Efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus

Aim

To confirm the efficacy and safety of teneligliptin in combination with pioglitazone in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy.

Materials and Methods

In an initial 12‐week, double‐blind, placebo controlled, parallel‐group study, patients (n = 204) were randomized to teneligliptin 20 mg or placebo once daily added to their stable pioglitazone therapy. This was followed by a 40‐week, open‐label period during which all patients received teneligliptin once daily. The primary end‐point was the change in hemoglobin A1c (HbA_1c) from baseline to week 12.

Results

Patients in the teneligliptin group showed significantly greater reductions in HbA_1c compared with the placebo group at week 12 (P < 0.001). The changes in HbA_1c from baseline to week 12 were −0.9 ± 0.0% (least‐squares mean ± standard error) in the teneligliptin group and −0.2 ± 0.0% in the placebo group. The change in fasting plasma glucose from baseline to week 12 was greater in the teneligliptin group than in the placebo group (P < 0.001). The blood glucose lowering effects of teneligliptin were sustained throughout the 40‐week open‐label period. Adverse events and adverse drug reactions occurred slightly more frequently in the teneligliptin group than in the placebo group, although the incidence of hypoglycemia was low. Bodyweight was unchanged in the double‐blind period, but was slightly increased in the open‐label period.

Conclusions

Add‐on therapy with teneligliptin was effective and generally well tolerated throughout the study period in Japanese patients with type 2 diabetes mellitus inadequately controlled with pioglitazone monotherapy. This trial was registered with ClinicalTrials.gov (no. NCT01026194).     

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus

Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin‐containing secretory granules of β‐cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β‐cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β‐cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8‐specific T cells and cytokine release by ZnT8‐specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus.     

Glucose-lowering action through targeting islet dysfunction in type 2 diabetes: Focus on dipeptidyl peptidase-4 inhibition

Dipeptidyl peptidase-4 (DPP-4) inhibition is a glucose-lowering medication for type 2 diabetes. It works through stimulation of insulin secretion and inhibition of glucagon secretion in a glucose-dependent manner, resulting in lowered fasting and postprandial glycemia with low risk of hypoglycemia. As impaired insulin secretion and augmented glucagon secretion are key factors underlying hyperglycemia in type 2 diabetes, DPP-4 inhibition represents a therapy that targets the underlying mechanisms of the disease. If insufficient in monotherapy, it can preferably be used in combination with metformin, which targets insulin resistance, and also in combination with sodium–glucose cotransporter 2 inhibition, thiazolidinediones and insulin, which target other mechanisms. In individuals of East Asian origin, islet dysfunction is of particular importance for the development of type 2 diabetes. Consequently, it has been shown in several studies that DPP-4 is efficient in these populations. This mini-review highlights the islet mechanisms of DPP-4 inhibition, islet dysfunction as a key factor for hyperglycemia in type 2 diabetes and that, consequently, DPP-4 is of particular value in populations where islet dysfunction is central, such as in individuals of East Asian origin.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy

Aim: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. Methods: After a 2‐week screening period, adult patients 18–80 years of age entered a 4‐week run‐in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run‐in period, patients were randomly assigned to double‐blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end‐point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end‐points included clinical response rates and changes in fasting plasma glucose, β‐cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C‐peptide, and homeostasis model assessment β‐cell function), body weight, and safety end‐points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. Results: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (?0.38%) and 25 mg (?0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25‐mg group had HbA1c levels ≤7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction ≥0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of β‐cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, ?0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63–64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0–2.5% across groups), and serious AEs (2.0–5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. Conclusions: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.     

Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy

Aim: To examine the efficacy and safety of vildagliptin vs. glimepiride as add‐on therapy to metformin in patients with type 2 diabetes mellitus in a 52‐week interim analysis of a large, randomized, double‐blind, multicentre study. The primary objective was to demonstrate non‐inferiority of vildagliptin vs. glimepiride in glycosylated haemoglobin (HbA_1c) reduction at week 52. Methods: Patients inadequately controlled on metformin monotherapy (HbA_1c 6.5–8.5%) and receiving a stable dose of metformin (mean dose 1898 mg/day; mean duration of use 36 months) were randomized 1:1 to receive vildagliptin (50 mg twice daily, n = 1396) or glimepiride (titrated up to 6 mg/day; mean dose 4.5 mg/day, n = 1393). Results: Non‐inferiority of vildagliptin was demonstrated (97.5% confidence interval 0.02%, 0.16%) with a mean (SE) change from baseline HbA_1c (7.3% in both groups) to week 52 endpoint of ?0.44% (0.02%) with vildagliptin and ?0.53% (0.02%) with glimepiride. Although a similar proportion of patients reached a target HbA_1c level of <7% with vildagliptin and glimepiride (54.1 and 55.5%, respectively), a greater proportion of patients reached this target without hypoglycaemia in the vildagliptin group (50.9 vs. 44.3%; p < 0.01). Fasting plasma glucose (FPG) reductions were comparable between groups (mean [SE] ?1.01 [0.06] mmol/l and ?1.14 [0.06] mmol/l respectively). Vildagliptin significantly reduced body weight relative to glimepiride (mean [SE] change from baseline ?0.23 [0.11] kg; between‐group difference ?1.79 kg; p < 0.001) and resulted in a 10‐fold lower incidence of hypoglycaemia than glimepiride (1.7 vs. 16.2% of patients presenting at least one hypoglycaemic event; 39 vs. 554 hypoglycaemic events, p < 0.01). No severe hypoglycaemia occurred with vildagliptin compared with 10 episodes with glimepiride (p < 0.01), and no patient in the vildagliptin group discontinued because of hypoglycaemia compared with 11 patients in the glimepiride group. The incidence of adverse events (AEs), serious AEs and adjudicated cardiovascular events was 74.5, 7.1 and 0.9%, respectively, in patients receiving vildagliptin, and 81.1, 9.5 and 1.6%, respectively, in patients receiving glimepiride. Conclusions: When metformin alone fails to maintain sufficient glycaemic control, the addition of vildagliptin provides comparable efficacy to that of glimepiride after 52 weeks and displays a favourable AE profile, with no weight gain and a significant reduction in hypoglycaemia compared with glimepiride.     

Case of emphysematous cholecystitis in a patient with type 2 diabetes mellitus associated with schizophrenia

Emphysematous cholecystitis is a rare, but life‐threatening, form of acute cholecystitis caused by gas‐forming organisms in the gallbladder. A 73‐year‐old male patient with type 2 diabetes mellitus complicated with neuropathy associated with schizophrenia was admitted to Okayama University Hospital, Okayama, Japan, because of a high fever and general malaise. On the fourth hospital day, despite normal liver function tests and little abdominal pain, his abdominal computed tomography showed huge gas formation in the gallbladder lumen along with a dilated gallbladder with a thickened wall, consistent with emphysematous cholecystitis. The patient underwent an emergency open cholecystectomy. Few abdominal symptoms appeared because of the hyposensitivity to pain caused by not only diabetic neuropathy, but also antipsychotic agents the patient was taking for schizophrenia. Emphysematous cholecystitis should be taken into consideration for the differential diagnosis of high fever in diabetic patients with schizophrenia, irrespective of the level of liver function tests and clinical symptoms.