Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases glycated haemoglobin compared with once-daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks of treatment in a randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide 0.75 mg monotherapy compared with once-daily liraglutide 0.9 mg in Japanese patients with type 2 diabetes (T2D) for 52 weeks. METHODS: We conducted a phase III, randomized, 52-week (26-week primary endpoint), active- and placebo-controlled trial comparing 492 Japanese patients (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70). Participants and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide (open-label comparator); after 26 weeks, patients randomized to placebo were switched to once-weekly dulaglutide 0.75 mg (open-label). The present paper reports results for patients treated with dulaglutide and patients treated with liraglutide for 52 weeks. RESULTS: At week 52, dulaglutide decreased HbA1c significantly from baseline compared with liraglutide [least squares mean difference: -0.20; 95% confidence interval (CI) -0.39, -0.01; p = 0.04]. At week 52 (last observation carried forward), dulaglutide significantly decreased pre- and post-dinner blood glucose (BG) levels, the mean of seven-point self-monitored BG profiles, the mean of all postprandial BG levels and circadian variation compared with liraglutide. Body weight was generally stable in both groups through 52 weeks. The most frequently reported adverse events were nasopharyngitis, constipation, nausea and diarrhoea. Eight dulaglutide-treated (2.9%) and four liraglutide-treated (2.9%) patients reported hypoglycaemia, with no event being severe. CONCLUSIONS: Monotherapy with once-weekly dulaglutide 0.75 mg was effective and safe in Japanese patients with T2D, with better glycaemic control compared with once-daily liraglutide 0.9 mg.

Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomized phase III study.

AIMS: To examine the efficacy and safety of once-weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once-daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes. METHODS: This was a phase III, 52-week (26-week primary endpoint), randomized, double-blind, placebo-controlled, open-label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set. RESULTS: At 26 weeks, once-weekly dulaglutide was superior to placebo and non-inferior to once-daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo -1.57% (95% confidence interval -1.79 to -1.35); dulaglutide vs liraglutide -0.10% (95% confidence interval -0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once-daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

Citrullinated antigens as C1q-binding and monoclonal rheumatoid factor (mRF)-binding peptides in synovial fluids from rheumatoid arthritis patients.

OBJECTIVE: Previous studies have demonstrated that immune complexes (ICs) may be involved in the pathogenesis of rheumatoid arthritis (RA). However, autoantigens contained in rheumatoid ICs remain to be elucidated. In the present study, we investigated whether the peptides captured by C1q and monoclonal rheumatoid factor (mRF), presumably associated with ICs, were citrullinated in synovial fluids from patients with RA. METHODS: Sixteen rheumatoid arthritis synovial fluids (RASFs), 7 osteoarthritis synovial fluids (OASFs), and 20 sera from RA patients were used for experiments. ICs were measured using commercially available kits based on the C1q-binding (C1q-IC) and mRF-binding (mRF-IC) assays. Citrullination of the peptides captured by C1q and mRF was detected by anti-modified citrulline antibody (Senshu Ab) after chemical modification. RESULTS: There was a significant correlation between levels of citrullination of C1q-binding peptides and those of mRF-binding peptides in RASFs (r=0.77), both of which were significantly higher than those in OASFs. No citrullinated Ags captured by C1q and mRF were detected in sera from patients with RA. CONCLUSIONS: We have demonstrated the presence of citrullinated Ags as C1q- and mRF-binding peptides in RASF. We suggest that citrullinated Ags may contribute to the pathogenesis of RA through IC formation in the joint.

Methylprednisolone accelerates the resolution of glomerulonephritis by sensitizing mesangial cells to apoptosis.

Glucocorticoid has long been used to treat patients with glomerulonephritis because it ameliorates mesangial cell proliferation and proteinuria, in part by suppressing nuclear factor-kappa B (NF-kappaB) activation, which regulates the transcription of various pro-inflammatory genes. Recent evidence shows that NF-kappaB activation increases the resistance to TNF-alpha-induced apoptosis in mesangial cells. We examined glomerular cell proliferation and apoptosis along with NF-kappaB activation in the Thy-1.1 nephritis model. We also evaluated TNF-alpha-induced apoptosis in cultured mesangial cells. Methylprednisolone treatment ameliorated mesangial hypercellularity in Thy-1.1 nephritis by decreasing proliferating cells and increasing apoptosis in the glomeruli. These effects were associated with suppressed NF-kappaB activation. This in vitro study revealed that treatment with methylprednisolone and TNF-alpha induced cultured mesangial cell apoptosis. These results suggest that methylprednisolone may accelerate the resolution phase of Thy-1.1 nephritis in part by sensitizing mesangial cells to apoptosis.

Malignant hypertension with a rare complication of pulmonary alveolar hemorrhage.

A 34-year-old Japanese male was admitted to Okayama University Hospital with severe hypertension, rapidly progressive renal failure, blurred vision, dyspnea and hemoptysis. Clinical diagnosis of malignant hypertension was given and antihypertensive therapy and hemodialysis were immediately started. Renal biopsy was performed on the sixth day in hospital to examine the underlying disease, such as microscopic form of polyarteritis, since the complaint of hemoptysis and pulmonary alveolar hemorrhage was noted by computed tomography of the lungs. Typical pathological changes of malignant hypertension, i.e. fibrinoid necrosis of the afferent arterioles and proliferative endoarteritis at the interlobular arteries were observed. There was no evidence of active necrotizing glomerulonephritis and crescent formation. Renal function was gradually recovered and pulmonary hemorrhage completely disappeared by treatment with antihypertensive agents. The authors report a case of malignant hypertension with a rare complication of pulmonary alveolar hemorrhage and speculate that it may be related to vascular injuries at the alveolar capillary level caused by malignant hypertension.

MTHFR gene variant is not associated with diabetic nephropathy in Japanese.

Genetic predisposition has been implicated in diabetic nephropathy. The C677T variant of the MTHFR gene has been suggested to play a role in the development of not only vascular diseases but also diabetic microangiopathies. By using polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method using Hinf I, we investigated whether this variant is associated with diabetic nephropathy in Japanese. By analysing 274 unrelated Japanese patients with type II DM with or without nephropathy, there was no significant difference in the genotype distribution of this variant. The distribution of the three genotypes were not different among patients with micro- or macroalbuminuria and those without nephropathy. Although previous reports suggest a role of this variant with diabetic microangiopathies, our observations suggest that this variant is does not play an important role in the pathogenesis of diabetic nephropathy in Japanese.

Mistyping frequency of the angiotensin-converting enzyme gene polymorphism and an improved method for its avoidance.

A DD genotype of the angiotensin I-converting enzyme gene has been implicated in various diseases. However, genotype frequencies differ between previous reports, and data on the association of DD genotype with disease are sometimes conflicting. Although elimination of mistyping is of crucial importance, assessment of the accuracy of currently adopted typing methods has rarely been performed. Mistyping of the DD genotype is reported to occur by a conventional method with insertion/ deletion (I/D) flanking primers using polymerase chain reaction (PCR). We investigated whether currently adopted genotyping methods by PCR are reliable or not. We genotyped 248 patients by conventional PCR methods with I/D flanking primers with or without dimethyl sulfoxide (DMSO), and confirmed the DD genotype with insertion-specific primers with or without DMSO. Mistyping occurred frequently, not only in both methods without DMSO but also in a modified method with I/D flanking primers with inclusion of DMSO. Typing by these methods proved to lead to erroneous results more frequently than had been previously thought. To reduce mistyping frequency, initial PCR genotyping with I/D flanking primers with an inclusion of DMSO, followed by confirmation of the DD genotype by insertion-specific primers with DMSO, is recommended.

Blinking is controlled primarily by ocular surface conditions.

PURPOSE: To investigate the relation between blinking and ocular surface conditions and to introduce and examine a new index, the maximum blink interval. METHODS: In a prospective study, the blink rate of subjects under relaxed conditions was determined from a video recording taken by a hidden observer. The maximum blink interval was defined as the longest time subjects can avoid blinking without feeling uncomfortable. RESULTS: Significant changes in the blink rate and maximum blink interval were induced by factors that directly or indirectly affect the ocular surface: topical anesthesia, changing exposed ocular surface area, and wind. Moreover, the blink rate and maximum blink interval were significantly different in dry eye patients compared with healthy volunteers, with the values of the former approaching the values of the latter after use of artificial tears. The maximum blink interval was decreased by the same factors that increased the blink rate, and there was a significant inverse correlation between blink rate and maximum blink interval. Use of video display terminals was associated with decreased maximum blink interval and, hence, the development of dry eye symptoms. CONCLUSIONS: There was an important association among blink rate, maximum blink interval, and ocular surface conditions. The blink rate and our newly introduced measurement, the maximum blink interval, should prove useful in assessing factors that cause dry eye. This prospective study should contribute to the understanding and treatment of dry eyes.

Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus.

Serum paraoxonase/arylesterase (PONA) is associated with high-density lipoprotein and may prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides. A recent report suggested an association of glutamine (A type)/arginine (B type) polymorphism at position 192 of PONA gene with coronary heart disease (CHD) among Caucasian patients with noninsulin-dependent diabetes mellitus (NIDDM). However, conflicting results have also been reported. To investigate the significance of this polymorphism in the pathogenesis of CHD, we performed an association study of this polymorphism with CHD in Japanese NIDDM patients. We genotyped 164 patients with NIDDM, 42 with CHD, and 122 without CHD. Other known risk factors for CHD were matched between the 2 groups. AB+BB isoforms were detected in 41 of 42 diabetic patients with CHD. The proportion of B allele carriers (AB+BB) was significantly higher than that of AA carriers among diabetic patients with CHD compared with those without CHD (chi 2 = 7.68, P = 0.003). Multivariate logistic regression analyses showed a markedly increased odds ratio (OR: 8.823, CI, 1.13-68.7) in B allele carriers, while ORs of other risk factors remained between 1.01 and 1.92. Carriers of the B allele of the Gln192Arg polymorphism in the PONA gene proved to be at increased risk for developing CHD in Japanese NIDDM patients. This association was independent of other known risk factors for CHD, suggesting an important role of the paraoxonase B isoform in the pathogenesis of CHD.