alogliptin and Hyperglycemia

Type 2 diabetes mellitus continues to be a global problem, placing an enormous burden on healthcare systems and resources. Effective treatment options to minimize the effects of hyperglycemia are essential. Most patients eventually need to take multiple drugs to maintain glycemic control, and many antidiabetic drugs are associated with adverse effects, such as hypoglycemia, weight gain or gastrointestinal effects. Dipeptidyl peptidase (DPP)-4 inhibitor is one of the newer classes of oral antidiabetic drug, and alogliptin is the most recently approved drug in this class.. This paper reviews the pharmacodynamic and pharmacokinetic properties of alogliptin and the results of clinical trials evaluating its efficacy at improving glycemic control in patients with type 2 diabetes both as monotherapy and in combination with other antidiabetic drugs. The drug's tolerability and safety profiles are also considered.. Alogliptin is a DPP-4 inhibitor that can help in improving glycemic control in patients with type 2 diabetes, including the elderly. It is generally well tolerated and does not increase the risk of hypoglycemia or weight gain.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Piperidines; Uracil

Treatment of patients with type 2 diabetes mellitus (T2DM) traditionally has involved a progression of phases, from conventional lifestyle interventions and monotherapy, to combination therapy involving oral agents, to insulin initiation and its use either alone or with oral pharmacotherapy. Currently, the need for antidiabetic therapies with fewer adverse effects (eg, weight gain, reduced rates of hypoglycemia) is unmet. In addition, most treatments fail to adequately control postprandial hyperglycemia. Traditional options have generally been directed at the "insulin demand" aspect and have targeted insulin secretion or insulin resistance in peripheral tissues. Only recently have agents been available to address the "glucose supply" aspect that leads to fasting hyperglycemia in patients with T2DM. Incretin-based therapies, however, address both aspects. Two classes of incretin-directed therapies are available and work by either increasing endogenous levels of glucagon-like peptide-1 (GLP-1) (ie, dipeptidyl peptidase-4 inhibitors) or by mimicking the activity of endogenous GLP-1 (ie, GLP-1 agonists). These therapies treat the key metabolic abnormalities associated with T2DM but do so with reduced rates of hypoglycemia and do not promote weight gain as compared with conventional therapies.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Incretins; Piperidines; Pyrazines; Sitagliptin Phosphate; Triazoles; Uracil

Successful management of type 2 diabetes mellitus (T2DM) requires attention to additional conditions often associated with hyperglycemia including overweight or obesity, dyslipidemia and hypertension, as each has some relationship with microvascular or macrovascular complications. Because control of cardiovascular risk factors is as important as glucose control in T2DM, these risk factors need to be addressed, and it is critical that antidiabetes medications do not exacerbate these risk factors. A patient-centered approach to treatment in which clinicians maximize patient involvement in the selection of antidiabetes therapy may lead to increased adherence and improved clinical outcomes. The incretin hormones, which include glucagon-like peptide-1 (GLP-1), are involved in glucoregulation and have become an important focus of T2DM research and treatment. Incretin-based therapies, such as the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-IV inhibitors, have shown beneficial effects on hyperglycemia, weight, blood pressure and lipids with a low incidence of hypoglycemia.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Obesity; Patient Compliance; Peptides; Piperidines; Precision Medicine; Primary Health Care; Pyrazines; Pyrrolidines; Risk Factors; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Attenuation of the prandial incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), contributes to hyperglycemia in type 2 diabetes mellitus (T2DM). Since the launch of sitagliptin in 2006, a compelling body of evidence has accumulated showing that dipeptidyl peptidase-4 (DPP-4) inhibitors, which augment endogenous GLP-1 and GIP levels, represent an important advance in the management of T2DM. Currently, three DPP-4 inhibitors - sitagliptin, vildagliptin and saxagliptin - have been approved in various countries worldwide. Several other DPP-4 inhibitors, including linagliptin and alogliptin, are currently in clinical development. As understanding of, and experience with, the growing number of DPP-4 inhibitors broadens, increasing evidence suggests that the class may offer advantages over other antidiabetic drugs in particular patient populations. The expanding evidence base also suggests that certain differences between DPP-4 inhibitors may prove to be clinically significant. This therapeutic diversity should help clinicians tailor treatment to the individual patient, thereby increasing the proportion that safely attain target HbA(1c) levels, and reducing morbidity and mortality. This review offers an overview of DPP-4 inhibitors in T2DM and suggests some characteristics that may provide clinically relevant differentiators within this class.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Intestinal Mucosa; Linagliptin; Neurons; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).. The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.. Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P. There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Cohort Studies; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incidence; Male; Middle Aged; Piperidines; Risk Factors; Secondary Prevention; Severity of Illness Index; Uracil

This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + metformin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was -0.19% with placebo, -0.86% with alogliptin, -1.04% with metformin and -1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P  < .0001) in lowering HbA1c than either alogliptin or metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes.

Topics: China; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exercise; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunity, Mucosal; Incidence; Malaysia; Metformin; Middle Aged; Piperidines; Republic of Korea; Respiratory Tract Infections; Taiwan; Uracil

A phase IV, multicentre, randomized, double-blind, parallel-group, comparative study was conducted in Japanese subjects with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control, despite treatment with alogliptin in addition to diet and/or exercise therapy. Subjects with glycated haemoglobin (HbA1c) concentrations of 6.9-10.5% were randomized to receive 16 weeks' double-blind treatment with pioglitazone 15 mg, 30 mg once daily or placebo added to alogliptin 25 mg once daily. The primary endpoint was the change in HbA1c from baseline at the end of treatment period (week 16). Both pioglitazone 15 and 30 mg combination therapy resulted in a significantly greater reduction in HbA1c than alogliptin monotherapy [-0.80 and -0.90% vs 0.00% (the least squares mean using analysis of covariance model); p < 0.0001, respectively]. The overall incidence rates of treatment-emergent adverse events were similar among the treatment groups. Pioglitazone/alogliptin combination therapy was effective and generally well tolerated in Japanese subjects with T2DM and is considered to be useful in clinical settings.

Topics: Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Drug Therapy, Combination; Exercise; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Japan; Pioglitazone; Piperidines; Thiazolidinediones; Uracil

To evaluate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin plus metformin (A + M) initial combination therapy versus either as monotherapy in drug-naïve T2DM patients.. This international, randomized, double-blind, placebo-controlled, 26-week study involved T2DM patients with hyperglycaemia (HbA1c 7.5-10.0%) following diet/exercise therapy. Patients (N = 784) received placebo, alogliptin (A, 12.5 mg BID or 25 mg QD), metformin (M, 500 or 1000 mg BID) or A + M (12.5/500 or 12.5/1000 mg BID); placebo, A25 for secondary analyses only.. week 26 changes from baseline in HbA1c (primary), fasting plasma glucose (FPG) and 2-h postprandial glucose (PPG); incidences of clinical response and hyperglycaemic rescue.. Week 26 mean HbA1c reductions from baseline (8.45%) were -1.22 and -1.55% with A + M 12.5/500 and 12.5/1000 versus -0.56, -0.65, and -1.11% with A12.5, M500 and M1000 (p<0.001, A + M vs. component monotherapies). FPG reductions were -1.76 and -2.55 mmol/L with 12.5/500 and 12.5/1000 versus -0.54, -0.64 and -1.78 mmol/L with A12.5, M500 and M1000 (p < 0.05, A + M vs. component monotherapies). Significantly more A + M-treated patients achieved HbA1c < 7% (47.1-59.5% vs. 20.2-34.3% with monotherapy), significantly fewer required hyperglycaemic rescue (2.6-12.3% vs. 10.8-22.9% with monotherapy). A + M caused only mild/moderate hypoglycaemia (1.9-5.3%) and weight loss (0.6-1.2 kg).. Alogliptin plus metformin initial combination therapy was well tolerated yet more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines; Treatment Outcome; Uracil

To prospectively evaluate the efficacy and safety of alogliptin versus glipizide in elderly patients with type 2 diabetes mellitus (T2DM) over 1 year of treatment.. This was a randomized, double-blind, active-controlled study of elderly T2DM patients (aged 65-90 years) with mild hyperglycaemia on diet/exercise therapy alone [glycosylated haemoglobin (HbA1c) 6.5-9.0%] or plus oral antidiabetic monotherapy (HbA1c 6.5-8.0%). Patients were randomized to once-daily alogliptin 25 mg or glipizide 5 mg titrated to 10 mg, if needed. Hypoglycaemic episodes were systematically captured under predefined criteria.. In the primary analysis, HbA1c mean changes from a baseline of 7.5% were -0.14% with alogliptin (n = 222) and -0.09% with glipizide (n = 219) at the end of the study, demonstrating non-inferiority of alogliptin to glipizide [least squares (LS) mean difference = -0.05%; one-sided 97.5% confidence interval (CI): -∞, 0.13%]. More clinically relevant HbA1c reductions occurred among patients who completed the study: -0.42 and -0.33% with alogliptin and glipizide, with non-inferiority again confirmed (LS mean difference = -0.09%; one-sided 97.5% CI: -∞, 0.07%). Overall, alogliptin was safe and well tolerated, with notably fewer hypoglycaemic episodes than glipizide [5.4% (31 episodes) vs. 26.0% (232 episodes), respectively]; three patients experienced severe hypoglycaemia, all with glipizide. Alogliptin also resulted in favourable weight changes versus glipizide (-0.62 vs. 0.60 kg at week 52; p < 0.001).. Alogliptin monotherapy maintained glycaemic control comparable to that of glipizide in elderly patients with T2DM over 1 year of treatment, with substantially lower risk of hypoglycaemia and without weight gain.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dizziness; Double-Blind Method; Female; Glipizide; Glycated Hemoglobin; Headache; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Male; Metformin; Piperidines; Prospective Studies; Treatment Outcome; Triglycerides; Uracil; Weight Gain

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

Topics: Acarbose; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Insulin; Insulin Secretion; Islets of Langerhans; Male; Middle Aged; Overweight; Piperidines; Uracil; Weight Gain

The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naïve subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naïve patients who visited the outpatient units. The patients randomly received 12.5-25 mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-R (HOMA-R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from 10.51 to 8.74% for alogliptin and from 10.01 to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA-R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles.

Topics: Adult; Diabetes Mellitus, Type 2; Diet, Diabetic; Diet, Fat-Restricted; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Hospitals, Municipal; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemia; Insulin Resistance; Japan; Male; Middle Aged; Outpatient Clinics, Hospital; Patient Dropouts; Piperidines; Uracil; Weight Loss

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1-10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83-1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A

Topics: Adamantane; Algorithms; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Monitoring; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Ligands; Liraglutide; Models, Molecular; Molecular Targeted Therapy; Nitriles; Peptides; Piperidines; Pyrrolidines; Reproducibility of Results; Sitagliptin Phosphate; Uracil; Venoms; Vildagliptin

Chronic kidney disease (CKD) is a risk factor for end-stage renal failure and cardiovascular disease, and a strategy to counteract CKD must be established. CKD caused by immunological abnormalities is treated by steroids, frequently resulting in steroid diabetes. Although insulin is the most effective drug against steroid diabetes, administering it to patients can be difficult. Dipeptidyl peptidase-4 (DPP-4) inhibitors were developed for diabetes mellitus with a new mechanism of action. However, their efficacies and mechanisms of action for steroid diabetes are unclear.. We studied 11 CKD patients treated with steroids admitted to our hospital (3 men and 8 women; age, 66.0 ± 15.9 years). DPP-4 inhibitor alogliptin was administered for steroid diabetes. Levels of markers related to glucose metabolism were measured before alogliptin treatment and after alogliptin treatment, before the prednisolone dose was reduced.. Alogliptin treatment significantly increased plasma glucagon-like peptide-1 (GLP-1) levels from 1.16 ± 1.71 pmol/L to 4.48 ± 1.53 pmol/L and significantly reduced levels of plasma glucose recorded 2 h after lunch and hemoglobin A1c (HbA1c). No significant differences were seen in insulin secretory ability of homeostasis model assessment (HOMA) (HOMA-β) and insulin resistance index of HOMA (HOMA-R) before and after alogliptin treatment. In contrast, alogliptin treatment significantly decreased plasma glucagon levels, from 116.1 ± 38.7 pg/mL to 89.6 ± 17.3 pg/mL. Moreover, there were significant correlations among HbA1c, GLP-1, and glucagon levels.. Alogliptin improves steroid-induced hyperglycemia by decrease of glucagon levels through an increase in plasma GLP-1 levels.

Topics: Aged; Asian People; Body Mass Index; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Japan; Kidney Function Tests; Male; Piperidines; Regression Analysis; Renal Insufficiency, Chronic; Steroids; Uracil; Vital Signs