Medical database analysis of the association between kidney function and achievement of glycemic control in older Japanese adults with type 2 diabetes who started with oral antidiabetic drugs.

AIMS/INTRODUCTION: Despite the emergence of new drugs with novel mechanisms of action, treatment options for older people and those with chronic kidney disease are still limited. MATERIALS AND METHODS: Using a medical database compiled from Diagnostic Procedure Combination hospitals, we retrospectively analyzed treatment status, glycemic control and kidney function over 3 years after the first oral antidiabetic drugs in Japanese adults with type 2 diabetes who were aged ≥65 years. RESULTS: Among 5,434 study participants, 3,246 (59.7%) were men, the median age was 72.0 years, the baseline median hemoglobin A1c was 7.1% and the baseline median estimated glomerular filtration rate was 66.6 mL/min/1.73 m2. Treatment was intensified in 40.0% of people during the 3-year observation period, and the median time to the first treatment intensification was 198 days. Insulin was the most commonly used agent for treatment intensification (36.9%, 802/2,175). Hemoglobin A1c of <7.0% was achieved in 3,571 (65.7%) at 360 ± 90 days. Multivariable logistic regression analysis found that baseline age, hemoglobin A1c and estimated glomerular filtration rate were negatively associated with achieving hemoglobin A1c of <7.0% at 360 ± 90 days. CONCLUSIONS: In older Japanese adults with type 2 diabetes, those with a lower estimated glomerular filtration rate were more likely to achieve hemoglobin A1c of <7.0%. To safely manage blood glucose levels in older adults with chronic kidney disease, physicians should remain vigilant about the risk of iatrogenic hypoglycemia.

Prevalence and predictors of clinical inertia in patients with type 2 diabetes who were treated with a single oral antidiabetic drug.

AIMS/INTRODUCTION: Clinical inertia, defined as a failure of healthcare providers to initiate or intensify treatment when indicated, is one of the challenges in achieving glycemic targets in type 2 diabetes patients. MATERIALS AND METHODS: Using a Japanese medical database compiled from Diagnostic Procedure Combination hospitals, this retrospective study investigated clinical inertia in type 2 diabetes patients treated with a single oral antidiabetic drug. We analyzed predictors of clinical inertia, measured the time to treatment intensification, and monitored patients' glycemic control and renal function for 2 years. The index date was defined as the first date of hemoglobin A1c ≥7.0% during the 180 (±60) days after the first oral antidiabetic drug was prescribed. RESULTS: Clinical inertia was identified in 35.3% of patients. The median time to treatment intensification from the index date was 75.5 days. The proportion of patients achieving hemoglobin A1c <7.0% within 2 years was 33.8% with clinical inertia, and 47.9% without clinical inertia. Multivariate logistic regression analysis showed that Charlson Comorbidity Index score and an interval between visits of ≥6 weeks significantly increased the risk of developing clinical inertia, and hyperlipidemia and higher hemoglobin A1c at baseline significantly decreased the risk. CONCLUSIONS: This study showed that clinical inertia in type 2 diabetes patients treated with a single oral antidiabetic drug might have a lasting effect on long-term glycemic control. Our findings will inform clinicians of the characteristics of patients associated with clinical inertia and the importance of providing appropriate treatment under clinical practice guidelines.

A Claims Database Analysis of Dose-Dependency of Metformin and Incidence of Lactic Acidosis in Japanese Patients with Type 2 Diabetes.

INTRODUCTION: Patients with type 2 diabetes (T2D) in Japan are prescribed a lower dose of metformin that their counterparts in Western countries due to concerns for the risk of lactic acidosis incidence. Here we report our study on the association between high-dose metformin administration and the incidence of lactic acidosis in Japanese patients with T2D. METHODS: A Japanese claims database (April 2008-November 2018) was analyzed. Factors associated with the incidence of lactic acidosis were first identified from the database records by conducting a case-control study, and these were then used as confounding factors in subsequent analyses. The association between high-dose metformin administration (≥ 1000 mg/day) and the incidence of lactic acidosis was compared with that between low-dose metformin (< 1000 mg/day) or no metformin administration and lactic acidosis incidence by using the following approaches: a logistic regression analysis hypothesizing that metformin-associated lactic acidosis is short term; a time-dependent proportional hazard model hypothesizing that the influence of metformin is cumulative; and a case-control study in which lactic acidosis incidence was the case and metformin administration within 3 months prior to the incidence of lactic acidosis (or corresponding date for the control) was the exposure. RESULTS: Prescriptions for biguanide and vitamin B complex and volume depletion were identified as factors associated with the incidence of lactic acidosis. The incidence rate was higher in patients prescribed metformin than in those not receiving metformin; however, it was not higher in those prescribed high-dose metformin compared to those prescribed low-dose metformin. The estimated regression coefficient for high-dose metformin administration was 0.816 (p < 0.001); this was not higher than those for low-dose metformin (1.047), vitamin B complex (2.725) and volume depletion (3.301). The time-dependent proportional hazard analysis did not indicate any effect of metformin prescription. CONCLUSION: The results suggest an association between metformin administration and the incidence of lactic acidosis, but an increase in the incidence rate of lactic acidosis was not observed in those patients receiving high-dose metformin compared to those receiving low-dose metformin.

Effects of Increasing Metformin Dose vs Adding/Switching to Dipeptidyl Peptidase-4 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes.

INTRODUCTION: Metformin has dose-dependent hypoglycemic effects on patients with type 2 diabetes (T2D). In Japan, metformin has been prescribed at lower doses than in Western countries. We analyzed the effect of increasing the metformin dose on glycemic control and compared it to a combination therapy with dipeptidyl peptidase-4 inhibitors (DPP-4i) and a replacement therapy with DPP-4i. METHODS: This is a cohort study using a Japanese claims database. Patients with T2D who had been initially treated with low-dose metformin (≥ 500 mg/day and < 1000 mg/day) and then given a prescription change by increasing metformin to a higher dose (≥ 1000 mg/day) (increased-dose), adding DPP-4i (drug-added), or switching to DPP-4i (drug-switched) were included in this study. The primary outcome was the change in HbA1c levels at 12 months from the baseline period. RESULTS: Among 2,726,437 patients with T2D, 494 were included. Of these patients, 226, 240, and 28 patients were classified as increased-dose, drug-added, and drug-switched groups, respectively. The HbA1c levels at 12 months from the index significantly decreased compared to that during the baseline period. The change was the highest in the drug-added group (- 1.06%), followed by the increased-dose (- 0.91%) and the drug-switched groups (- 0.37%). Among the subset of patients who did not receive any antidiabetic drugs other than metformin or DPP-4i, the highest change in HbA1c levels was observed in the increased-dose group (- 0.84%), followed by the drug-added (- 0.67%) and the drug-switched (- 0.42%) groups. The order of decrease from baseline remained the same for all the study groups after the propensity score weighting adjustment. CONCLUSION: The effect on glycemic control when increasing the metformin dose was studied in patients who had been receiving low-dose metformin. Increasing metformin dosage shows effectiveness and could be one of the next treatment options in patients who were prescribed low-dose metformin as the first-line treatment.

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial.

BACKGROUND & AIMS: Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. METHODS: We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. RESULTS: The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P = .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P = .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). CONCLUSIONS: In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

Impact of chronic constipation on health-related quality of life and work productivity in Japan.

BACKGROUND AND AIM: The impact of chronic constipation on health-related quality of life (HRQoL), work productivity, and healthcare resource use in Japan is not well understood. This study aimed to evaluate and compare the humanistic burden of respondents with chronic constipation to respondents without chronic constipation and to respondents with type 2 diabetes mellitus (T2DM), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD), respectively. METHODS: This cross-sectional study collected demographic and general health data and HRQoL data as measured by the Short Form 12-Item (Version 2) Health Survey and EuroQol 5-dimension health surveys. Health impacts on employment-related activities and indirect costs were measured using the Work Productivity and Activity Impairment questionnaire. Propensity score matching was used to identify a control group without chronic constipation. Multivariate generalized linear models were used to identify potential factors that may impact the outcomes of respondents. RESULTS: A total of 30 001 individuals responded to the Japan National Health and Wellness Survey 2017, whereof 3373 (11.2%) reported having chronic constipation; 963 were physician diagnosed. Compared with matched controls, patients with physician-diagnosed chronic constipation had lower mean HRQoL scores and higher mean absenteeism, presenteeism, total Work Productivity and Activity Impairment, and indirect costs. Physician-diagnosed chronic constipation was associated with a higher health burden than T2DM, IBS, and GERD. CONCLUSIONS: Chronic constipation is associated with a considerable health burden, which is higher compared with T2DM, IBS, and GERD. These results suggest an urgent need for effective treatment of Japanese patients with chronic constipation to improve their quality of life.

Randomised clinical trial: minesapride vs placebo for irritable bowel syndrome with predominant constipation.

BACKGROUND: Agonists of 5-hydroxytryptamine 4 receptor are potential agents for irritable bowel syndrome with predominant constipation (IBS-C). However, only tegaserod has been approved for a very limited population in the US. AIM: To evaluate the efficacy and safety of minesapride in patients with Rome IV defined IBS-C. METHODS: A double-blind, placebo-controlled, dose-finding study was performed. Overall, 411 patients were randomised to receive minesapride at 10, 20 or 40 mg/d, or placebo for 12 weeks. The primary endpoint was Food and Drug Administration (FDA) composite endpoint (responder: a patient who reported an increase in one or more complete spontaneous bowel movements from baseline and improvement of ≥30% from baseline in weekly average of worst abdominal pain score, both in the same week for ≥6/12 weeks). RESULTS: The FDA composite responder rate was 13.6% (14/103) in the placebo group, 13.6% (14/103) in the 10 mg group, 19.2% (20/104) in the 20 mg group and 14.9% (15/101) in the 40 mg group, and no dose-response relationship was found. A greater percentage of minesapride 40 mg-treated patients than placebo-treated patients met both responder requirements for ≥9/12 weeks as the stricter composite evaluation (P < 0.05). Furthermore, minesapride 40 mg significantly increased SBM frequency compared with placebo (adjusted P < 0.001 at Week 12). The most common adverse event was mild diarrhoea. CONCLUSIONS: Minesapride was safe and well-tolerated. Although the primary endpoint was negative, minesapride 40 mg is likely to improve the stricter composite endpoint and SBM frequency. Japan Pharmaceutical Information Center Number: Japic CTI-163459.