This study determined the effects of anti-diabetic medication adherence on the long-term all-cause mortality and hospitalization for cerebrovascular disease and myocardial infarction among newly diagnosed patients. The study used retrospective cohort from the National Health Insurance Service. Study participants were 65,076 newly diagnosed type 2 diabetes mellitus patients aged ≥40 years. The medication adherence was evaluated from the proportion of days covered (PDC) between 2006 and 2007. Outcome variables were mortality, newly diagnosed cerebrovascular disease (CVD) and myocardial infarction (MI) in 2008-2017. Cox-proportional hazard regression analysis was performed. After adjusting for sex, age, monthly contribution, insurance type, medical institution type, Charlson comorbidity index score, disability, hypertension, and active ingredients of oral hypoglycemic agents, the adjusted hazard ratio (aHR) for all-cause-mortality of the lowest PDC group (<0.20) was 1.45 (95% confidence interval [CI] = 1.36-1.54) as compared to the highest PDC (≥0.8). The aHR for all-cause-mortality associated with PDC levels of 0.60-0.79, 0.40-0.59, and 0.20-0.39 were 1.19, 1.26, and 1.34, respectively (Ptrend < 0.001). Compared to the highest PDC group, diabetic patients with the lowest PDC had elevated risk for CVD (aHR = 1.41; 95% CI = 1.30-1.52; Ptrend < 0.001). Improving anti-diabetic medication adherence among newly diagnosed type 2 diabetes mellitus patients is essential to the reduce risk for cardiovascular disease and long-term all-cause mortality.
Continuity of care, a provider factor, and medication adherence, a patient factor, in chronic disease management affect both the health outcome and the healthcare expenditure in chronic disease management[
We used customized retrospective cohort data from the National Health Information Database (NHID) of the National Health Insurance Service (NHIS-2016-1-058). The NHID includes healthcare utilization data based on claims data, that include the entire population of South Korea; and eligibility data containing socioeconomic status, such as insurance type and monthly contributions based on the income level. More than 99% of claims data, including prescription records required for calculating medication adherence, were submitted electronically. Because of the separation of prescription and dispensing systems in South Korea, almost all diabetic medications require prescription. Using National Health Insurance claim data in South Korea started in 1986, 892 domestic and international research papers have been identified until 2015[
Study participants were newly diagnosed type 2 DM patients aged ≥40 years in 2006. We assessed medication adherence in 2006-2007, then followed up with data on hospitalization and death starting from 2008 to 2017. For reference, the prevalence of type 2 diabetes in South Korea was 12.6% with 6.6% newly diagnosed patients in 2001-2002 based on a community-based cohort study[
In our study, newly diagnosed patients were defined as those who did not visit healthcare institutions in 2002-2004 for type 2 DM (with or without complications), but did visit in 2005 for type 2 DM according to the International Classification of Disease (ICD) 10th revision codes (E11). The analysis did not include those patients with cancer (C00-D48), myocardial infarction (MI) (I21-I23), and cerebrovascular disease (CVD) (I60-I69, G45-G46) until 2005. We used a whole diagnosis codes from the healthcare utilization data to meet the exclusion criteria and a primary diagnosis code to meet the inclusion criteria. In order to evaluate the level of comorbidities, the Charlson Comorbidity Index (CCI) was calculated from the entire inpatient and outpatient healthcare utilization records (only primary diagnosis code) from 2002-2004. We used the same scoring criteria that used in a study by Steffen et al. for comorbidities[
The medication adherence of newly diagnosed patients was evaluated, using the healthcare utilization database section of the NHID between 2006 and 2007. The proportion of days covered (PDC), the recently preferred method of measuring medication adherence[
Outcome variables were mortality (from the eligibility database of the NHID) and newly diagnosed CVD and MI (based on the ICD-10 code from the healthcare utilization database of the NHID). To identify the incident (new-onset) cases, we used the first hospitalization for CVD or MI as an operational definition of a new onset diagnosis. The date of death and date of first admission under the ICD-10 codes for CVD and MI defined as the date of the event. Data on participants were examined from the index date of follow-up (January 1, 2008) until December 31, 2017. A total of 65,067 participants were included in the study after excluding the entire missing value and the cases which exclusion conditions were met.
The survival analysis was performed using the cox-proportional hazard regression model. The model was adjusted for age, sex, disability, insurance type, monthly contributions, medical institution type, the CCI, hypertension, and active ingredients of oral hypoglycemic agents. We also performed stratified analysis by independent variables, with PDC as the main independent variable of interest. All variables, including PDC were used for analysis as categorical variables, not continuous variables. PDC was categorized into five groups (<0.2, 0.2-0.39, 0.4-0.59, 0.6-0.79, 0.8-). The date of death, CVD onset, and MI onset were the outcome variables, and considered as continuous variables. The proportional hazards assumption in the Cox model was assessed with graphical methods. The Wald chi-square test was conducted for evaluating linear trends in the hazard ratio of the regression. The sensitivity analyses for additional variables of lifestyle factor, such as smoking, alcohol drinking frequency in a week, obesity (body mass index more than 30 kg/m
This study received an exemption from the Korea National Institute for Bioethics Policy Institutional Review Board (P01-201607-21-001).
General characteristics of the study participants based on the PDC are shown in Table 1. The majority of participants were men in their 50 s who paid contributions of Korean Won (KRW) 20,000-39,999 (~US$ 18-37) monthly. They were dependents of the employees who were insured and generally visited the clinic, had a zero CCI score. They were not disabled, and were comprised ≥0.80 of the PDC proportion (34.2% of the study participants). They were not patients of hypertension, and predominantly prescribed sulfonylurea.
The survival analysis was performed using a Cox proportional hazard regression model. The adjusted hazard ratio (aHR) of the lowest PDC for all-cause mortality was 1.45 (95% confidence interval [CI] = 1.36-1.54) as compared to the highest PDC (≥0.80), after adjusting for factors, including sex, age, monthly contribution, insurance type, medical institution type, CCI score, disability, hypertension, and active ingredients of oral hypoglycemic agents (Table 2). The HR for all-cause mortality based on the PDC levels of 0.60-0.79, 0.40-0.59, and 0.20-0.39 were 1.19, 1.26, and 1.34, respectively (p for trend < 0.001). The HR of the non-adjusted model (model 1) was higher than that of the multivariate-adjusted model (model 2) in the lowest PDC group. The effects of the lowest PDC on all-cause mortality appeared to be greater in men than in women based on the stratified analysis, using sex as the stratification variable (Table 2). The 5-year age and sex standardized cumulative mortality rates of the lowest and highest PDC groups were 7.46% and 5.06%, respectively (P < 0.001). The 5-year age and sex standardized cumulative incidence of CVD and MI in the lowest and highest PDC groups were 5.00% and 3.48%, and 0.86% and 0.83%, respectively (Fig. 1).Five year age and sex standardized cumulative death (A) and incidence rate of cerebrovascular disease (B) and myocardial infarction (C) according to the proportion of the days covered (PDC). *Age and sex standardized with 2005 Korean Census population.
The results of Cox-proportional hazard regression analysis for first admission, related to CVD and MI, are presented in Table 3. Compared to the highest PDC group (≥0.80), diabetic patients with the lowest PDC (<0.20) had an elevated risk for CVD-related first admission (aHR = 1.41; 95% CI = 1.30-1.52; P
In this large cohort study with a long duration follow-up, we found that patients with poor medication adherence within the first 2 years following DM diagnosis had an increased risk for long-term all-cause mortality and cardiovascular disease. Specifically, we found that poor medication adherence increased the mortality rate by 45%, and the incidence of CVD by 41%.
Dose-response associations were observed between the level of medication adherence and risk of death and cardiovascular disease. The gradual increase in mortality and morbidity associated with the reduction in the level of PDC (except MI) was identified, using a trend test. Although several previous studies[
We used medication adherence instead of intermediate outcomes, such as glycated hemoglobin level and lifestyle modification. The intermediate outcome is influenced by both patient and physician factors. In terms of the patient, it is possible that patients with poor medication adherence have an irregular lifestyle and indifference to healthy behavior, which is known as the “health adherer effect”[
We have focused on medication adherence within newly diagnosed DM patients for several reasons. First, to the best of our knowledge, only a few previous studies assessed these associations in patients with newly diagnosed DM. Previous studies generally included populations that were previously treated or management program-registered diabetic patients, and therefore, failed to address the importance of improving anti-diabetic medication adherence among newly diagnosed patients. Second, it is known that newly diagnosed DM patients already have diabetes-related complications. Iraj et al.[
There are some limitations to this study. First, unmeasured factors affecting medication adherence, such as social support, satisfaction with care, patient knowledge, and physician characteristics[
In conclusion, we found that poorer medication adherence led to the worsening of health outcomes, which was not addressed in the previous studies. Improving patient’s adherence to anti-diabetic medication in the early stage, following the diagnosis of DM is necessary to prevent the risk of long-term all-cause mortality and cardiovascular disease.
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant no. 2017R1D1A1B03033721).
Y.Y.K., J.S.L. and S.M.P. designed the study. Y.Y.K. did the literature search. Y.Y.K., J.S.L., H.J.K. and S.M.P. did the data collection, data analyses, data interpretation, figures, and tables. Y.Y.K. and S.M.P. wrote the manuscript. All authors revised the manuscript, approved the final version and agreed to be accountable for the work.
The datasets analysed during the current study are not publicly available due to the policy of the National Health Insurance Service in Korea.
The authors declare no competing interests.
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Supplementary information accompanies this paper at 10.1038/s41598-018-30740-y.
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PHOTO (COLOR): Supplementary tables
By Yeon-Yong Kim; Jin-Seok Lee; Hee-Jin Kang and Sang Min Park