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.

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.

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.