Impact of Medication Adherence and Glycemic Control on the Risk of Micro- and Macrovascular Diseases in Patients with Diabetes.

PURPOSE: Our purpose in the research was to clarify the impact of medication adherence to oral hypoglycemic agents during a 1-year period and subsequent glycemic control on the risk of micro- and macrovascular diseases. METHODS: Examined was a nationwide claims database on 13,256 individuals with diabetic eye disease without requiring prior treatment, 7,862 without prior initiation of dialysis, 15,556 without prior coronary artery disease, 16,243 without prior cerebrovascular disease, and 19,386 without prior heart failure from 2008 to 2016 in Japan. Medication adherence was evaluated by the proportion of days covered. Patients were considered to have poor adherence if the proportion of days covered was <80%. Multivariate Cox regression model identified risks of micro- and macrovascular diseases. RESULTS: In each group, mean age was 53 to 54 years, HbA1c was 7.1% to 7.2%, and median follow-up period was 4.6 to 5.1 years, and the percentage of poor adherence was approximately 30%. During the study period, 532 treatment-requiring diabetic eye disease, 75 dialysis, 389 coronary artery disease, 316 cerebrovascular disease, and 144 heart failure events occurred. Multivariate Cox regression model revealed that the hazard ratio (95% confidence interval) of dialysis in the poor adherence group was 2.04 (1.27-3.30) compared with the good adherence group. The hazard ratios in the poor adherence/poor glycemic control group were 3.34 (2.63-4.24) for treatment-requiring diabetic eye disease, 4.23 (2.17-8.26) for dialysis, 1.69 (1.23-2.31) for coronary artery disease, and 2.08 (1.25-3.48) for heart failure compared with the good adherence/good glycemic control group. CONCLUSIONS: Poor medication adherence was an independent risk factor for the initiation of dialysis, suggesting that clinicians must pay close attention to these patients.

Impact of prior cerebrovascular disease and glucose status on incident cerebrovascular disease in Japanese.

BACKGROUND: Although both a history of cerebrovascular disease (CVD) and glucose abnormality are risk factors for CVD, few large studies have examined their association with subsequent CVD in the same cohort. Thus, we compared the impact of prior CVD, glucose status, and their combinations on subsequent CVD using real-world data. METHODS: This is a retrospective cohort study including 363,627 men aged 18-72 years followed for ≥ 3 years between 2008 and 2016. Participants were classified as normoglycemia, borderline glycemia, or diabetes defined by fasting plasma glucose, HbA1c, and antidiabetic drug prescription. Prior and subsequent CVD (i.e. ischemic stroke, transient ischemic attack, and non-traumatic intracerebral hemorrhage) were identified according to claims using ICD-10 codes, medical procedures, and questionnaires. RESULTS: Participants' mean age was 46.1 ± 9.3, and median follow up was 5.2 (4.2, 6.7) years. Cox regression analysis showed that prior CVD + conferred excess risk for CVD regardless of glucose status (normoglycemia: hazard ratio (HR), 8.77; 95% CI 6.96-11.05; borderline glycemia: HR, 7.40, 95% CI 5.97-9.17; diabetes: HR, 5.73, 95% CI 4.52-7.25). Compared with normoglycemia, borderline glycemia did not influence risk of CVD, whereas diabetes affected subsequent CVD in those with CVD- (HR, 1.50, 95% CI 1.34-1.68). In CVD-/diabetes, age, current smoking, systolic blood pressure, high-density lipoprotein cholesterol, and HbA1c were associated with risk of CVD, but only systolic blood pressure was related to CVD risk in CVD + /diabetes. CONCLUSIONS: Prior CVD had a greater impact on the risk of CVD than glucose tolerance and glycemic control. In participants with diabetes and prior CVD, systolic blood pressure was a stronger risk factor than HbA1c. Individualized treatment strategies should consider glucose tolerance status and prior CVD.

Associations of Systolic Blood Pressure and Diastolic Blood Pressure With the Incidence of Coronary Artery Disease or Cerebrovascular Disease According to Glucose Status.

OBJECTIVE: To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. RESEARCH DESIGN AND METHODS: Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. RESULTS: During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120-129, 130-139, 140-149, ≥150 mmHg) gradually increased from 2.10 (1.73-2.56)/1.46 (1.27-1.68) in quintile 2 to 3.21 (2.37-4.34)/4.76 (3.94-5.75) in quintile 5 for normoglycemia, from 1.39 (1.14-1.69)/1.70 (1.44-2.01) in quintile 2 to 2.52 (1.95-3.26)/4.12 (3.38-5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19-1.90)/1.72 (1.31-2.26) in quintile 2 to 2.52 (1.95-3.26)/3.54 (2.66-4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75-79, 80-84, 85-89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. CONCLUSIONS: Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.

Rates and risk factors for amputation in people with diabetes in Japan: a historical cohort study using a nationwide claims database.

BACKGROUND: The prevalence of diabetes is rising, and diabetes develops at a younger age in East Asia. Although lower limb amputation negatively affects quality of life and increases the risk of cardiovascular events, little is known about the rates and predictors of amputation among persons with diabetes from young adults to those in the "young-old" category (50-72 y). METHODS: We analyzed data from a nationwide claims database in Japan accumulated from 2008 to 2016 involving 17,288 people with diabetes aged 18-72 y (mean age 50.2 y, HbA1c 7.2%). Amputation occurrence was determined according to information from the claims database. Cox regression model identified variables related to lower limb amputation. RESULTS: The mean follow-up time was 5.3 years, during which time 16 amputations occurred (0.17/1000 person-years). Multivariate Cox regression analysis showed that age (hazard ratio [HR] 1.09 [95% confidence intervals] 1.02-1.16, p = 0.01) and HbA1c (HR 1.46 [1.17-1.81], p < 0.01) were independently associated with amputations. Compared with those aged < 60 years with HbA1c < 8.0%, the HR for amputation was 27.81 (6.54-118.23) in those aged ≥60 years and HbA1c ≥8.0%. CONCLUSIONS: Age and HbA1c were associated with amputations among diabetic individuals, and the rates of amputation were significantly greater in those ≥60 years old and with HbA1c ≥8.0%.

Accuracy of Japanese claims data in identifying diabetes-related complications.

PURPOSE: To evaluate the accuracy of various claims-based definitions of diabetes-related complications (coronary artery disease [CAD], heart failure, cerebrovascular disease and dialysis). METHODS: We evaluated data on 1379 inpatients who received care at the Niigata University Medical & Dental Hospital in September 2018. Manual electronic medical chart reviews were conducted for all patients with regard to diabetes-related complications and were used as the gold standard. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of each claims-based definition associated with diabetes-related complications based on Diagnosis Procedure Combination (DPC), International Classification of Diseases, Tenth Revision (ICD-10) codes, procedure codes and medication codes were calculated. RESULTS: DPC-based definitions had higher sensitivity, specificity, and PPV than ICD-10 code definitions for CAD and cerebrovascular disease, with sensitivity of 0.963-1.000 and 0.905-0.952, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. Sensitivity, specificity, and PPV were high using procedure codes for CAD and dialysis, with sensitivity of 0.963 and 1.000, specificity of 1.000 and 1.000, and PPV of 1.000 and 1.000, respectively. DPC and/or ICD-10 codes + medication were better for heart failure than the ICD-10 code definition, with sensitivity of 0.933, specificity of 1.000, and PPV of 1.000. The PPVs were lower than 60% for all diabetes-related complications using ICD-10 codes only. CONCLUSION: The DPC-based definitions for CAD and cerebrovascular disease, procedure codes for CAD and dialysis, and DPC or ICD-10 codes with medication codes for heart failure could accurately identify these diabetes-related complications from claims databases.

Severity of hypertension as a predictor of initiation of dialysis among study participants with and without diabetes mellitus.

To determine associations between severity of hypertension and risk of starting dialysis in the presence or absence of diabetes mellitus (DM). A nationwide database with claims data on 258 874 people with and without DM aged 19-72 years in Japan was used to elucidate the impact of severity of hypertension on starting dialysis. Initiation of dialysis was determined from claims using International Classification of Diseases-10 codes and medical procedures. Using multivariate Cox modeling, we investigated the severity of hypertension to predict the initiation of dialysis with and without DM. Hypertension was significantly associated with the initiation of dialysis regardless of DM. The incidence of starting dialysis in those with systolic blood pressure (SBP) ≤119 mm Hg and DM (DM+) was almost the same as in those with SBP ≥150 mm Hg and absence of DM (DM-). In comparison with SBP ≤119 mm Hg, SBP ≥150 mm Hg significantly increased the risk of the initiation of dialysis about 2.5 times regardless of DM+ or DM-. Compared with DM- and SBP ≤119 mm Hg, the HR for DM+ and SBP ≥150 mm Hg was 6.88 (95% CI 3.66 to 12.9). Although the risks of hypertension differed only slightly regardless of the presence or absence of DM, risks for starting dialysis with DM+ and SBP ≤119 mm Hg were equivalent to DM- and SBP ≥150 mm Hg, indicating more strict blood pressure interventions in DM+ are needed to avoid dialysis. Future studies are required to clarify the cut-off SBP level to avoid initiation of dialysis considering the risks of strict control of blood pressure.

Skipping breakfast, late-night eating and current smoking are associated with medication adherence in Japanese patients with diabetes.

AIMS: Little is known about the relationship between medication adherence for oral hypoglycemic agents (OHAs) and glycemic control after adjusting healthy adherer effect in large scale study. Thus, adjusting for health-related behaviors, we investigated the clinical variables associated with medication adherence and the relationship between medication adherence and glycemic control using a large claims database. METHODS: Analyzed were 8805 patients with diabetes whose medication records for OHA were available for at least 1year. Medication adherence was evaluated by the proportion of days covered (PDC). Multivariate logistic regression model was used to identify clinical variables significantly associated with non-adherence. Multiple regression analysis evaluated the relationship between PDC and HbA1c after adjusting for health-related behaviors. RESULTS: Mean PDC was 80.1% and 32.8% of patients were non-adherence. Logistic analysis indicated that older age and taking concomitant medications were significantly associated with adherence while skipping breakfast (odds ratio 0.66 [95% CI 0.57-0.76]), late-night eating (0.86 [0.75-0.98]), and current smoking (0.89 [0.80-0.99]) were significantly associated with non-adherence. CONCLUSIONS: Skipping breakfast, late-night eating and current smoking were significantly associated with medication adherence, suggesting that clinicians pay attention to those health-related behaviors to achieve good medication adherence.

Risk of coronary artery disease according to glucose abnormality status and prior coronary artery disease in Japanese men.

OBJECTIVE: Although glucose abnormality status (GAS), prior coronary artery disease (CAD), and other traditional risk factors affect the incidence of subsequent CAD, their impact in the same cohort has been scantly studied. RESEARCH DESIGN AND METHODS: We analyzed data from a nationwide claims database in Japan that was accumulated during 2008-2016 involving 138,162 men aged 18-72 years. Participants were classified as having normoglycemia, borderline glycemia, or diabetes mellitus (DM) with prior CAD (CAD+) or without prior CAD (CAD-). Cox regression model identified variables related to the incidence of CAD. RESULTS: Among CAD-, management of traditional risks differed from those with and without subsequent CAD events. On the other hand, such differences were weaker in borderline glycemia and DM CAD+, and the influence of traditional risk factors on subsequent CAD was not observed. Cox regression model showed that borderline glycemia and DM confer approximately 1.2- and 2.8-fold excess risks of CAD, respectively, compared with CAD- with normoglycemia. CAD+ confers approximately a 5- to 8-fold increased risk. The impacts of DM and prior CAD additively reached a hazard ratio (HR) of 15.74 (95% confidence interval [CI]: 11.82-21.00). However, the HR in those with borderline glycemia and CAD+ was 7.20 (95% CI: 5.01-10.34), which was not different from those with normoglycemia and CAD+. CONCLUSION: Control status of traditional risk factors and impact on subsequent CAD differ among categories of glycemic status with and without prior CAD. Individualizing treatment strategies is needed in consideration of risk factors, such as GAS and CAD+.

Overt Proteinuria, Moderately Reduced eGFR and Their Combination Are Predictive of Severe Diabetic Retinopathy or Diabetic Macular Edema in Diabetes.

Purpose: Since the combined effects of proteinuria and a moderately decreased eGFR on incident severe eye complications in patients with diabetes are still largely unknown, these associations were determined in a large historical cohort of Japanese patients with diabetes mellitus. Methods: We evaluated the effects of overt proteinuria (OP) (dipstick 1+ and over) and/or moderately reduced estimated glomerular filtration rate (eGFR) (MG) (baseline eGFR 30.0-54.9 mL/min/1.73 m2) on the incidence of treatment-required diabetic eye diseases (TRDED). We divided 7709 patients into four groups according to the presence or absence of OP and MG: no OP without MG (NP[MG-]), OP without MG (OP[MG-]), no OP with MG (NP[MG+]), and OP with MG (OP[MG+]). Multivariate Cox analyses were performed to calculate hazard ratios (HRs) with 95% confidence intervals for combinations of the presence and/or absence of OP and MG on the risk of developing TRDED. Results: During the median follow-up period of 5.6 years, 168 patients developed TRDED. HRs for OP and MG for incident TRDED were 1.91 (95% confidence interval, 1.27-2.87) and 1.90 (1.11-3.23), respectively. HRs for incident TRDED were 1.73 (1.11-2.69) and 5.57 (2.40-12.94) for OP(MG-) and OP(MG+), respectively, in comparison with NP(MG-). Conclusions: In Japanese patients with diabetes, OP and MG were separately as well as additionally associated with higher risks of TRDED. Results indicate the necessity of the simultaneous assessment of proteinuria and eGFR for appropriate evaluation of risks of severe eye complications in patients with diabetes.

Pulse Pressure is a Stronger Predictor Than Systolic Blood Pressure for Severe Eye Diseases in Diabetes Mellitus.

Background Evidence of the role of systolic blood pressure ( SBP ) in development of severe diabetic retinopathy is not strong, although the adverse effect of low diastolic blood pressure has been a partial explanation. We assessed the predictive ability of incident severe diabetic retinopathy between pulse pressure ( PP ) which considers both SBP and diastolic blood pressure, compared with SBP . Methods and Results Eligible patients (12 242, 83% men) aged 19 to 72 years from a nationwide claims database were analyzed for a median observational 4.8-year period. Severe diabetic retinopathy was defined as vision-threatening treatment-required diabetic eye diseases. Multivariate Cox regression analysis revealed that hazard ratios (95% CI ) of treatment-required diabetic eye diseases for 1 increment of standard deviation and the top tertile compared with the bottom tertile were 1.39 (1.21-1.60) and 1.72 (1.17-2.51), respectively, for PP and 1.22 (1.05-1.41) and 1.43 (0.97-2.11), respectively, for SBP adjusted for age, sex, body mass index, hemoglobin A1c, fasting plasma glucose, lipids, and smoking status. In a model with SBP and PP simultaneously as covariates, the hazard ratios of only PP (hazard ratios [95% CI ], 1.57 [1.26-1.96]) but not SBP (0.85 [0.68-1.07]) were statistically significant. Delong test revealed a significant difference in the area under the receiver operating characteristic curve between PP and SBP (area under the receiver operating characteristic curve [95% CI ], 0.58 [0.54-0.63] versus 0.54 [0.50-0.59]; P=0.03). The strongest predictor remained as hemoglobin A1c (area under the receiver operating characteristic curve [95% CI ], 0.80 [0.77-0.84]). Conclusions After excluding the significant impact of glycemic control, PP in comparison with SBP is a better predictor of severe diabetic retinopathy, suggesting a role of diastolic blood pressure and arterial stiffness in pathology.

Relationship Between Number of Multiple Risk Factors and Coronary Artery Disease Risk With and Without Diabetes Mellitus.

PURPOSE: To determine the degree of control of multiple risk factors under real-world conditions for coronary artery disease (CAD) according to the presence or absence of diabetes mellitus (DM) and to determine whether reaching multifactorial targets for blood pressure (BP), low-density lipoprotein-cholesterol (LDL-C), HbA1c, and current smoking is associated with lower risks for CAD. METHODS: We investigated the effects on subsequent CAD of the number of controlled risk factors among BP, LDL-C, HbA1c, and current smoking in a prospective cohort study using a nationwide claims database of 220,894 individuals in Japan. Cox regression examined risks over a 4.8-year follow-up. RESULTS: The largest percentage of participants had two risk factors at target in patients with DM (39.6%) and subjects without DM (36.4%). Compared with those who had two targets achieved, the risks of CAD among those who had any one and no target achieved were two and four times greater, respectively, regardless of the presence of DM. The effect of composite control was sufficient to bring CAD risk in patients with DM below that for subjects without DM with any two targets achieved, whereas the risk of CAD in the DM group with all four risk factors uncontrolled was 9.4 times more than in the non-DM group who had achieved two targets. CONCLUSIONS: These findings show that composite control of modifiable risk factors has a large effect in patients with and without DM. The effect was sufficient to bring CAD risk in patients with DM below that in the non-DM group who had two targets achieved.

Higher pulse pressure predicts initiation of dialysis in Japanese patients with diabetes.

AIMS: To determine incidence and predictors of starting dialysis in patients with diabetes emphasizing blood pressure variables. METHODS: A nationwide database with claim data on 18 935 people (15 789 men and 3146 women) with diabetes mellitus aged 19 to 72 years in Japan was used to elucidate predictors for starting dialysis. Initiation of dialysis was determined from claims using ICD-10 codes and medical procedures. Using multivariate Cox modelling, interactions between glycaemic and blood pressure values were determined. RESULTS: During a median follow-up of 5.3 years, incidence of dialysis was 0.81 per 1000 person-years. Multivariate analysis of a model involving systolic and diastolic blood pressure (SBP and DBP) simultaneously as covariates showed that hazard ratios (HRs) for starting dialysis for each 1-SD elevation in SBP and DBP were 2.05 (95% confidence interval 1.58-2.64) and 0.66 (0.50-0.88), respectively, implying that pulse pressure (PP) was a promising predictor. For confirmation, a model involving SBP and PP simultaneously as covariates demonstrated that HRs for each 1-SD elevation in SBP and PP were 1.09 (0.81-1.48) and 1.54 (1.14-2.08), respectively, with PP the more potent predictor. Compared with HbA1c <8% and PP <60 mmHg, the HR for those with HbA1c ≥8% and PP ≥60 mmHg was 6.32 (3.42-11.7). CONCLUSIONS: In our historical cohort analysis, SBP and PP were independent predictors for starting dialysis. PP was the more potent, suggesting the contribution of increased arterial stiffness to the incidence of dialysis. Future studies are needed to conclude the independent influence of PP and HbA1c on dialysis considering other risk factors.