Efficacy and safety of combination therapy with an α‐glucosidase inhibitor and a dipeptidyl peptidase‐4 inhibitor in patients with type 2 diabetes mellitus: A systematic review with meta‐analysis

Aims/Introduction

The combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI.

Materials and Methods

We carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared.

Results

Of 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta‐analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference ?1.2%, 95% confidence interval ?1.6 to ?0.8), fasting plasma glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI.

Conclusions

The addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia.

     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor sitagliptin compared with α‐glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS‐2): a multicenter,randomized, open‐label,non‐inferiority trial

We assessed the efficacy and safety of sitagliptin compared with α‐glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active‐controlled, non‐inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by ?0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (?0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.     

Postprandial C‐peptide to glucose ratio as a predictor of β‐cell function and its usefulness for staged management of type 2 diabetes

Aims/Introduction

Type 2 diabetes is characterized by progressive deterioration of β‐cell function. Recently, it was suggested that the C‐peptide‐to‐glucose ratio after oral glucose ingestion is a better predictor of β‐cell mass than that during fasting. We investigated whether postprandial C‐peptide‐to‐glucose ratio (PCGR) reflects β‐cell function, and its clinical application for management of type 2 diabetes.

Materials and Methods

We carried out a two‐step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for β‐cell function in newly diagnosed and drug‐naïve patients after a mixed meal test. In the second step, participants with well‐controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group).

Results

In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of β‐cell function (HOMA‐β). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut‐off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001).

Conclusions

We suggest that PCGR might be a useful marker for β‐cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

α‐thalassaemia masked by β gene defects and a new polyadenylation site mutation on the α2‐globin gene

We report three examples of chronic anaemia involving complex combinations of α‐ and β‐globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [β26(B8)Glu→Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different α2 polyadenylation site mutations masked by a β‐thalassaemia heterozygosity. The third had an intermediate α‐thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [β6(A3)Glu→Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.     

Association between changes in bodyweight and cardiovascular disease risk factors among obese Japanese patients with type 2 diabetes

Aims/IntroductionWe aimed to assess the association between bodyweight reduction and cardiovascular disease risk factors, and to identify the minimum bodyweight reduction associated with significant improvement in cardiovascular disease risk factors among obese Japanese patients with type 2 diabetes.Materials and MethodsThe cohort comprised 1,753 patients with type 2 diabetes and body mass index ≥25 kg/m², who visited our clinic between 2013 and 2016. Multivariable linear regression analysis was carried out to assess the relationship between bodyweight changes and glycated hemoglobin A1c, serum lipids and blood pressure. Analyses of covariance were carried out to compare mean changes in cardiovascular disease risk factors across six groups of bodyweight change, <−5%, −5% to <−3%, −3% to <−1%, −1% to <1% (reference), 1% to <3% and ≥3%.ResultsLog‐transformed bodyweight change had a significantly positive relationship with log‐transformed glycated hemoglobin A1c, triglycerides, low‐density lipoprotein cholesterol and systolic blood pressure changes, and a negative relationship with high‐density lipoprotein cholesterol, after adjusting for sex, age, duration of diabetes, body mass index, use of glucose‐lowering, lipid‐lowering and antihypertensive agents, and changes in the use of these medications. A mean change in glycated hemoglobin A1c was significantly improved only in the <−5% group compared with the reference. Mean changes in triglycerides were improved in all groups, and significantly in the <−5% group.ConclusionsBodyweight change was significantly associated with cardiovascular disease risk factor changes, and >5% bodyweight reduction was associated with improved glycated hemoglobin A1c.