Association between dipeptidyl peptidase-4 inhibitors and increased risk for bullous pemphigoid within 3 months from first use: A 5-year population-based cohort study using the Japanese National Database.

AIMS/INTRODUCTION: We assessed the association between dipeptidyl peptidase-4 inhibitors (DPP-4is) and bullous pemphigoid (BP) and time-dependent changes in the risk for developing BP after DPP-4i initiation. MATERIALS AND METHODS: The present population-based, real-world study was carried out using the Japanese National Database dataset collected between 2013 and 2018. To assess independent correlations between DPP-4is and the development of BP, the self-controlled case series method was used. RESULTS: Among the cohort followed up for a median of 1,540 days, 53,027 patients were likely to develop BP. The possible incidence rate of BP in all 150,328,339 patients was 10.4/100,000 person-years. Among the 9,705,814 patients with type 2 diabetes, 15,634 were likely to develop BP. The possible incidence rate of BP in patients with type 2 diabetes was 38.1/100,000 person-years, whereas that in patients with type 2 diabetes who did and did not use DPP-4is was 40.7 and 30.0/100,000 person-years, respectively. Analysis of the 28,705 patients with type 2 diabetes likely to develop BP after initial DPP-4i use showed a risk ratio of 2.15 (95% confidence interval [CI] 1.75-2.63), 1.70 (95% CI 1.37-2.11), 1.44 (95% CI 1.15-1.82), 1.25 (95% CI 0.98-1.59), 0.84 (95% CI 0.63-1.10), 0.84 (95% CI 0.64-1.11) and 1.05 (95% CI 0.92-1.20), for the risk period of ≤30, 31-60, 61-90, 91-120, 121-150, 151-180 and 181-365 days, respectively. CONCLUSIONS: Although DPP-4is were associated with increased risk for BP, the risk was particularly significant within 3 months from first use.

Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system.

Accumulating evidence demonstrates that not only sustained elevation of blood glucose levels but also the glucose fluctuation represents key determinants for diabetic complications and mortality. Current closed-loop insulin therapy option is limited to the use of electronics-based systems, although it poses some technical issues with high cost. Here we demonstrate an electronics-free, synthetic boronate gel-based insulin-diffusion-control device technology that can cope with glucose fluctuations and potentially address the electronics-derived issues. The gel was combined with hemodialysis hollow fibers and scaled suitable for rats, serving as a subcutaneously implantable, insulin-diffusion-active site in a manner dependent on the subcutaneous glucose. Continuous glucose monitoring tests revealed that our device not only normalizes average glucose level of rats, but also markedly ameliorates the fluctuations over timescale of a day without inducing hypoglycemia. With inherent stability, diffusion-dependent scalability, and week-long & acute glucose-responsiveness, our technology may offer a low-cost alternative to current electronics-based approaches.

Real-life glycemic control in patients with type 2 diabetes treated with insulin therapy: A prospective, longitudinal cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT 9]).

AIMS/INTRODUCTION: We investigated the association between four insulin regimens, and increase in glycated hemoglobin (HbA1c) and insulin dose in a real-life clinical setting because there are no data about them among insulin regimens. MATERIALS AND METHODS: Participants included 757 patients with type 2 diabetes having been treated with insulin therapy for more than 1 year. The four insulin regimens were regimen 1 (long-acting insulin, once daily), regimen 2 (biphasic insulin, twice daily), regimen 3 (biphasic insulin, three times daily) and regimen 4 (basal-bolus therapy). Main outcomes were increases in HbA1c levels >0.5% and increases in daily insulin units after 1 year. We carried out multivariable analyses to examine differences in glycemic control and insulin dose with adjustment for possible confounders. RESULTS: Mean HbA1c level and duration of insulin therapy were 7.8% and 11.3 years, respectively. HbA1c levels increased by >0.5% at follow up in 22.8, 24.9, 20.7, and 29.3% of participants using regimen 1, 2, 3 and 4, respectively, with no significant differences between groups. Daily insulin doses increased in 62.3, 68.8, 65.3 and 38.6% of patients, respectively (P < 0.001). Multivariable regression analysis showed that patients who received regimen 4 had significantly lower odds of requiring future insulin dose increases than those who had received regimen 2 (adjusted odds ratio 0.24, 95% confidence interval 0.14-0.41; P < 0.001). CONCLUSIONS: Many patients receiving insulin therapy showed increases in HbA1c levels and insulin doses 1 year later. The smallest increase in insulin dose was observed in the basal-bolus therapy group compared with other regimens.

Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice.

Although previous studies have attempted to create "electronics-free" insulin delivery systems using glucose oxidase and sugar-binding lectins as a glucose-sensing mechanism, no successful clinical translation has hitherto been made. These protein-based materials are intolerant of long-term use and storage because of their denaturing and/or cytotoxic properties. We provide a solution by designing a protein-free and totally synthetic material-based approach. Capitalizing on the sugar-responsive properties of boronic acid, we have established a synthetic polymer gel-based insulin delivery device confined within a single catheter, which exhibits an artificial pancreas-like function in vivo. Subcutaneous implantation of the device in healthy and diabetic mice establishes a closed-loop system composed of "continuous glucose sensing" and "skin layer"-regulated insulin release. As a result, glucose metabolism was controlled in response to interstitial glucose fluctuation under both insulin-deficient and insulin-resistant conditions with at least 3-week durability. Our "smart gel" technology could offer a user-friendly and remarkably economic (disposable) alternative to the current state of the art, thereby facilitating availability of effective insulin treatment not only to diabetic patients in developing countries but also to those patients who otherwise may not be strongly motivated, such as the elderly, infants, and patients in need of nursing care.

Serum uric acid levels are associated with increased risk of newly developed diabetic retinopathy among Japanese male patients with type 2 diabetes: A prospective cohort study (diabetes distress and care registry at Tenri [DDCRT 13]).

OBJECTIVE: We assessed the prospective association between baseline serum uric acid levels and consequent risk of developing diabetic retinopathy. RESEARCH DESIGN AND METHODS: Data for 1839 type 2 diabetes patients without diabetic retinopathy were obtained from a Japanese diabetes registry. A Cox proportional hazards model with time-varying exposure information by sex was used and adjusted for potential confounders to assess the independent correlations between baseline serum uric acid levels and incidence rate of diabetic retinopathy. RESULTS: Newly developed diabetic retinopathy was recognized in 188 patients (10.2%) during the observation period of 2 years. Compared to the first serum uric acid quartile level, the multivariate adjusted hazards ratio for diabetic retinopathy development in male patients was 1.97 (95% CI, 1.14-3.41; P = .015), 1.92 (95% CI, 1.18-3.13; P = .008), and 2.17 (95% CI, 1.40-3.37; P = .001) for the second, third, and fourth serum uric acid quartile levels, respectively. But this was not the case with female patients. CONCLUSION: Higher serum uric acid levels were associated with increased risk of developing diabetic retinopathy in male patients with type 2 diabetes, but not in female patients. Serum uric acid may be a useful biomarker for predicting the future risk of developing diabetic retinopathy in male patients with type 2 diabetes.

Higher levels of physical activity are independently associated with a lower incidence of diabetic retinopathy in Japanese patients with type 2 diabetes: A prospective cohort study, Diabetes Distress and Care Registry at Tenri (DDCRT15).

We assessed the prospective association between baseline levels of physical activity (PA) and the incidence of newly developed diabetic retinopathy (DR) in patients with type 2 diabetes. Data from 1,814 patients with type 2 diabetes without DR were obtained from a Japanese diabetes registry at Tenri Hospital, Nara, Japan. To assess the independent correlations between baseline PA levels and newly developed DR, the participants were divided into five categories based on their PA levels. A Cox proportional hazards model with time-varying exposure information was used and adjusted for potential confounders to assess the independent correlations. At baseline, the mean age, BMI, and hemoglobin A1c levels of the patients were 65.5 years, 24.5 kg/m2, and 7.2% (54 mmol/mol), respectively. After 2 years, newly developed DR was confirmed in 184 patients (10.1%). Patients with newly developed DR had longer duration of type 2 diabetes (14.7 versus 11.0 years, p < 0.0001), higher systolic blood pressure (139.2 versus 135.1 mmHg, p = 0.0012), lower estimated glomerular filtration rate (74.0 versus 77.1 mL/min/1.73 m2, p = 0.0382), greater urinary albumin-creatinine ratio (4.00 versus 2.45 mg/mmol, p < 0.0039), and higher HbA1c levels (7.5 versus 7.2%, p = 0.0006) than those without newly developed DR. The multivariable-adjusted hazard ratios for DR development were 0.87 (95% CI, 0.53-1.40; p = 0.557), 0.83 (95% CI, 0.52-1.31; p = 0.421), 0.58 (95% CI, 0.35-0.94; p = 0.027), and 0.63 (95% CI, 0.42-0.94; p = 0.025)for the second, third, fourth, and fifth PA categories, respectively, compared with the reference category of patients with a mean PA of 0 metabolic equivalent of task-hours/week). Higher PA levels are independently associated with a lower incidence of DR in Japanese patients with type 2 diabetes.

Serum uric acid levels are associated with a high risk of rapid chronic kidney disease progression among patients with type 2 diabetes: a prospective cohort study [Diabetes Distress and Care Registry at Tenri (DDCRT 12)].

BACKGROUND: We assessed the prospective association between baseline serum uric acid (SUA) concentrations and consequent risk of chronic kidney disease (CKD) progression in type 2 diabetes patients. METHODS: Longitudinal data from a Japanese diabetes registry including 3454 type 2 diabetes patients were obtained. To assess the independent correlations between SUA and rapid CKD progression [i.e., 30 % reduction in estimated glomerular filtration rate (eGFR) over 2 years], participants were divided into five groups based on SUA levels: <5.0, ≥5.0-6.0, ≥6.0-7.0, ≥7.0-8.0, and ≥8.0 mg/dl. Cox proportional hazards model adjusted for potential confounders was used for analysis. RESULTS: After 2 years, rapid CKD progression was recognized in 169 patients (4.89 %) who showed longer duration of type 2 diabetes (15.5 vs. 13.5 years, p = 0.005); higher systolic blood pressure (142.0 vs. 138.3 mmHg, p = 0.016), SUA (6.15 vs. 5.32 mg/dl, p < 0.001), and urinary albumin-creatinine ratio (1127.4 vs. 184.7 mg/gCr, p < 0.001); and lower diastolic blood pressure (69.7 vs. 72.8 mmHg, p = 0.003). Multivariate ratios for rapid CKD progression were 1.19 (p = 0.371), 1.02 (p = 0.937), 1.18 (p = 0.625), and 3.04 (p = 0.004), respectively, for the first, third, fourth, and fifth serum UA range groups; a second group was used as a reference. CONCLUSIONS: Higher SUA levels, independent of possible confounders, were associated with rapid eGFR decline and CKD progression in type 2 diabetes patients. SUA may be a useful biomarker for predicting future risk of rapid diabetic CKD progression.

Diabetes treatment-related quality of life is associated with levels of self-care activities in insulin injection among Japanese patients with type 2 diabetes: Diabetes Distress and Care Registry at Tenri (DDCRT 8).

AIMS: We investigated the association between diabetes treatment-related quality of life (QOL) and levels of self-care activities in insulin injection among Japanese patients with type 2 diabetes. METHODS: Data from 1394 patients with type 2 diabetes on insulin therapy were obtained from a diabetes registry in Japan. We used the Diabetes Therapy-Related QOL (DTR-QOL) questionnaire and relative risk regression analysis to assess the independent association of high levels of self-care activities in insulin injection and DTR-QOL scores while adjusting for possible confounders. RESULTS: The mean age, BMI and HbA1c level were 65.8 years, 24.8 kg/m(2) and 62 mmol/mol (7.8 %), respectively. The frequency of insulin injection omission was associated with DTR-QOL scores. In the multivariable-adjusted model, the relative risks for high levels of self-care activities in insulin injection was 1.15 (95 % confidence interval, 1.05-1.26) in the highest quintile compared with those in the lowest quintile of DTR-QOL scores. Subgroup analysis confirmed this association in patients <65 years. CONCLUSIONS: DTR-QOL was associated with self-reported levels of self-care activities in insulin injection, particularly among Japanese patients <65 years with type 2 diabetes. DTR-QOL might be a useful tool to identify patients who consequently omit insulin. For patients with low DTR-QOL score, healthcare providers should discuss their treatment-related problems to prevent insulin injection omission.

Switching from insulin to liraglutide improved glycemic control and the quality of life scores in a case of type 2 diabetes and active Crohn's disease.

A 44-year-old man with type 2 diabetes of five years' duration was admitted for the management of poor glycemic control despite the administration of insulin therapy. On admission, he received vigorous treatment for a 28-year history of Crohn's disease and a 14-year history of a psychiatric disorder. His glycosylated hemoglobin A1c (HbA1c) level was 11.3%, his fasting blood glucose level was 567 mg/dL and his C-peptide level was 1.0 ng/mL. His quality of life (QOL) was severely impaired as a result of frequent episodes of hyperglycemia and hypoglycemia. Treatment with liraglutide was commenced in place of insulin, which improved the patient's glycemic control to an HbA1c level of 5.5% and markedly increased his QOL score with no hypoglycemia.

Patient-reported adherence to insulin regimen is associated with glycemic control among Japanese patients with type 2 diabetes: Diabetes Distress and Care Registry at Tenri (DDCRT 3).

AIMS: We investigated the association between self-reported adherence to an insulin regimen and glycemic control in Japanese patients with type 2 diabetes. METHODS: Data from 1441 patients with type 2 diabetes who were treated with insulin were obtained from a diabetes registry in Japan. We obtained information on self-reported adherence to an insulin regimen. Relative risk regression analysis was employed to assess the independent association of various demographic factors with good glycemic control (HbA1c<7.0% [53 mmol/mol]) while adjusting for possible confounders. RESULTS: The mean age, body mass index, and number of daily insulin injections of participants were 65.4 years, 24.7 kg/m(2), and 2.3, respectively. Of all patients, 70.6% reported high adherence to their insulin regimen. Compared with participants with higher adherence, the crude relative risk of good glycemic control was 0.82 (95% CI, 0.67-1.00) for those with middle adherence and 0.64 (95% CI, 0.31-1.31) for those with lower adherence (P=0.029 for trend). Subgroup analysis confirmed this association in patients below 65 years old, but not in those 65 years old and over. CONCLUSIONS: A higher adherence to a daily insulin regimen was associated with a greater likelihood of good glycemic control in Japanese type 2 diabetes patients. This association was not seen in patients of 65 years old or over. Self-reported adherence to an insulin regimen may prove useful in titrating insulin dose in patients in the younger age group, but requires further investigation.

Predictor variables and an equation for estimating HbA1c attainable by initiation of basal supported oral therapy.

UNLABELLED: Aims/Introduction: A method of estimating HbA1c attained after initiation of basal supported oral therapy (BOT) has not been reported previously. The aim of the present study was to determine which characteristics of patients could influence the effectiveness of BOT introduction, and to obtain an equation to estimate HbA1c after BOT initiation. MATERIALS AND METHODS: Sixty consecutive insulin-naive type 2 diabetic patients with poor glycemic control (HbA1c ≥7.5%) started once-daily injections of insulin glargine. Simple correlations were calculated between parameters such as HbA1c at baseline, HbA1c at week 24, reduction rate of HbA1c over 24 weeks (calculated as: [HbA1c level at baseline - HbA1c level at week 24]/HbA1c level at baseline), duration of diabetes, and the number of classes of coadministered oral antidiabetic drugs. Using multiple linear regression models, the independent effects of these parameters on HbA1c at week 24 were evaluated separately. RESULTS: Multiple linear regression analysis revealed that duration of diabetes (ß = 0.561; P < 0.001) and HbA1c at baseline (ß = 0.284; P = 0.006) were significant predictors of HbA1c at week 24. The best fitting multiple regression equation was: HbA1c at week 24 = 0.078 × duration of diabetes + 0.218 × HbA1c at baseline + 4.628 (r (2) = 0.437). CONCLUSIONS: The equation based on the multiple linear regression models indicates necessary conditions for type 2 diabetic patients to achieve target HbA1c. The present findings emphasize the principle that early initiation of BOT in type 2 diabetes effectively achieves good glycemic control. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00164.x, 2011).