anagliptin and Diabetes-Mellitus--Type-2

Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Structure-Activity Relationship

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a class of anti-hyperglycemic agents with proven efficacy in patients with type 2 diabetes mellitus (T2DM).. This review considers the pharmacokinetic profile, adverse effects and drug interactions of DPP-4 inhibitors. DPP-4 inhibitors have certain differences in their structure, metabolism, route of elimination and selectivity for DPP-4 over structurally related enzymes, such as DPP-8/DPP-9. They have a low potential for drug interactions, with the exception of saxagliptin that is largely metabolized by cytochrome CYP3A4/A5. Reports of pancreatitis and pancreatic cancer have raised concerns regarding the safety of DPP-4 inhibitors and are under investigation. Post-marketing surveillance has revealed less common adverse effects, especially a number of skin- and immune-related adverse effects. These issues are covered in the present review.. DPP-4 inhibitors are useful and efficient drugs. DPP-4 inhibitors have similar mechanism of action and similar efficacy. However, DPP-4 inhibitors have certain differences in their pharmacokinetic properties that may be associated with different clinical effects and adverse event profiles. Although clinical trials indicated a favorable safety profile, post-marketing reports revealed certain safety aspects that need further investigation. Certainly, more research is needed to clarify if the differences among DPP-4 inhibitors could lead to a different clinical and safety profile.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Nitriles; Piperidines; Piperidones; Purines; Pyrazines; Pyrazoles; Pyrimidines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Thiazolidines; Triazoles; Uracil; Vildagliptin

Topics: Cholesterol, LDL; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Pyrimidines; Time Factors; Triglycerides

To determine whether the twice-daily (BID) regimen is superior to the once-daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD.. A double-blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase-4 (DPP-4) inhibitor treatment to compare glycaemic variability.. The decrease from baseline in MAGE at 12 weeks after DPP-4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P < .05); -30.4 ± 25.6 mg/dl (P < .001) in the anagliptin group versus -9.5 ± 38.0 mg/dl (P = .215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P < .001) in the anagliptin group and by 14.6% ± 28.2% (P = .014) in the sitagliptin group, with a statistically significant difference (P = .009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG).. The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Protease Inhibitors; Sitagliptin Phosphate; Treatment Outcome

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial.. PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization.. Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07).. PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.

Topics: Aged; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Platelet Count; Proprotein Convertase 9; Pyrimidines; Sitagliptin Phosphate; Triglycerides

This study investigated the impact of the dipeptidyl peptidase-4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status.. Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C-peptide area under the curve 0-120 min to insulin area under the curve 0-120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status.. Anagliptin significantly reduced glycosylated hemoglobin levels (P < 0.001 vs placebo) and HIC levels (P < 0.01). Longer duration of diabetes, lower body mass index, higher glycosylated hemoglobin and lower insulin secretion capacity were observed with increases in baseline HIC levels. Improvements in glycosylated hemoglobin, glycoalbumin and 1,5-anhydroglucitol levels were greater in the relatively higher HIC group (baseline HIC levels ≥median) than in the lower HIC group (

Topics: Aged; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Insulin; Liver; Male; Middle Aged; Pyrimidines

Type 2 diabetes and dyslipidemia are diseases that collectively increase the risk of patients developing cardiovascular complications. Several incretin-based drugs are reported to improve lipid metabolism, and one of these medications, anagliptin, is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been shown to decrease serum triglyceride and low-density lipoproteins cholesterol. This study aimed to conduct an investigation into the effects of anagliptin on serum lipid profiles. This multicenter, open-label, randomized (1:1), parallel group study was designed to evaluate the effects of anagliptin on serum lipid profiles (triglycerides, lipoproteins, apolipoproteins, and cholesterol fractions). The study involved 24 patients with type 2 diabetes at two participating hospitals for a period of 24 weeks. Patients were randomly assigned to the anagliptin (n = 12) or control (n = 12) groups. Patients in the anagliptin group were treated with 200 mg of the drug twice daily. Patients in the control group did not receive anagliptin, but continued with their previous treatment schedules. Lipid metabolism was examined under fasting conditions at baseline and 24 weeks. Patients treated with anagliptin for 24 weeks exhibited significantly reduced levels of serum apolipoprotein B-48, a marker for lipid transport from the intestine, compared with the control group patients (P < 0.05). After 24 weeks of treatment, serum adiponectin levels were significantly raised, whereas glycated hemoglobin (HbA1c) levels were significantly lower compared with the baseline in the anagliptin group (P < 0.05), but not in the control group. This study showed that the DPP-4 inhibitor anagliptin reduces fasting apolipoprotein B-48 levels, suggesting that this drug may have beneficial effects on lipid metabolism possibly mediated by the inhibition of intestinal lipid transport.

Topics: Adiponectin; Aged; Apolipoprotein B-48; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Fasting; Female; Glycated Hemoglobin; Humans; Hypolipidemic Agents; Lipid Metabolism; Lipoproteins; Male; Middle Aged; Pyrimidines; Triglycerides

Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial.. As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy.. The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group.. Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Dyslipidemias; Fatty Acid-Binding Proteins; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyrimidines; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Glucagon has an important role in glucose homeostasis. Recently, a new plasma glucagon assay based on liquid chromatography-high resolution mass spectrometry was developed. We evaluated the influence of a dipeptidyl peptidase-4 inhibitor (anagliptin) on plasma glucagon levels in Japanese patients with type 2 diabetes by using this new assay.. Twenty-four patients with type 2 diabetes were enrolled in a prospective, single-center, randomized, open-label study and were randomly allocated to 4 weeks of treatment with metformin (1000 mg/day) or anagliptin (200 mg/day). A liquid test meal labeled with sodium [. Twenty-two patients completed the study (metformin group: n = 10; anagliptin group: n = 12). Glycemic control showed similar improvement in both groups. In the anagliptin group, there was a slight decrease of the incremental area under the plasma concentration versus time curve for glucagon after the test meal (P = 0.048). In addition, the plasma level of active GLP-1 and GIP was increased, and plasma C-peptide was also increased versus baseline. Neither anagliptin nor metformin delayed gastric emptying.. In patients with type 2 diabetes maintained endogenous insulin secretion, anagliptin increased the plasma level of active GLP-1 and GIP in association with a slight stimulation of insulin secretion and slight inhibition of glucagon secretion, but did not delay gastric emptying. Clinical Trial Registry: University hospital Medical Information Network UMIN000028293.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Gastric Emptying; Glucagon; Humans; Hypoglycemic Agents; Male; Mass Spectrometry; Metformin; Middle Aged; Prospective Studies; Pyrimidines; Young Adult

Anagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.. We therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).. There was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).. These findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

Topics: Aged; Biomarkers; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dyslipidemias; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Japan; Male; Middle Aged; Phytosterols; Pyrimidines; Sitagliptin Phosphate; Sitosterols; Time Factors; Treatment Outcome

Additional reductions in low-density lipoprotein-cholesterol (LDL-C) via antidiabetic therapies should be considered in statin-using patients with sub-optimal LDL-C levels. We compared the efficacy of anagliptin and sitagliptin, two antidiabetic therapies, in reducing LDL-C in type 2 diabetic patients. A randomized, open-label, parallel-group trial was conducted at 17 centres in Japan between April 2015 and January 2018. Adults (age ≥20 years) with type 2 diabetes, any atherosclerotic vascular lesions, and statin prescriptions were included. Anagliptin or sitagliptin were administered for 52 weeks. Primary and secondary endpoints were changes in LDL-C and haemoglobin A1C (HbA1c) levels, respectively. We assessed the superiority (primary endpoint) and non-inferiority (secondary endpoint) of anagliptin over sitagliptin. This study was registered at Clinicaltrials.gov (NCT02330406). Of 380 participants, 353 were eligible and randomized. Mean participant age was 68 years, and 61% were males. Baseline median LDL-C and HbA1c were 108 mg/dL and 6.9%, respectively. Changes in LDL-C were -3.7 mg/dL with anagliptin and +2.1 mg/dL with sitagliptin at 52 weeks, and the estimated treatment difference was a significant -4.5 mg/dL (P = 0.01 for superiority). Changes in HbA1c were +0.02% with anagliptin and +0.12% with sitagliptin (P < 0.0001 for non-inferiority). Overall, anagliptin was superior to sitagliptin in lowering LDL-C without deteriorating HbA1c.

Topics: Aged; Cholesterol, LDL; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Pyrimidines; Sitagliptin Phosphate

Anagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase-4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients.. The study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase-4 inhibitors for ≥8 weeks and had a low-density lipoprotein cholesterol (LDL-C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks.. There was no significant difference in percentage change in LDL-C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL-C levels, one of the secondary end-points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B-100 levels, and the percentage change in LDL-C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B-100 levels in the ANA group.. The LDL-C-lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL-C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B-100 synthesis.

Topics: Aged; Apolipoprotein B-100; Blood Glucose; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Lipid Metabolism; Lipids; Male; Piperidines; Pyrimidines; Treatment Outcome; Uracil

Reduction of low-density lipoprotein cholesterol (LDL-C) is important for patients with a high risk for atherosclerotic events, such as patients with diabetes and other risk factors. Anagliptin was reported to reduce LDL-C for 12 weeks in phase III trials regardless of the use of statins, but it is uncertain whether this effect is common to other dipeptidylpeptidase-4 (DPP-4) inhibitors.. A multicenter, randomized, open-label, parallel-group trial was conducted to confirm the superiority of anagliptin to sitagliptin in terms of the primary endpoint of reduction of LDL-C for 52 weeks in patients with type 2 diabetes and atherosclerotic vascular lesions, as well as the non-inferiority of anagliptin to sitagliptin in terms of change in hemoglobin A1c (HbA1c). Patients are randomly assigned to receive anagliptin or sitagliptin at a ratio of 1:1, with those in the anagliptin group receiving anagliptin 100 mg orally twice per day and those in the sitagliptin group receiving sitagliptin 50 mg orally once per day. During the trial period, hypoglycemic agents and anti-dyslipidemia drugs should not be added and neither should their dosages be changed. A total sample size of 300 was estimated to provide a power of 0.8 with a two-sided alpha of 0.05 for LDL-C, considering a 30% dropout rate. Pre-specified factors for subgroup analyses are HbA1c, use of DPP-4 inhibitors, sex, body mass index, LDL-C, age, and the presence of treatment for existing ischemic heart disease.. If anagliptin were to be shown to reduce LDL-C in patients with type 2 diabetes and atherosclerotic vascular lesions despite pre-existing statin treatment, more intensive cholesterol management would be appropriate.. Clinicaltrials.gov NCT02330406.

Topics: Anticholesteremic Agents; Atherosclerosis; Biomarkers; Blood Glucose; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Dyslipidemias; Female; Glycated Hemoglobin; Humans; Japan; Male; Multicenter Studies as Topic; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome

Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a therapeutic target for type 2 diabetes (T2DM). Arterial stiffness, a predictor of future cardiovascular events and all-cause mortality, is augmented in these patients. However, effects of DPP-4 inhibitors on arterial stiffness remain unknown. In this study, we compared effects of anagliptin, an inhibitor of DPP-4 on arterial stiffness evaluated by cardio-ankle vascular index (CAVI) with those of an equipotent glucose-lowering agent, glimepiride in patients with T2DM.. The study involved 50 consecutive outpatients (33 males and 17 females; mean age of 72.5±9.5 years) who visited our hospitals for a risk-screening test or treatment for T2DM. They underwent complete history and physical examination, and determination of blood chemistry and anthropometric variables, and then were randomized to receive either anagliptin (n=26) or glimepiride (n=24) for 6 months.. After 6-months treatment, fasting plasma glucose and HbA1c values were comparably reduced in both groups. Anagliptin, but not glimepiride treatment significantly decreased low-density lipoprotein cholesterol, malondialdehyde-modified LDL, remnant-like particle (RLP) cholesterol, CAVI, alanine transaminase (ALT), γ-glutamyl transferase and visceral fat volume. In multiple regression analysis, absolute changes from baseline of RLP cholesterol and ALT after anagliptin treatment for 6 months (ΔRLP cholesterol and ΔALT) were independently correlated with ΔCAVI (R2=0.445).. The present study suggests that anagliptin may exert a beneficial effect on arterial stiffness in patients with T2DM, which is independent of its blood glucose-lowering property. Anagliptin may ameliorate arterial stiffness partly via reduction of RLP cholesterol and improvement of liver function.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Biomarkers; Blood Glucose; Cholesterol; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Japan; Lipoproteins; Male; Middle Aged; Prospective Studies; Pyrimidines; Sulfonylurea Compounds; Time Factors; Treatment Outcome; Triglycerides; Vascular Stiffness

Metformin, α-glucosidase inhibitors (α-GIs), and dipeptidyl peptidase 4 inhibitors (DPP-4Is) reduce hyperglycemia without excessive insulin secretion, and enhance postprandial plasma concentration of glucagon-like peptide-1 (GLP-1) in type-2 diabetes mellitus (T2DM) patients. We assessed add-on therapeutic effects of DPP-4I anagliptin in Japanese T2DM patients treated with metformin, an α-GI miglitol, or both drugs on postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of the appetite-suppressing hormone leptin. Forty-two Japanese T2DM patients with inadequately controlled disease (HbA1c: 6.5%-8.0%) treated with metformin (n=14), miglitol (n=14) or a combination of the two drugs (n=14) received additional treatment with anagliptin (100mg, p.o., b.i.d.) for 52 weeks. We assessed glycemic control, postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of leptin in those patients. Add-on therapy with anagliptin for 52 weeks improved glycemic control and increased the area under the curve of biologically active GLP-1 concentration without altering obesity indicators. Total GIP concentration at 52 weeks was reduced by add-on therapy in groups treated with miglitol compared with those treated with metformin. Add-on therapy reduced leptin concentrations. Add-on therapy with anagliptin in Japanese T2DM patients treated with metformin and miglitol for 52 weeks improved glycemic control and enhanced postprandial concentrations of active GLP-1/total GIP, and reduce the leptin concentration.

Topics: 1-Deoxynojirimycin; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Leptin; Male; Metformin; Middle Aged; Pyrimidines; Treatment Outcome

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Proinsulin; Pyrimidines; Sitagliptin Phosphate

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

Topics: Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Placebos; Proinsulin; Pyrimidines

The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes.. Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month.. After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed.. These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers.

Topics: Adult; Aged; Biomarkers; Cholestanol; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Lipids; Lipoproteins, HDL; Male; Middle Aged; Phytosterols; Pilot Projects; Pyrimidines; Sitosterols; Young Adult

Topics: Atherosclerosis; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Proprotein Convertase 9; Pyrimidines; Sitagliptin Phosphate

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent the degradation of glucagon-like peptide-1 (GLP-1) and improve glycemic control. The GLP-1 insulinotropic effect involves a pathway through vagus nerve GLP-1 receptors in the gut, in addition to a direct effect on the pancreas. Therefore, this study verified whether DPP-4 inhibition in the gut contributed to the improvement of glycemic control. Anagliptin, a DPP-4 inhibitor, was administered orally or subcutaneously (with or without passing through the gastrointestinal tract, respectively) to mice. The association between blood glucose suppression following oral glucose challenge and DPP-4 inhibition in the small intestine and plasma was assessed. Oral administration of anagliptin (0.03-0.3 mg/kg) in normal mice significantly suppressed blood glucose, which was associated with an increase in insulin secretion at a dose of ≥0.1 mg/kg (P < 0.05). Subcutaneous administration of anagliptin (0.01-0.1 mg/kg) produced similar results. However, plasma DPP-4 inhibition following oral administration was weaker than that following subcutaneous administration; blood glucose suppression was significantly correlated with small intestinal DPP-4 inhibition (r = 0.949, P < 0.01), but not with plasma DPP-4 inhibition. Additionally, similar results were observed in a type 2 diabetes model (r = 0.975, P < 0.001). Thus, these results demonstrated that an improvement in glycemic control was dependent upon small intestinal DPP-4 inhibition. As these effects were accompanied by the elevation of intact GLP-1 in the portal, this suggests that improvement in glucose tolerance after anagliptin treatment might be related to an increase in GLP-1 receptor signaling in the small intestine and portal vein.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Incretins; Intestines; Male; Mice; Mice, Inbred C57BL; Pyrimidines

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase-4 (DPP-4) inhibitors has been a concern. Although DPP-4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP-4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP-4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP-4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP-4 inhibitors.

Topics: Aged, 80 and over; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Pemphigoid, Bullous; Pyrimidines; Sitagliptin Phosphate

Topics: Cardiovascular Diseases; Cholesterol, LDL; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Pyrimidines; Risk Factors; Sitagliptin Phosphate

Topics: Administration, Cutaneous; Aged, 80 and over; Betamethasone; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Substitution; Glucocorticoids; Humans; Male; Pemphigoid, Bullous; Pyrimidines; Treatment Outcome; Vildagliptin

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drugs, Chinese Herbal; Eleutherococcus; Fasting; Humans; Hypoglycemic Agents; Japan; Lipid Metabolism; Male; Middle Aged; Oxidative Stress; Postprandial Period; Pyrimidines

The aim of this case study was to examine the efficacy of a dipeptidyl peptidase-4 inhibitor (anagliptin) and an α-glucosidase inhibitor (miglitol) when added to ongoing insulin treatment in patients with type 2 diabetes mellitus. Continuous glucose monitoring was performed in four Japanese insulin-treated inpatients with type 2 diabetes. Baseline data were collected on day 1. Miglitol was administered on days 2 and 3. On day 4, miglitol and anagliptin were coadministered before breakfast. On days 1, 3, and 5, blood was drawn for plasma glucose, serum C-peptide, plasma glucagon, total and active glucagon-like peptide-1 (GLP-1), and total and active glucose-dependent insulinotropic peptide (GIP) measurements. Coadministration of anagliptin with miglitol resulted in additional improvements in glycemic control over the entire day in three of the four patients. The C-peptide, glucagon, and total and active GLP-1 and GIP responded differently to the medications for each patient, suggesting interindividual differences in hormonal responses, which may be complicated by multifactorial effects.

Topics: 1-Deoxynojirimycin; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Pyrimidines

Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes.. Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10weeks.. Both doses of anagliptin significantly inhibited the plasma DPP-4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the β-cell mass in both genotypes of mice.. High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Energy Intake; Glucagon-Like Peptide 1; Glucokinase; Glucose Intolerance; Haploinsufficiency; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pyrimidines; Weight Gain

Topics: Angioedema; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Male; Middle Aged; Pyrimidines