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Backgruound: Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy., Methods: The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety., Results: After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy., Conclusion: Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Backgruound: This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin., Methods: In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135)., Results: At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (-0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, highdensity lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%)., Conclusion: Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin.

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

Backgruound: Enavogliflozin is a novel sodium-glucose cotransporter-2 inhibitor currently under clinical development. This study evaluated the efficacy and safety of enavogliflozin as an add-on to metformin in Korean patients with type 2 diabetes mellitus (T2DM) against dapagliflozin., Methods: In this multicenter, double-blind, randomized, phase 3 study, 200 patients were randomized to receive enavogliflozin 0.3 mg/day (n=101) or dapagliflozin 10 mg/day (n=99) in addition to ongoing metformin therapy for 24 weeks. The primary objective of the study was to prove the non-inferiority of enavogliflozin to dapagliflozin in glycosylated hemoglobin (HbA1c) change at week 24 (non-inferiority margin of 0.35%) (Clinical trial registration number: NCT04634500)., Results: Adjusted mean change of HbA1c at week 24 was -0.80% with enavogliflozin and -0.75% with dapagliflozin (difference, -0.04%; 95% confidence interval, -0.21% to 0.12%). Percentages of patients achieving HbA1c <7.0% were 61% and 62%, respectively. Adjusted mean change of fasting plasma glucose at week 24 was -32.53 and -29.14 mg/dL. An increase in urine glucose-creatinine ratio (60.48 vs. 44.94, P<0.0001) and decrease in homeostasis model assessment of insulin resistance (-1.85 vs. -1.31, P=0.0041) were significantly greater with enavogliflozin than dapagliflozin at week 24. Beneficial effects of enavogliflozin on body weight (-3.77 kg vs. -3.58 kg) and blood pressure (systolic/diastolic, -5.93/-5.41 mm Hg vs. -6.57/-4.26 mm Hg) were comparable with those of dapagliflozin, and both drugs were safe and well-tolerated., Conclusion: Enavogliflozin added to metformin significantly improved glycemic control in patients with T2DM and was non-inferior to dapagliflozin 10 mg, suggesting enavogliflozin as a viable treatment option for patients with inadequate glycemic control on metformin alone.

Background: Sedentary behavior (SB) has emerged as a new risk factor for cardiovascular accidents. We investigated whether physical activity levels or SB were related to percent body fat (%BF) in type 2 diabetes mellitus (T2DM)., Methods: In this cross sectional study, we measured the duration of SB, light physical activity (LPA), moderate to vigorous physical activity (MVPA), total energy expenditure, and step counts using a wireless activity tracker (Fitbit HR; FB) for 7 days in free-living conditions, along with %BF using a bio impedance analyzer (Inbody; Biospace) in 120 smartphone users with T2DM. Subjects were divided into exercise (Exe, n =68) and non-exercise (nonExe, n =52) groups based on self-reports of whether the recommended exercises (30 min/day, 3 days/week for 3 months) were performed. SBt, LPAt, MVPAt were transformed from SB, LPA, MVPA for normally distributed variables., Results: Participants were: female, 59.2%; age, 59.3±8.4 years; body mass index, 25.5±3.4 kg/m²; glycosylated hemoglobin (HbA1c), 7.6%±1.2%; %BF, 30.4%±7.1%. They performed SB for 15.7±3.7 hr/day, LPA for 4.4±1.7 hr/day, and MVPA for 0.9±0.8 hr/day. The %BF was related to SBt and LPAt, but not to MVPA after adjustments for age, gender, and HbA1c. VPA was significantly higher in the Exe group than in the nonExe group, but SB, LPA, and moderate physical activity were not different. Predicted %BF was 89.494 to 0.105 (age), -13.047 (gender), -0.507 (HbA1c), -7.655 (LPAt) (F[4, 64]=62.929, P <0.001), with an R ² of 0.785 in multiple linear regression analysis., Conclusion: Reduced body fat in elderly diabetic patients might be associated with reduced inactivity and increased LPA., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 Korean Diabetes Association.)

Background: Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia., Methods: This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment., Results: After 8 weeks of treatment, the percent changes from baseline in TG (-29.8% vs. 3.6%, P <0.001) and non-HDL-C (-10.1% vs. 4.9%, P <0.001) levels were significantly greater in the ATOMEGA group ( n =97) than in the atorvastatin group ( n =103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P <0.001). The incidence of adverse events did not differ between the two groups., Conclusion: The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia., Competing Interests: This work was financially supported by the Kuhnil Pharmaceutical Co., Ltd. (Seoul, Republic of Korea). The company funder had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the article for publication., (Copyright © 2020 Korean Diabetes Association.)

Background: Arterial stiffness is an important factor in atherosclerosis. Thus we examined whether aerobic exercise could reduce arterial stiffness in obese women with type 2 diabetes without diabetic complication., Methods: A total of 35 women with type 2 diabetes (body mass index, 26.6±2.8 kg/m(2); age, 56.4±1.9 years; duration of diabetes, 4.7±4.8 years) were assigned to aerobic exercise group (AEG) or control group (CG). AEG completed a 12-week exercise program (3.6 to 5.2 metabolic equivalents, 3 day/week, 60 min/day), with their exercise activities monitored by accelerometers. We measured abdominal total fat area (TFA), visceral fat area (VFA), and subcutaneous fat area (SFA) by computed tomography, insulin sensitivity by insulin tolerance test (KITT), and augmentation index (AIx) by SphygmoCor at baseline and at the end of the 12-week program., Results: The AIx was improved in the AEG compared with the CG (P<0.001). The percent change of AIx had significant correlation with the improvement of physical activity energy expenditure (PAEE), aerobic capacity, TFA, and SFA (r=-0.416, P=0.013; r=0.560, P<0.001; r=0.489, P=0.003; r=0.531, P=0.001, respectively), but not with insulin sensitivity, energy intake, or VFA., Conclusion: Improvement in aortic stiffness by aerobic exercise is related with the improvement of aerobic capacity, PAEE, and total fat but not with insulin sensitivity or energy intake in obese women with type 2 diabetes.

Background: Central fat mass (CFM) correlates with insulin resistance and increases the risk of type 2 diabetes and cardiovascular complications; however, peripheral fat mass (PFM) is associated with insulin sensitivity. The aim of this study was to investigate the relation of absolute and relative regional adiposity to insulin resistance index and adipokines in type 2 diabetes., Methods: Total of 83 overweighted-Korean women with type 2 diabetes were enrolled, and rate constants for plasma glucose disappearance (K(ITT)) and serum adipokines, such as retinol binding protein-4 (RBP4), leptin, and adiponectin, were measured. Using dual X-ray absorptiometry, trunk fat mass (in kilograms) was defined as CFM, sum of fat mass on the lower extremities (in kilograms) as PFM, and sum of CFM and PFM as total fat mass (TFM). PFM/TFM ratio, CFM/TFM ratio, and PFM/CFM ratio were defined as relative adiposity., Results: Median age was 55.9 years, mean body mass index 27.2 kg/m(2), and mean HbA1c level 7.12±0.84%. K(ITT) was positively associated with PMF/TFM ratio, PMF/CFM ratio, and negatively with CFM/TFM ratio, but was not associated with TFM, PFM, or CFM. RBP4 levels also had a significant relationship with PMF/TFM ratio and PMF/CFM ratio. Adiponectin, leptin, and apolipoprotein A levels were related to absolute adiposity, while only adiponectin to relative adiposity. In correlation analysis, K(ITT) in type 2 diabetes was positively related with HbA1c, fasting glucose, RBP4, and free fatty acid., Conclusion: These results suggest that increased relative amount of peripheral fat mass may aggravate insulin resistance in type 2 diabetes.

Background: We investigated the effects of exercise intensity on abdominal and mid-thigh adipose tissue, attenuation of skeletal muscle, and insulin sensitivity in overweight women with type 2 diabetes mellitus (T2DM)., Methods: Twenty-eight patients were randomly assigned to control (CG, n=12), moderate intensity exercise (MEG, n=8), or vigorous intensity exercise (VEG, n=8) group. Subjects in both exercise groups completed a 12-week exercise program (MEG, 3.6 to 5.2 METs; VEG, ≥5.2 METs) that was monitored by accelerometers. We assessed body mass index (BMI), total fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), mid-thigh intramuscular adipose tissue (TIMAT), total skeletal muscle (TTM), low density skeletal muscle (TLDM), and normal density skeletal muscle (TNDM) using computed tomography, and measured insulin sensitivity with an insulin tolerance test (K(ITT)), before and after the intervention., Results: At baseline, the mean age was 53.8±7.9 years, duration of diabetes was 3.8±2.3 years, and BMI was 26.6±2.6 kg/m(2). After 12 weeks, the percent change (%C) in BMI, TIMAT, and TLDM were not different among three groups. However, %C in TFA and VFA were significantly reduced in MEG compared to CG (P=0.026 and P=0.008, respectively). %C SFA was significantly reduced in VEG compared to CG (P=0.038) and %C TTM, TNDM, and K(ITT) were significantly increased in VEG compared to the CG (P=0.044, P=0.007, and P=0.016, respectively)., Conclusion: Although there was no difference in the change in BMI among groups, TFA and VFA were more reduced in MEG, and only VEG increased TTM, TNDM, and insulin sensitivity compared to CG.

Background: Patients with type 2 diabetes have an increased risk of cardiovascular disease. Few studies have evaluated the cardiovascular disease (CVD) risk simultaneously using the United Kingdom Prospective Diabetes Study (UKPDS) risk engine and non-invasive vascular tests in patients with newly diagnosed type 2 diabetes., Methods: Participants (n=380; aged 20 to 81 years) with newly diagnosed type 2 diabetes were free of clinical evidence of CVD. The 10-year coronary heart disease (CHD) and stroke risks were calculated for each patient using the UKPDS risk engine. Carotid intima media thickness (CIMT), flow mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AI) were measured. The correlations between the UKPDS risk engine and the non-invasive vascular tests were assessed using partial correlation analysis, after adjusting for age, and multiple regression analysis., Results: The mean 10-year CHD and 10-year stroke risks were 14.92±11.53% and 4.03±3.95%, respectively. The 10-year CHD risk correlated with CIMT (P<0.001), FMD (P=0.017), and PWV (P=0.35) after adjusting for age. The 10-year stroke risk correlated only with the mean CIMT (P<0.001) after adjusting for age. FMD correlated with age (P<0.01) and systolic blood pressure (P=0.09). CIMT correlated with age (P<0.01), HbA1c (P=0.05), and gender (P<0.01)., Conclusion: The CVD risk is increased at the onset of type 2 diabetes. CIMT, FMD, and PWV along with the UKPDS risk engine should be considered to evaluate cardiovascular disease risk in patients with newly diagnosed type 2 diabetes.

Background: There is controversy over whether aerobic or resistance exercise is more effective for improving endothelial function in type 2 diabetes mellitus (T2DM). This study was aimed to investigate the effects of an aerobic and resistance training program on endothelial function, and the influences of glycemic control, body weight changes, and aerobic capacity in T2DM., Methods: Total 40 overweight women with T2DM were assigned into 3 groups: an aerobic exercise group (AEG, n=13), resistance exercise group (REG, n=12), and control group (CG, n=15), and followed either brisk walking for the AEG or resistance band training for the REG, 60 minutes per day, 5 days per week for 12 weeks with monitoring daily activity using accelerometers. We assessed endothelial function by flow-mediated dilation (FMD), and aerobic capacity by oxygen uptake at anaerobic threshold (AT&#95;VO(2)) at baseline and following training program., Results: The mean participants' age was 57.0±6.8 years, and body mass index (BMI) was 27.0±2.3 kg/m(2). After intervention, FMD increased by 2.2±1.9% in AEG, which differed from REG and CG (P=0.002), despite of decreased body weight (BW) in both AG and RG (2.8±2.5%, P=0.002; 1.6±2.0%, P=0.017, respectively). A significant increased AT&#95;VO(2) and decreased HbA1c were found only in AEG. In all participants, FMD was changed with the significant relations to the AT&#95;VO(2) (r=0.348, P=0.035), but not to HbA1c levels or BW., Conclusion: Aerobic exercise appears to be more beneficial than resistance exercise for improving endothelial function in T2DM. In addition, aerobic capacity could be a better predictor of changes in FMD than BW and glycemic control.

Background: Insulin resistance is related to central obesity and the amount of skeletal muscle. A simple and practical anthropometric marker for muscle mass is not known, although waist circumference (WC) is used as an indicator of abdominal obesity. The aims of this study were to investigate whether arm (AC) and thigh circumferences (TC) can be used as an indicator of muscle mass and if they are related to muscle strength., Methods: A total of 110 obese (body mass index [BMI]≥25 kg/m(2)) women with type 2 diabetes were enrolled, and WC, AC, and TC were measured. Abdominal visceral fat (AVF), subcutaneous fat (ASF), and total fat (ATF) were assessed by computed tomography, regional muscle (MM), and fat mass by dual-energy X-ray absorptiometry, muscle strength by one repetition maximum (1RM) of both extremities (chest and leg press) and insulin resistance by K(ITT)., Results: The mean age was 56.2±7.3 years, duration of diabetes was 4.2±4.4 years, and BMI was 27.2±2.8 kg/m(2). WC was correlated with ATF, AVF, and ASF (r=0.728, P<0.001; r=0.515, P<0.001; r=0.608, P<0.001, respectively). Arm MM was correlated with AC (r=0.500, P<0.001), and leg MM with TC (r=0.291, P=0.002). Upper 1RM was related to AC/WC ratio (r=0.359, P<0.001), and lower 1RM was to TC/WC ratio (r=0.286, P=0.003). Insulin resistance had significant relations with AVF, WC, and total MM (r=-0.262, P=0.008; r=-0.217, P=0.029; r=0.160, P=0.031, respectively)., Conclusion: The muscle mass was related to extremity circumferences, and muscle strength was to extremity/waist circumference ratio in obese women with type 2 diabetes.

Background: Koreans eat rice, which is usually served in a rice bowl. We investigated the effect of a meal plan using small rice bowls on the total energy intake (TEI) and the marcronutrient intake in Korean men with type 2 diabetes., Methods: A total of 62 men with type 2 diabetes were divided by body mass index (BMI) (normal weight [NW], BMI<23 kg/m(2); overweight [OW], 23≤BMI<25 kg/m(2); obese [OB], BMI≥25 kg/m(2)) and proportions of carbohydrate intake to TEI (PCI) (low carbohydrate intake [LC], <55%; recommended carbohydrate intake [RC], ≥55% and ≤60%; high carbohydrate intake [HC], >60%). The 3-day dietary records were analyzed for TEI and proportions of macronutrients, before and 2 weeks after a small-sized (300 mL) rice bowl based education was given., Results: There were no significant differences in the age and BMI within the sub-groups by BMI and PCI groups. In baseline, the ratio of TEI to recommended total energy intake (RTR) of OW and OB were higher than that of NW. The PCI of HC was higher than that of LC and alcohol intake of HC was lower than that of LC. After education, the reduction of RTREI in OB was higher than that in OW and NW. The reduction of PCI in HC was higher than that of LC., Conclusion: A small rice bowl based meal plan was effective for the reduction of energy intake and control of marcronutrient intake in Korean obese men with type 2 diabetes consuming a high carbohydrate diet.

Background: Hypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension., Methods: We used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan., Results: In the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels., Conclusion: Short-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.