Diverse Strategies for Modulating Insulin Resistance: Causal or Consequential Inference on Metabolic Parameters in Treatment-Naïve Subjects with Type 2 Diabetes.

Bacground and Objectives: The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in treatment-naïve subjects with T2DM. Subjects and Methods: A total of 212 subjects were assigned to receive either a tight Japanese diet (n = 65), pioglitazone at doses ranging from 15-30 mg/day (n = 70), or canagliflozin at doses ranging from 50-100 mg/day (n = 77) for a duration of three months. Correlations and changes (Δ) in metabolic parameters relative to insulin resistance were investigated. Results: Across these distinct therapeutic interventions, ΔHOMA-R exhibited significant correlations with ΔFBG and ΔHOMA-B, while demonstrating a negative correlation with baseline HOMA-R. However, other parameters such as ΔHbA1c, ΔBMI, ΔTC, ΔTG, Δnon-HDL-C, or ΔUA displayed varying patterns depending on the treatment regimens. Participants were stratified into two groups based on the median value of ΔHOMA-R: the lower half (X) and upper half (Y). Group X consistently demonstrated more pronounced reductions in FBG compared to Group Y across all treatments, while other parameters including HbA1c, HOMA-B, TC, TG, HDL-C, non-HDL-C, TG/HDL-C ratio, or UA exhibited distinct regulatory responses depending on the treatment administered. Conclusions: These findings suggest that (1) regression to the mean is observed in the changes in insulin resistance across these therapies and (2) the modulation of insulin resistance with these therapies, either causally or consequentially, results in differential effects on glycemic parameters, beta-cell function, specific lipids, body weight, or UA.

Alogliptin: a DPP-4 inhibitor modulating adipose tissue insulin resistance and atherogenic lipid.

AIMS: The purpose of this study is to investigate the regulation of adipose tissue insulin resistance with DPP-4 inhibitors in treatment-naive subjects with T2DM and to examine its relation to other diabetic parameters. SUBJECTS AND METHODS: A total of 147 subjects were treated with alogliptin 12.5-25 mg/day (n = 55), sitagliptin 25-50 mg/day (n = 49), or teneligliptin 10-20 mg/day (n = 43) monotherapy for 3 months. Changes in adipo-IR, a mathematical model used to evaluate adipose tissue insulin resistance, and various diabetic parameters were analyzed in this prospective, non-randomized observational study. RESULTS: Among these three drugs, only alogliptin significantly reduced adipo-IR (-25.9%, p < 0.004) and some lipid parameters, such as LDL-C, T-C/HDL-C, log(TG)/HDL-C, non-HDL-C/HDL-C, and LDL-C/HDL-C. Subjects in the alogliptin group were divided into two groups with distinct changes in adipo-IR. Group A had a significant decrease in adipo-IR (-56.5%, p < 0.00001, n = 28), whereas group B had an insignificant increase (19.1%, p = 0.055, n = 27). Significant reductions in FBG or HbA1c were observed in groups A and B, respectively. Group A also showed significant reductions in HOMA-R, T-C/HDL-C, TG, log(TG)/HDL-C, non-HDL-C/HDL-C, LDL-C/HDL-C, and FFA, as well as increases in QUICKI or HDL-C. In contrast, group B showed significant reductions in QUICKI or LDL-C, and increases in HOMA-R, insulin, HOMA-B, C-peptide, or CPR-index. CONCLUSIONS: In contrast to other tested DPP-4 inhibitors, alogliptin demonstrated the ability to down-regulate insulin resistance in adipose tissue, as well as certain atherogenic lipids. This study provides the initial evidence of a DPP-4 inhibitor's potential to regulate adipose tissue insulin resistance. Furthermore, adipo-IR is associated with non-LDL-C lipid parameters instead of glycemic control in those receiving alogliptin.

Complementary effects on glycaemic and non-glycaemic parameters between responders and non-responders treated with pioglitazone and canagliflozin in drug-naive subjects with type 2 diabetes.

OBJECTIVES: The aim of this study was to investigate the differential regulation of metabolic parameters between pioglitazone and canagliflozin in relation to their glycaemic efficacies. METHODS: Drug-naive subjects with T2DM received pioglitazone 15-30 mg/day or canagliflozin 50-100 mg/day monotherapy for 3 months. Those who had a ≥1% reduction in HbA1c were defined as responders and others who had a <1% reduction were defined as non-responders. RESULTS: In the pioglitazone group, baseline BMI, FFA, HOMA-R or adipo-IR was significantly higher, and HDL-C was significantly lower in responders vs non-responders. In the canagliflozin group, baseline HbA1c or FBG was significantly higher, and HOMA-B or age was significantly lower in responders vs non-responders. In pioglitazone responders, significant decreases in HbA1c (from 10.75% to 8.31%), FBG (-29.7%), FFA (-37.7%), non-HDL-C (-13.4%), TG (-30.1%), HOMA-R (-35.6%) or adipo-IR (-38.7%), and increases in BMI (2.8%) or HDL-C (14.2%) were observed. In pioglitazone non-responders, none of the parameters were regulated. In canagliflozin responders, significant decreases in HbA1c (from 11.31% to 8.60%), FBG (32.1%), BMI (-2%) or HOMA-R (-33.8%), and increases in HOMA-B (50%) were observed. In canagliflozin non-responders, significant decreases in BMI (-2.4%), insulin (-21.8%) or HOMA-R (-33.6%) were observed. CONCLUSIONS: (i) Glycaemic efficacy of pioglitazone is linked to body weight and atherogenic lipids while this is not the case with canagliflozin. (ii) Responders (or non-responders) to pioglitazone have some distinct features from non-responders (or responders) to canagliflozin. Collectively, a combination of pioglitazone and canagliflozin may compensate for each other's metabolic drawbacks or augment their advantages, thereby achieving overall improvements in the metabolic profiles and pathogenic defects of patients with T2DM.

Efficacy and safety of dulaglutide in patients with absolute insulin deficiency.

OBJECTIVE: While dulaglutide has been approved inpatients with type 2 diabetes (T2DM) in combination with insulin, it has not been studied in insulin-deficient patients, not whether they have type 1 diabetes (T1DM) or T2DM. The aim of this study is to assess the efficacy and safety of dulaglutide 0.75 mg/once weekly (QW) in patients with absolute insulin deficiency (n=10). SUBJECTS AND RESULTS: Significant reductions of HbA1c (9.30±1.03% to 8.61±1.21%; p<0.02) and body mass index (BMI; 23.61±3.95 to 23.41±4.24; p<0.02) levels were observed at 3 months with the addition of dulaglutide to the existing pharmacotherapy. However, in all the patients, post-meal C-peptide levels remained undetectable. One patient had gastrointestinal adverse events and discontinue dulaglutide within the first month. One patient was a non-responder, who had little if any changes in HbA1c levels at 3 months. CONCLUSIONS: The results indicate that dulaglutide is effective in patients with T1DM or T2DM with absolute insulin deficiency, though gastrointestinal adverse events might be of concern. The improvements in glycemic control could not be due to enhanced insulin secretion, but may be as a result of a combination of the other effects of glucagon like peptide 1 (GLP-1), such as postprandial glucagon suppression, delayed gastric emptying, and weight loss.

Regulation of serum uric acid with canagliflozin monotherapy in type 2 diabetes: A potential link between uric acid and pancreatic ß-cell function
.

OBJECTIVES: This aim of this study is to investigate the regulation of serum uric acid (SUA) levels with canagliflozin in relation to diabetic parameters. MATERIALS AND METHODS: Drug-naïve subjects with type 2 diabetes (T2DM) received 50 - 100 mg/day canagliflozin monotherapy (n = 40) for 3 months. Levels of SUA and some diabetic parameters were monitored. RESULTS: In the overall subjects, significant negative correlations were observed between the changes (Δ) of SUA and the baseline SUA levels (R = -0.392, p < 0.02). The subjects were divided into two subgroups (n = 20 each) according to the changes of SUA levels (above the median (group A): from 4.79 ± 1.22 to 5.34 ± 1.39 mg/dL; and below the median (group B): from 5.80 ± 1.08 to 4.98 ± 0.97 mg/dL). Significant increases of SUA levels were observed in group A (11.4%, p < 0.0002), while significant decreases of SUA levels were seen in group B (-14.1%, p < 0.00001). Significant correlations were seen between the baseline levels of SUA and those of homeostasis model assessment (HOMA)-B (R = 0.463, p < 0.04) and between the changes of SUA and those of HOMA-B (R = 0.420, p < 0.05) only in group A. Higher degrees of elevations of HOMA-B and decreases of HbA1c/fasting blood glucose (FBG) were seen in group A versus group B. CONCLUSION: These results suggest that 1) high SUA levels decreased while low SUA levels increased with canagliflozin; 2) better glycemic efficacies and higher degrees of enhancement of ß-cell function were observed in those with elevated SUA levels with canagliflozin; 3) SUA might be linked to modulation of ß-cell function.

REGULATION OF FREE FATTY ACID BY SITAGLIPTIN MONOTHERAPY IN DRUG-NAÏVE SUBJECTS WITH TYPE 2 DIABETES.

OBJECTIVE: The aim of this study was to investigate the effects of sitagliptin on the regulation of free fatty acid (FFA) and other metabolic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM). METHODS: This was a prospective, nonrandomized, observational study. Drug-naïve subjects with T2DM received 25 to 50 mg/day sitagliptin monotherapy (n = 64). At 3 months, FFA and other metabolic parameters were compared with those at baseline. FFA was measured by colorimetry with enzymatic reactions. As a comparator, 12.5 to 25 mg/day alogliptin monotherapy was given to drug-naïve subjects with T2DM (n = 55). RESULTS: Significant reductions in FFA (-13.2%, P<0.01) levels were observed with sitagliptin but not alogliptin. Both drugs showed similar glycemic efficacies. Significant correlations were observed between the changes (Δ) of FFA and Δglycated hemoglobin A1c (HbA1c), Dtotal cholesterol (TC), Δnon-high-density lipoprotein cholesterol (HDL-C), or Δlow-density lipoprotein cholesterol (LDL-C), and significant negative correlations were seen between ΔFFA and Δhomeostasis model assessment-B (HOMA-B), ΔC-peptide immunoreactivity (CPR)-index or Δbody mass index (BMI) in the sitagliptin group. The subjects in the sitagliptin group were further divided into 2 subgroups (n = 32 each) according to the changes of FFA (group B [above the median] ΔFFA = 23.1 %, P<.0005; group A [below the median] ΔFFA = -37.3 %, P<.00001). At baseline, FFA levels were significantly higher in group A versus group B ( P<.001). Higher degrees of reductions of FBG (-14.6% vs. -9.3%, P<0.05) or HbA1c (-20.6% vs. -16.9%, P<.05), and increases of HOMA-B (52.7% vs. 38.3%, P<.03) or CPR-index (37.5% vs. 18.8%, P<.02) were observed in group A versus group B. Significant reductions of TC (-5.8%, P<.002), non-HDL-C (-7.8%, P<.001) or LDL-C (-6.3%, P<.02), and significant increases of C-peptide (11.3%, P<.05) were seen only in group A. CONCLUSION: Sitagliptin could downregulate high FFA levels. Subjects with reductions of FFA levels had better glycemic efficacies and higher degrees of enhancement of beta-cell function than others. Reductions of atherogenic cholesterols were seen in these populations. ABBREVIATIONS: CPR = C-peptide immunoreactivity; DPP-4 = dipeptidyl peptidase 4; FBG = fasting blood glucose; FFA = free fatty acid; HbA1c = glycated hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; HOMA-R = homeostasis model assessment-R; HOMA-B = homeostasis model assessment-B; non-HDL-C = non-HDL-cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; T2DM = type 2 diabetes; TG = triglyceride; UA = uric acid.

Alogliptin: a new dipeptidyl peptidase-4 inhibitor with potential anti-atherogenic properties.

OBJECTIVES: The aim of this study is to evaluate the effects of alogliptin on metabolic profiles in relation to those of glycemic control. PATIENTS AND METHODS: Treatment naïve subjects with type 2 diabetes received 12.5-25 mg/d alogliptin monotherapy (n = 59). A novel parameter called A1c index was used to assess the glycemic efficacy. The subjects were divided into three groups according to this index; super-responders, average responders and poor-responders. At 3 months, levels of the metabolic parameters were compared with those at baseline between super-responders (n = 20) and poor-responders (n = 21). RESULTS: At baseline, total cholesterol, non-high density lipoprotein cholesterol and atherogenic index were significantly higher in super-responders than poor-responders. At 3 months, significant increases of beta-cell function (HOMA-B) and decreases of insulin resistance (HOMA-R) or these atherogenic lipids were observed in super-responders, while significant increases of HOMA-R were observed in poor-responders. Significant correlations were observed between A1c index and the changes of these atherogenic lipids. In super-responders, significant correlations were observed between the changes (Δ) of glycemic parameters (A1c index or fasting blood sugar) and ΔHOMA-R and/or ΔHOMA-B, while in poor-responders, significant correlations were observed between ΔHOMA-R and ΔHOMA-B. Lean subjects gained weight and the changes of body mass index had significant negative correlations with A1c index. CONCLUSIONS: These results indicate that (1) glucose lowering efficacy of alogliptin is closely linked to atherogenic lipids. (2) alogliptin can down-regulate atherogenic lipids. (3) glycemic efficacy of alogliptin appears to be determined by the balance of its capacity in modulating insulin resistance and beta-cell function.

Effect of Pioglitazone on Serum Uric Acid Levels in Newly Diagnosed, Drug-Naïve Patients with Type 2 Diabetes.

OBJECTIVES: The aim of this study was to investigate the effect of pioglitazone on serum uric acid (UA) levels and several diabetic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: The patients (n = 68) received 7.5-30 mg/day pioglitazone monotherapy. They were divided into three groups based on their baseline UA levels (low, medium, and high). These parameters were followed for 12 weeks. RESULTS: At baseline, HbA1c and fasting blood glucose (FBG) levels were in negative proportion to those of UA, while homeostasis model assessment-beta (HOMA-B) levels were in proportion to those of UA. Insulin, homeostasis model assessment-R (HOMA-R), and body mass index (BMI) levels had a tendency to be in proportion to those of UA. While similar glycemic effects were observed in all the groups, UA levels significantly decreased in the high UA group while they insignificantly increased in the low UA group. Multiple regression analysis revealed that the baseline UA level and age were the significant determinants for the changes of UA levels. In the high UA group, significant decreases of insulin and HOMA-R levels were observed, and their changes (Δ) were significantly correlated with those of UA. Other parameters including insulin, HOMA-R, HOMA-B, and BMI were also differentially regulated between these groups. CONCLUSIONS: These results indicate that (1) while similar glycemic effects were observed, distinct regulations of UA and other diabetic parameters were observed with pioglitazone depending on the baseline UA levels; (2) pioglitazone downregulated hyperuricemia by possibly relieving insulin resistance; and (3) the level of UA together with other parameters might provide some diabetic characteristics of the subjects.

Regulation of Adipose Tissue Insulin Resistance and Diabetic Parameters in Drug Naïve Subjects with Type 2 Diabetes Treated with Canagliflozin Monotherapy.

The objective of this study is to investigate the link between the baseline/changes of body weight and those of diabetic parameters during treatment with an SGLT-2 inhibitor. Drug naïve subjects with T2DM received canagliflozin monotherapy for 3 months. Adipo-IR was selected as the significant factor responsible for the changes of (Δ)BMI with this drug. While no correlations were noted between ΔBMI and ΔFBG, ΔHbA1c, ΔHOMA-R or ΔQUICKI, significant negative correlations were observed between ΔBMI and Δadipo-IR (R=-0.308). The subjects were divided into two groups with baseline BMI<25 (n=31, group alpha) or≥25 (n=39, group beta). Baseline levels of FBG, HbA1c, T-C, TG, non-HDL-C, LDL-C showed no differences between group alpha and beta. The subjects were also divided into two equal numbers of subjects (n=35 each) based on the changes of weight: the lower half (-3.6%, p<0.00001, group A) and the upper half (0.1%, n.s., group B) of ∆BMI. FBG, HbA1c or HOMA-R significantly, similarly decreased, while QUICKI increased in group A and B. TG significantly decreased, while HDL-C increased in group A. HOMA-B significantly increased, while adipo-IR insignificantly decreased in group B. Collectively, these results suggest that 1) adipose tissue insulin resistance is responsible for the weight changes with canagliflozin. 2) baseline levels of glycemic and some lipid parameters were similar between obese and non-obese populations. 3) weight changes with canagliflozin were not associated with its glycemic or insulin sensitizing efficacies but were linked to adipose-tissue insulin resistance, some lipids, and beta-cell function.

Regulations of Free Fatty Acids and Diabetic Parameters in Drug Naïve Subjects with Type 2 Diabetes Treated with Canagliflozin Monotherapy.

The objective of this study is to investigate the regulations of FFA with canagliflozin in relation to metabolic parameters. Drug naïve subjects with T2DM were administered 50-100 mg/day canagliflozin monotherapy (n=70) for 3 months. Significant correlations between the changes of (Δ) FFA and Δadipo-IR (R=0.496), but no correlations between ΔFFA and ΔHOMA-R were observed. The subjects were divided into three groups with similar numbers according to Δ FFA: group A: highest tertile: (ΔFFA=38.7%, n=23); group B: intermediate tertile: (ΔFFA=2%, n=23); group C: lowest tertile: (ΔFFA=-36%, n=24). Metabolic parameters were compared between group A and group C. At baseline, FFA was higher in group C than group A (p<0.002). Greater degrees of HbA1c reduction and increases of insulin were observed in group C than group A (both p<0.05). In group A, significant reductions of BMI (-2.6%) and HOMA-R (-30%) were seen. In group C, significant reductions of non-HDL-C (-6.2%), UA (-7.6%) or adipo-IR (-28.7%), and increases of HOMA-B (+85.6%) were observed. Taken together, 1) certain population treated with canagliflozin showed decreased FFA. 2) beta-cell function increased while atherogenic cholesterol, UA and adipo-IR decreased in those with reduced FFA. Better glycemic efficacies were seen in these populations. 3) body weight and whole body insulin resistance (HOMA-R) significantly decreased in those with elevated FFA. 4) FFA is linked to adipose insulin resistance (adipo-IR), while it does not appear to impact whole body insulin resistance (HOMA-R).

Sitagliptin as an Initial Therapy and Differential Regulations of Metabolic Parameters Depending on its Glycemic Response in Subjects with Type 2 Diabetes.

The aim of this study is to investigate whether sitagliptin can be used as an initial drug for T2DM and to evaluate its effects on metabolic parameters in relation to its glycemic efficacies. The subjects received 25-50 mg/day sitagliptin monotherapy (n=69). At 3 months, they were divided into three groups (n=23 each) according to the novel parameter called "A1c index" which is designed to assess glycemic efficacy. The metabolic parameters were compared between good-responders and poor-responders. These two groups acted as a control each other. In the overall subjects, efficient reductions of HbA1c (10.16-8.22%) were observed with few adverse events. Significant correlations were seen between the A1c index and changes of (∆)nonHDL-C (R=0.250) or ∆LDL-C (R=0.368). At baseline, T-C, nonHDL-C and BMI levels were significantly lower in good-responders than poor-responders. At 3 months, in good-responders, HbA1c levels effectively decreased (11.03-7.00%). Indexes for insulin sensitivity/resistance [HOMA-R and 20/(C-peptide x FBG)] and beta-cell function (HOMA-B and CPR-index) ameliorated. T-C, nonHDL-C and LDL-C significantly decreased, while BMI increased. However, in poor-responders, no changes in these parameters were noted. Collectively, these results suggest that 1) Sitagliptin can be used as a first-line drug for T2DM and its glycemic efficacy is linked to some atherogenic lipids. 2) Those with lower T-C, nonHDL-C and BMI appear to respond better with this drug. 3) Good glycemic efficacy of sitagliptin is medicated through reduced insulin resistance as well as enhanced beta-cell functions. Body weight increased, while some atherogenic cholesterol decreased in good-responders.

Link between serum uric acid and pancreatic beta-cell function in drug naïve subjects with type 2 diabetes treated with sitagliptin.

Aim: The objective of this study is to investigate the changes of UA with sitagliptin in relation to its glycemic/non-glycemic efficacies.Methods: Drug naïve subjects with T2DM (n = 62) were administered 25-50 mg/day sitagliptin monotherapy for 3 months. The subjects were divided into two subgroups according to the changes in (Δ) UA (above the median [group A, n = 31]: ΔUA = 23.3%, p < 0.00001, and below the median [group B, n = 31]: ΔUA = -0.9%, n.s.). Changes in glycemic/non-glycemic parameters were compared between these two groups, which acted as a control for each other.Results: In the overall subjects, UA significantly increased (10.8%, p < 0.00001). Significant correlations between ΔUA and ΔBMI (R = 0.252), ΔHOMA-B (R = 0.309) or ΔCPR-index (R = 0.258), and significant negative correlations between ΔUA and ΔHbA1c (R = -0.290) or ΔFFA (R = -0.271) were seen. Between group A and group B, some parameters displayed distinct regulatory patterns. HbA1c significantly decreased in both groups (group A: from 9.97% to 7.65%, group B: from 10.41% to 8.85%) with significant inter-group differences (higher reductions in group A, p < 0.05). C-peptide (+10.6%) and BMI (+1.7%) significantly increased, and FFA (-20.5%) decreased in group A. HOMA-R or 20/(C-peptide x FBG) had no changes in either group, while HOMA-B (group A: +85.1%, group B: +38.8%) or CPR-index (group A: +37.7%, group B: +20.5%) increased in both groups with significant inter-group differences (both p < 0.01). TG (-18.8%) significantly decreased, and T-C (-3.5%) and non-HDL-C (-4%) had a tendency to decrease in group B.Conclusions: These results suggest that UA and beta-cell functions/glycemic efficacy are closely linked during sitagliptin therapy. Those with elevated UA had better beta-cell enhancing and glyemic efficacies. Body weights increased and FFA decreased in these populations. By contrast, those without changes in UA had favorable profiles in atherogenic lipids.

Differential effects of pioglitazone on metabolic parameters in newly diagnosed, drug-naïve Japanese patients with type 2 diabetes with or without metabolic syndrome.

OBJECTIVE: The aim of this study was to evaluate the efficacy of pioglitazone on metabolic parameters in drug-naïve Japanese type 2 diabetic patients with (Diabetes Mellitus Metabolic Syndrome [DMMS] group, n = 36) and without (Diabetes Mellitus non-Metabolic Sundrome [DMNMS] group, n = 36) metabolic syndrome. PATIENTS AND METHODS: The patients received monotherapy of 15-30 mg/day pioglitazone for 3 months. The baseline levels of metabolic parameters were compared with the levels after 3 months. RESULTS: At baseline, the two groups showed no significant difference in HbA1c (10.05 vs. 9.81%, n.s.) or systolic blood pressure (134.5 vs. 133.0 mmHg, n.s.), but had significant differences in diastolic blood pressure (84.7 vs. 78.9 mmHg, p < 0.05), insulin (14.96 vs. 7.09 microU/mL, p < 0.001), homeostasis model assessment insulin resistance index (HOMA-R) (8.49 vs. 3.96, p < 0.001), triglyceride (TG) (231.4 vs. 131.5 mg/dL, p < 0.0005), high-density lipoprotein (HDL)-C (46.6 vs. 56.1 mg/dL, p < 0.005), body weight (BW) (77.97 vs. 62.52 kg, p < 0.001), and body mass index (BMI) (28.14 vs. 22.86, p < 0.00001). In the DMMS group, significant changes of HbA1c (from 10.05 to 8.01%, p < 0.00001), insulin (-22.7%, p < 0.05), HOMA-R (-48.9%, p < 0.0002), TG (-20.8 %, p < 0.05), HDL-C (+12.0%, p < 0.00001), BW (+1.0 kg/+1.3%, p < 0.05), and BMI (+1.4%, p < 0.02) were observed after 3 months. In the DMNMS group, the reduction of HbA1c (from 9.81 to 8.33%, p < 0.00001) was similar to that in the DMMS group, but the changes of insulin (-4.7%, n.s.), HOMA-R (-15.6%, n.s.), and TG (-12.9%, n.s.) were smaller and not significant. Significant increases of HDL-C (+9.2%, p < 0.02), BW (+0.64 kg/+1.0%, p < 0.05), and BMI (+1.0%, p < 0.02) were observed, but these changes were also smaller than the respective changes in the DMMS group. Based on the change of each parameter relative to its baseline value, significant intergroup differences were found for TG, insulin, or HOMA-R, whereas no such differences were observed for HDL-C, BW, and BMI. No subjects showed any clinically significant adverse events. CONCLUSIONS: These results suggest that the glucose-lowering effect of pioglitazone is comparable in patients with type 2 diabetes with or without metabolic syndrome, but that the drug has different effects on nonglycemic parameters including TG, insulin and HOMA-R in the two groups of patients.

Link between body weight changes and metabolic parameters in drugs naïve subjects with type 2 diabetes treated with canagliflozin monotherapy.

OBJECTIVES: The aim of this study is to investigate the correlations between the changes of body weight and metabolic parameters during canagliflozin treatment. METHODS: Drug naïve subjects with T2DM (n = 84) received canagliflozin monotherapy for 3 months. The subjects were divided into three groups with equal numbers of subjects (n = 28 each) according to the reductions of BMI levels; highest (group A), intermediate (group B), and lowest (group C) reductions. Changes of the metabolic parameters were compared between group A and group C. These two groups acted as a control of each other. RESULTS: Significant reductions of BMI levels (-4.1%, p < 0.00001) were observed in group A, while, surprisingly, significant increases (+1.5%, p < 0.00001) were seen in group C. In these two groups, similar reductions of HbA1c, FBG, or HOMA-R, and increases of HOMA-B levels were observed. Significant reductions of TG levels (-18.6%) were seen only in group A. At baseline, HbA1c levels were significantly lower in group A versus group C (p < 0.03). In group A, significant correlations between the changes of BMI and those of HbA1c (R = 0.496) were seen. By contrast, in group C, significant negative correlations were observed between these parameters (R = -0.463). CONCLUSIONS: These results suggest that certain populations treated with canagliflozin gained weight, though similar glycemic and beta-cell/insulin sensitivity enhancing properties were observed in comparison to those with efficient weight reductions. Those who lost more weight had better glycemic efficacy in group A. By contrast, those who gained more weight had better glycemic efficacy in group C. Distinct glucose-lowering mechanisms might be operating between these two groups. Involvement of some factors including glucagons and free fatty acids is hypothesized.

Effect of Canagliflozin on Heart Function Involving Ketone Bodies in Patients with Type 2 Diabetes.

This report describes the effect of administration (n=3) or withdrawal (n=2) of canagliflozin, a sodium-glucose co-transporters 2 (SGLT-2) inhibitor, on cardiac function in relation to ketone bodies. Three cases received and two cases discontinued canagliflozin. Changes of heart function with ultrasonography (EF: ejection fraction and %FS: functional shortening) and cardiometabolic parameters including ketone bodies (acetoacetate/beta-hydroxybutylate) were compared at 3 months. 69, 68 and 60 years old male patients A, B and C, respectively with moderately decreased heart function received canagliflozin 100 mg/day. EF, %FS and acetoacetate/beta-hydroxybutylate levels increased. 60 and 59 years old female patients D and E with normal and borderline heart function, respectively discontinued canagliflozin 50 mg/day. EF, %FS and acetoacetate/beta-hydroxybutylate levels decreased. Taken together, these results suggest that concomitant changes between ketone bodies and heart function were observed with or without canagliflzoin. This drug might have effects on cardiac function through modulating ketone bodies.

Two Glucose-Lowering Mechanisms of Canagliflozin Depending on Body Weight Changes in Drug-Naïve Subjects with Type 2 Diabetes.

OBJECTIVES: The aim of this study was to investigate the relations between the changes in body weight and those of glycemic and non-glycemic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) treated with canagliflozin monotherapy. METHODS: Subjects received 50-100 mg/day canagliflozin monotherapy for 3 months (n = 36), and were then divided into two groups: (1) those who lost weight [changes in (Δ)BMI ≤ - 0.45, p < 0.00001: Group L(ost), n = 20); and (2) those who did not lose weight [ΔBMI > - 0.45, p = non-significant: Group N(eutral), n = 16]. At 3 months, the levels of glycemic and non-glycemic parameters were compared with those at baseline. RESULTS: Significant reductions of BMI levels (- 2.1%, p < 0.00001) were observed for the overall subjects. At baseline, fasting blood glucose (FBG) and HbA1c levels were significantly higher, and homeostasis model assessment-B (HOMA-B) levels were significantly lower in Group N versus Group L. Similar reductions of HbA1c (Group L: 9.54 ± 2.58% to 7.54 ± 1.27%, p < 0.05; Group N: 11.23 ± 2.27% to 9.19 ± 1.64%, p < 0.0002) and homeostasis model assessment-R (HOMA-R; Group L: - 32.3%, p < 0.005; Group N: - 36.5%, p < 0.02) levels were seen in these two groups. However, other parameters showed distinct regulatory patterns. (1) Group L: significant reductions in uric acid (UA) levels (- 6.9%, p < 0.02) were observed. Significant correlations between the changes in FBG and HOMA-R (R = 0.458, p < 0.05) were seen. (2) Group N: significant increases in HOMA-B (+ 69.4%, p < 0.007) and reductions in free fatty acid (FFA; - 25.8%, p < 0.02) levels were observed. Significant negative or positive correlations between the changes in (Δ)FBG and ΔHOMA-B (R = - 0.557, p < 0.03), and between ΔFBG and ΔHOMA-R (R = 0.458, p < 0.05) were seen. CONCLUSIONS: These results indicate that (1) body weight changes with canagliflozin were not associated with its glycemic efficacy; and (2) distinct glucose-lowering pathways may exist with canagliflozin, reducing insulin resistance in those who lose weight and enhancing ß-cell function, as well as reducing insulin resistance, possibly via the decreased FFA levels, in those who do not lose weight.

Characterization of Metabolic Parameters in Responders and Nonresponders Treated with Canagliflozin Monotherapy in Drug-naive Subjects with Type 2 Diabetes.

OBJECTIVES: The aim of this project is to compare the effect of canagliflozin monotherapy on metabolic parameters between responders and nonresponders with this drug. This study is a prospective, unblinded, observational study. SUBJECTS AND METHODS: Drug-naïve patients with type 2 diabetes mellitus received only 50-100 mg/day canagliflozin for 3 months (n = 39). They were divided into two groups according to the novel "A1c index" to assess glycemic efficacies; responders (n = 24) and nonresponders (n = 15). RESULTS: At baseline, glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) were significantly higher and homeostatic model assessment (HOMA)-B and body mass index (BMI) were significantly lower in responders. In both groups, similar, significant reductions of BMI (-1.9% with responder and -1.8% with nonresponder) and HOMA-R (-35.8% for responder and -31.5% for nonresponder) were observed. However, differences were seen with other parameters as follows: 1) responders: significant reductions of HbA1c (10.95%-8.44%), FBG (-29.6%) or free fatty acid (FFA) (-16.2%), and significant increases of HOMA-B (79.7%) were observed. 2) Nonresponders: significant reductions of serum uric acid (UA) (-8.6%) levels were seen. Significant correlations were observed between the baseline levels of serum UA and those of HOMA-B (R = 0.7259). However, this link became uncorrelated with the treatment with canagliflozin. CONCLUSIONS: These results suggest that (1) responders with canagliflozin have lower BMI and beta-cell function. Reductions of body weight with canagliflozin were not associated with its glycemic efficacy, (2) reduced FFA levels and enhanced insulin sensitivity/beta-cell function could be a potential mechanism of good glycemic efficacy of canagliflozin, and (3) serum UA might be involved in modulating beta-cell function during canagliflozin treatment.

Canagliflozin as an Initial Therapy in Drug-Naïve Subjects with Type 2 Diabetes Mellitus: A Potential Involvement of Atherogenic Lipids in its Glycemic Efficacy.

BACKGROUND AND OBJECTIVES: The aim of this study is to investigate canagliflozin as an initial therapy in type 2 diabetes mellitus and to explore the effects on metabolic parameters in relation to effects on glycemic control. SUBJECTS AND METHODS: Treatment-naïve subjects with type 2 diabetes mellitus received canagliflozin 50-100 mg/day monotherapy. At 3 months, levels of glycemic and non-glycemic parameters were compared with those at baseline (n = 39). As a comparator, our previous data of baseline glycosylated hemoglobin (HbA1c)-matched treatment-naïve subjects with ipragliflozin 25-50 mg monotherapy (n = 27) were employed. RESULTS: Significant reductions in HbA1c (from 9.96 to 8.33%), fasting blood glucose (-23.9%), homeostasis model assessment-R (HOMA-R, -33.5%), body mass index (-1.8%), and uric acid (UA, -5.2%) levels and significant increases in homeostasis model assessment-B (HOMA-B, 30.1%) levels were observed. Approximately one third of the subjects experienced certain adverse events. Similar results were obtained with ipragliflozin. Baseline levels of HbA1c, triglycerides, non-high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were chosen as significant contributing factors for the changes in HbA1c levels with canagliflzoin, while only baseline HbA1c levels were selected as such a factor with ipragliflozin. Significant positive correlations between the changes in HbA1c and changes in non-HDL-C (R = 0.3954) or between changes in HbA1c and changes in LDL-C (R = 0.4317) were observed with canagliflozin. With ipragliflozin, no such correlations were noted. No correlations between the changes in HbA1c and changes in body mass index were seen with both drugs. CONCLUSIONS: These results suggest that (1) canagliflozin appears to offer clinically beneficial outcomes as an initial therapy in subjects with type 2 diabetes mellitus, although with certain adverse events. (2) Atherogenic cholesterols including non-HDL-C and LDL-C could be involved in the glycemic efficacy of canagliflozin. This was not the case with ipragliflozin. (3) Unexpectedly, weight reductions with canagliflozin are not associated with its glycemic efficacy.

Teneligliptin, a Chemotype Prolyl-Thiazolidine-Based Novel Dipeptidyl Peptidase-4 Inhibitor with Insulin Sensitizing Properties.

BACKGROUND AND OBJECTIVES: Teneligliptin, a chemotype prolyl-thiazolidine-based novel dipeptidyl peptidase (DPP)-4 inhibitor, was preliminarily shown to reduce insulin resistance in patients with type 2 diabetes mellitus (T2DM). The objective of this study is to further investigate the insulin sensitising properties of teneligliptin in comparison to those of sitagliptin. METHODS: Treatment-naïve subjects with T2DM were administered 20 mg/day teneligliptin monotherapy (n = 45). As a comparator, 25-50 mg/day sitagliptin monotherapy was performed in a non-randomized manner (n = 71). No other drugs were administered. At 3 months, levels of diabetic parameters were compared with those at baseline. RESULTS: At 3 months, while similar reductions of glycated hemoglobin (HbA1c) levels were observed with these two drugs, indexes for insulin sensitivity [homeostasis model assessment (HOMA)-R and 20/(C-peptide × fasting blood glucose (FBG)) levels] ameliorated only with teneligliptin. Then, the subjects were divided into two groups representing distinct degrees of insulin resistance; high HOMA-R (≥4) and low HOMA-R (<2) groups. With teneligliptin, similar decreases of HbA1c levels were observed in high (9.85-7.66 %, p < 0.0005) and low (10.12-8.51 %, p < 0.01) HOMA-R groups. HOMA-R (-32.6 %, p < 0.05) and non-high density lipoprotein cholesterol (non-HDL-C, -6 %, p < 0.05) levels significantly decreased and 20/(C-peptide × FBG) levels significantly increased (53 %, p < 0.001) in high HOMA-R group. HOMA-B levels increased in both groups with significant inter-group differences (+101.7 % in low HOMA-R group vs. +55.4 % in high HOMA-R group). Group 2. With sitagliptin, similar decreases of HbA1c levels were observed from those of teneligliptin in either high or low HOMA-R group, but no changes of HOMA-R, non-HDL-C or 20/(C-peptide × FBG) levels were noted. Increases of HOMA-B levels with sitagliptin were comparable to those with teneligliptin in either high or low HOMA-R group. CONCLUSIONS: These results indicate that: (i) teneligliptin ameliorates insulin sensitivity and non-HDL-C levels in subjects with high degrees of insulin resistance. This is not the case with sitagliptin, though similar glycemic efficacies were observed. (ii) glycemic efficacy of teneligliptin may be determined by the balance of its capacity in modulating insulin resistance and beta-cell function depending on the degrees of baseline insulin resistance.

Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors have been shown to reduce body weight. However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters. OBJECTIVES: The aim of this study was to investigate the link between the changes in body weight and those in metabolic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) receiving ipragliflozin monotherapy. METHODS: Subjects received ipragliflozin monotherapy 25-50 mg/day for 3 months (n = 33). They were then divided into two groups: group L ('lost'; n = 17) comprised patients who lost weight (change [Δ] in body mass index [BMI] ≤ -0.75, p < 0.00001), and group N ('neutral'; n = 16) comprised patients who did not lose weight (ΔBMI > -0.75, not significant [NS]). RESULTS: In these two groups, similar reductions were observed in glycated hemoglobin (HbA1c) levels (group L: 9.76-8.02%, p < 0.00001; group N: 10.07-8.36%, p < 0.0005). Homeostasis model assessment (HOMA)-B levels increased in both groups, with inter-group differences (p < 0.05; +38.91 vs. +96.83% in group L and N, respectively). However, some parameters showed distinct regulatory patterns. For instance, in group L, reductions were observed in HOMA-R (-20.18%, p < 0.04) and uric acid (UA; -8.91%, p < 0.02) levels. Correlations were seen between the change in HOMA-R and those in fasting blood glucose (FBG) levels (R = 0.557, p < 0.02). Non-significant increases in free fatty acid (FFA) levels and decreases in non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C) levels were also noted. In group N, reductions in FFA levels (-17.07%, p < 0.05) were observed, and negative correlations were seen between ΔHOMA-B and ΔFBG (R = -0.4781, p < 0.05) and between Δ FFA and Δ HOMA-B levels (R = -0.4305, p < 0.05). Non-significant increases in non-HDL-C and LDL-C levels were also noted. Inter-group differences existed between group L and group N in the changes in non-HDL-C and LDL-C levels (both p < 0.05). CONCLUSIONS: These results indicate that ipragliflozin may possess distinct dual glucose-lowering mechanisms depending on body weight changes. Degrees of insulin resistance decrease in subjects who lose weight. Conversely, ipragliflozin reduces lipotoxicity (FFA levels), thereby activating beta-cell function, in subjects who do not lose weight. Similar glycemic efficacies were observed in both cases. In patients who lost weight, ipragliflozin was associated with improvements in the levels of metabolic parameters related to cardiovascular risk factors, including UA and atherogenic lipid levels (non-HDL-C and LDL-C) compared with those who did not lose weight.