The Effect of Linagliptin versus Metformin Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: There have been no studies directly comparing the effect of dipeptidyl peptidase-4 inhibitors with that of metformin on treatment-related quality of life (QOL) when used as first-line therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: This study is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. Forty-four participants who failed to achieve target glycemic control with diet and exercise therapy were randomly allocated to receive linagliptin or metformin therapy. We compared treatment-related QOL among the two groups using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2) and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire. RESULTS: After randomization, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set. Biochemical parameters, incidence of adverse effects, and rate of adherence to medication were comparable between the two groups. Over the 24-week treatment period, no significant differences in overall OHA-Q scores between the groups were observed, although the subscale 1 (treatment convenience) score was significantly higher in the linagliptin group than in the metformin group. The overall DTR-QOL score did not differ between the two groups; however, the DTR-QOL scores significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment. CONCLUSION: We did not find significantly better treatment-related QOL with linagliptin among Japanese patients with T2DM. In terms of treatment convenience, our data showed that linagliptin was superior to metformin. FUNDING: This study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. The journal's article processing fees were covered by a research fund from Juntendo University. CLINICAL TRIAL REGISTRATION: UMIN000022953.

Efficacy and safety of repaglinide added to sitagliptin in Japanese patients with type 2 diabetes: A randomized 24-week open-label clinical trial.

Although sitagliptin and repaglinide monotherapies improve postprandial hyperglycemia, the long-term effects and safety of their combination has not been examined. In this randomized 24-week trial of Japanese patients with poor control (HbA1c 7.0-8.5%) by sitagliptin, we divided 40 patients randomly into two equal groups of the repaglinide add-on to sitagliptin (ADD-ON, n=20), or sitagliptin switched to repaglinide (SWITCH, n=20). The meal tolerance test was carried out at weeks 0 and 24. The primary outcomes were changes in HbA1c and area under the curves (AUC) of glucose from the baseline to week 24. The mean change in HbA1c from baseline to week 24 was larger in the ADD-ON (-0.87±0.63%, mean±SD), compared with the SWITCH (0.03±0.65%, p=0.000). Significant improvements were noted in the mean changes in fasting glucose and AUCs of glucose in the ADD-ON vs. SWITCH (p=0.007 and p=0.000). Insulin secretion relative to glucose elevation (ISG; defined as AUC insulin/AUC glucose) increased significantly in the ADD-ON, although the mean change in fasting insulin level was significantly decreased in the ADD-ON (p=0.015 and p=0.026). The AUC of glucagon was significantly lower at 24-week relative to baseline in the ADD-ON, but was not significant in the two groups (p=0.047 and p=0.056, respectively). The combination therapy produced significant reductions in HbA1c, AUC of glucose and fasting glucose compared with switching to repaglinide without weight gain or severe hypoglycemia. The improved glycemic control with this combination therapy may be at least in part due to augmentation of repaglinide-induced insulin secretion by sitagliptin.

Relationship between sleep disordered breathing and diabetic retinopathy: Analysis of 136 patients with diabetes.

AIMS: Sleep disordered breathing (SDB) is associated with poor glycemic control. However, whether SDB contributes to diabetic microangiopathies, especially diabetic retinopathy (DR), is unknown. The aim of this study was to assess the relationship between SDB and DR. METHODS: Between January 2010 and November 2012, 136 patients underwent a sleep test and were divided into two groups according to the presence or absence of DR. Sleep test results and known risk factors for DR were compared between groups. Optic fundi were examined using indirect ophthalmoscope or retinal photographs and diagnosed by experienced ophthalmologists. Multivariate stepwise (backward) logistic regression analysis was performed to assess factors associated with DR. RESULTS: Ninety-nine patients without DR (NDR) and 37 patients with DR were assessed. Patients in the DR group had significantly longer duration of diabetes, were more likely to have hypertension and cardiovascular disease (CVD), and were more likely to be taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers (p=0.000 for each). In the multivariate backward logistic regression analysis, minimum SO2 (odds ratio [OR], 0.89; p=0.001), HbA1c (OR, 1.40; p=0.021), duration of diabetes (OR, 1.23; p<0.001), and history of CVD (OR, 8.96; p=0.008) remained significant. CONCLUSIONS: Minimum SO2 values were associated with DR independent from glycemic control level, duration of diabetes, and history of CVD. This finding suggests that SDB may contribute to the development of DR not through frequency, but due to the degree of intermittent hypoxia.

A SNP of NPC1L1 affects cholesterol absorption in Japanese.

AIM: Ezetimibe is known to target Niemann-Pick Type C1 Like1 (NPC1L1), a key protein in intestinal cholesterol absorption, and thus to decrease serum LDL-cholesterol (LDL-C) levels. The response of serum LDL-C levels to ezetimibe was reported to differe among NPC1L1 haplotypes.We analyzed NPC1L1 genotypes in Japanese and investigated differences in markers of cholesterol synthesis/absorption among the genotypes. METHODS: Blood samples were collected from 42 adult volunteers to measure markers of cholesterol synthesis (lathosterol) and absorption (sitosterol and campesterol) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on a study by Hegele RA et al. in Canada, we selected three SNPs (1735 C>G, 25342 A>C and 27677 T>C (numbers relative to the transcription start site)) and analyzed them using PCR-RFLP. RESULTS: The frequencies of genotypes were as follows: 1735 C/G (46%)>C/C (35%)>G/G (19%), 25342 A/A (97%)>A/C (3%)>C/C (0%) and 27677 T/T (97%)>T/C (3%)>C/C (0%). Serum campesterol levels were significantly higher in the 1735 G/G group than 1735 C/G+C/C group, but lathosterol levels showed no significant differences between the genotypes. CONCLUSION: Our results revealed differences in the frequency of the NPC1L1 polymorphism between Japanese and Canadians. In Japanese, the 1735 G/G group showed enhanced cholesterol absorption from the intestine, as compared to the 1735 C/G+C/C group.

Increased serum apolipoprotein B48 concentration in patients with metabolic syndrome.

AIM: Postprandial hyperlipidemia is characterized by an increase of chylomicron remnants (CM-R), and is a risk factor for atherosclerosis. Apolipoprotein (apo) B48 exists exclusively in chylomicroms and CM-R, and fasting plasma levels of apo B48 may reflect high postprandial levels of chylomicrons and/or CM-R. We hypothesized that fasting apo B48 levels may be increased in metabolic syndrome. METHODS: We investigated 1,349 inhabitants (528 men and 821 women aged 62.4+/-12.8 y; mean+/-S.D.) of two towns in rural Hokkaido, who underwent health checks in 2005. RESULTS: The fasting apo B48 level was significantly higher in males than females (geometric mean 1.92; 95% CI 1.802.04 microg/mL, vs. 1.69; 95% CI 1.611.76 microg/mL; p< 0.001). Ln (apo B48) showed a significant positive correlation with total cholesterol and ln (triglycerides), and a negative correlation with HDL-cholesterol. The correlation between ln (apo B48) and ln (triglycerides) was strong. Apo B48 was significantly higher in men and women with than without metabolic syndrome. Regression analysis revealed that ln (apo B48) was significantly associated with age, BMI, total cholesterol, HDL cholesterol, LDL cholesterol, and ln (triglyceride). CONCLUSION: Fasting apo B48 levels are raised in individuals with metabolic syndrome.

[Dislipidemia and steatohepatitis with visceral fat].

The prevalence of metabolic syndrome has been increased recently because of westernized dietary habits and low physical activity in Japan. Metabolic syndrome is diagnosed by the accumulation of dislipidemia, glucose intolerance and/or high blood pressure caused by visceral obesity. The dislipidemia in metabolic syndrome is characterized by the presence of high plasma triglyceride and low HDL-cholesterol, which are associated with increase in small dense LDL and remnant lipoproteins, highly atherogenic lipoproteins. Metabolic syndrome is also often associated with fatty liver, which may be led to non-alcoholic steatohepatitis (NASH). Reduction of body weight and increase in physical activities are highly recommended in overweight patients to inhibit the development of metabolic syndrome, the dislipidemia and NASH.

Myo-inositol treatment increases serum plasmalogens and decreases small dense LDL, particularly in hyperlipidemic subjects with metabolic syndrome.

BACKGROUND AND AIM: We have previously shown that serum plasmalogen levels positively correlate with HDL, and significantly decrease with aging, and may be related to LDL particle size. The objective of the present study was to investigate the effects of increased serum plasmalogens on lipidosis, particularly the appearance of atherogenic small dense LDL (sdLDL), of subjects with hyperlipidemia and metabolic syndrome (MetS). METHODS AND RESULTS: The effects of increased serum plasmalogen levels, induced by 2 wk of myo-inositol treatment, on several clinical and biochemical parameters were examined in 17 hyperlipidemic subjects including some with MetS. After myo-inositol treatment, significant increases in plasmalogen-related parameters, particularly ChoPlas, and significant decreases in atherogenic cholesterols including sdLDL, were observed. Among the hyperlipidemic subjects treated with myo-inositol, compared to subjects without MetS, subjects with MetS had a significant increase in plasmalogens and a tendency towards reduced sdLDL, high sensitivity C-reactive protein (hsCRP), and blood glucose levels. Correlation analyses between the measured parameters showed that plasmalogens, as well as HDL, function as beneficial factors, and that sdLDL is a very important risk factor that shows positive correlations with many other risk factors. CONCLUSION: These results suggest that increased plasmalogen biosynthesis and/or serum levels are especially effective in improving MetS among hyperlipidemic subjects with MetS.

Plasmalogens in human serum positively correlate with high- density lipoprotein and decrease with aging.

AIM: The objective of the present study was to propose plasmalogens as a beneficial factor in human plasma by showing a highly positive correlation with high-density lipoprotein (HDL) and a significant reduction with aging. METHODS: For 148 elderly subjects suspected of coronary artery disease (CAD), clinical characteristics such as coronary stenosis, hyperlipidemia, abnormal glucose tolerance, and hypertension were investigated, and serum biochemical markers including plasmalogens were determined. RESULTS: Serum plasmalogens levels tended to fall in significant coronary stenosis and abnormal glucose tolerance. Correlative analyses among serum biochemical markers revealed that plasmalogens positively correlate with HDL-related values, particularly apolipoprotein A-I (apo A-I), and that the molar ratio of choline plasmalogen (ChoPlas) to ethanolamine plasmalogen (EtnPlas) correlates positively with low-density lipoprotein (LDL) particle size, and negatively with apo A-II and fasting triglyceride (TG) levels. Comparison of plasmalogens in elderly subjects with those of 119 healthy young subjects showed a marked decrease in serum plasmalogens levels by aging. CONCLUSION: These results suggest that serum plasmalogens, antioxidant phospholipids, function as a beneficial factor as well as HDL, and that the measurement of serum plasmalogens is useful in clinical diagnosis.