  = 0.127). In multiple logistic regression analysis, the odds ratio for the risk of diabetes was 3.53 (95% confidence interval: 2.04-6.10) in the highest tertile of Metrnl compared to the lowest after adjustment for confounding factors., Conclusions: This study is the first to demonstrate that Metrnl level is elevated in human subjects with type 2 diabetes and is inversely related to various cardiometabolic risk factors, including renal function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims/introduction: To assess the time to initiation of insulin therapy, and concurrently investigate both patient- and physician-related factors associated with delaying insulin therapy in Korean patients with type 2 diabetes uncontrolled by oral hypoglycemic agents (OHAs)., Materials and Methods: This prospective, observational disease registry study was carried out across 69 centers in Korea. Type 2 diabetes patients who had received two or more OHAs within the past 5 years, had a glycated hemoglobin ≥8% in the past 6 months and had not received insulin were included. Data recorded on data collection forms during a 12-month period were analyzed., Results: Of 2168 patients enrolled, 1959 were evaluated and classified as the insulin-initiated or insulin-delayed group. Insulin was prescribed for just 20% of the patients during a 1-year follow-up period, and less than half (44.5%) of the patients who were taking two OHAs started insulin after 6 years. Patient-related factors for delay in insulin initiation included older age, shorter duration of diabetes and lower glycated hemoglobin. Physician-related factors included age (~50 to <60 years), sex (women) and number (<1000) of patients consulted per month. Patient refusal (33.6%) and physicians' concerns of patient non-compliance (26.5%) were the major physician-reported reasons for delaying insulin therapy. Inconvenience of insulin therapy (51.6%) and fear of injection (48.2%) were the major reasons for patient refusal., Conclusions: Insulin initiation is delayed in patients with type 2 diabetes uncontrolled by two or more OHAs in Korea. Patient- and physician-related factors associated with this delay need to be addressed for better diabetes management., (© 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)