https://orcid.org/0000-0003-3772-1891
Figures
Abstract
Objectives
The impact of concurrent adherence to antihypertensives, antidiabetics, and statins on cardiovascular disease (CVD) outcomes and intermediate clinical outcomes in people with hypertension and diabetes remains unclear. This study aimed to evaluate the association between medication adherence and CVD outcomes in such patients.
Methods
This retrospective cohort study analyzed the electronic medical records of 36,211 adults aged 18 or older diagnosed with hypertension and diabetes between January 2008 and June 2016 in Canada. Patients were prescribed antihypertensives, antidiabetics, and statins, with a minimum 1-year follow-up post-diagnosis. Medication adherence was determined by the proportion of days covered (PDC). For monotherapy, a PDC≥80% and <80% was reflected high and low adherence respectively. In multiple medication scenarios, adherence was considered high when each medication was at PDC≥80%; low when any medication fell below 80%. The primary outcome encompassed cardiac events, including coronary heart disease, stroke, and heart failure. Intermediate clinical outcomes included changes in diastolic blood pressure (DBP), Systolic Blood Pressure (SBP), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC). Cox regression models assessed the association between medication adherence and CVD morbidity, all-cause mortality, and intermediate clinical outcomes.
Results
High adherence to antidiabetic and statin monotherapy was associated with a lower all-cause mortality risk (aHR=0.67, P=0.001; aHR=0.68, P<0.001, respectively). For patients simultaneously prescribed three medications, higher adherence was linked to significant reductions in DBP (6 months: coefficient −0.52, P=0.01; 12 months: coefficient −0.44, P=0.02; 18 months: coefficient −0.55, P=0.004) and LDL-C (6 months: coefficient −0.04, P=0.02; 12 months: coefficient −0.05, P=0.01; 18 months: coefficient −0.04, P=0.02).
Conclusions
High adherence to antidiabetic and statin monotherapy correlated with lower all-cause mortality risk and improved intermediate clinical outcomes. However, simultaneous adherence to three medications did not significantly affect CVD outcomes, but influenced intermediate outcomes. Therefore, improving adherence to antihypertensives, antidiabetics, and statins among patients with hypertension and diabetes is important in primary care settings.
Citation: Su M, Qin XS, Li Y, Upshur R, Sullivan F, Légaré F, et al. (2025) Association between medication adherence and cardiovascular outcomes in patients with both diabetes and hypertension in primary care settings in Canada: A retrospective cohort study. PLoS ONE 20(4): e0319991. https://doi.org/10.1371/journal.pone.0319991
Editor: Amir Hossein Behnoush, Tehran University of Medical Sciences, IRAN, ISLAMIC REPUBLIC OF
Received: November 12, 2024; Accepted: February 11, 2025; Published: April 16, 2025
Copyright: © 2025 Su et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The aggregated data and code necessary to execute these models, as well as descriptions of the models, can be found at the following link: http://dx.doi.org/10.2196/13571. Data access to the Diabetes Action Canadian National Diabetes Repository requires filling in an electronic application (via https://diabetesaction.ca/repository/).
Funding: This study was funded by the Strategy for Patient-Oriented Research (SPOR) network in Chronic Diseases, Diabetes Action Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
The paradigm of chronic disease management is shifting toward the concurrent treatment of multiple comorbidities, such as diabetes and hypertension, as these conditions substantially contribute to multimorbidity in middle-aged and older populations. Previous epidemiological studies have reported that the occurrence of hypertension in diabetic patients is approximately twice as high as in those without diabetes [1,2]. Hypertension and diabetes are widely recognized as the primary factors contributing to an elevated risk of adverse outcomes in cardiovascular disease (CVD) and increased healthcare expenditure [3–6].
Clinical guidelines recommend adherence to pharmacotherapies that have been shown to reduce mortality and hospitalization rates in patients with hypertension and diabetes [7–13]. Specifically, in individuals with hypertension, adherence to anti-hypertensive medications is associated with a decreased risk of death and hospitalizations related to CVD, such as myocardial infarction, ischemic heart disease, stroke, unstable angina, coronary artery disease, and chronic heart failure [7–13]. Similarly, in people with diabetes, adherence to anti-diabetic medications, particularly metformin, is linked to a decrease in mortality and hospitalizations related to diabetes [14,15]. Moreover, statins have been proven effective in preventing CVD, particularly when used as part of therapy for patients with diabetes and hypertension [16–18]. However, nonadherence to statin medications among individuals with hypertension and diabetes is associated with increased CVD-related hospitalizations and poorer treatment outcomes [19–22].
Medication adherence is crucial for individuals with coexisting hypertension and diabetes who often require multiple medications to achieve optimal treatment outcomes. However, those subject to such polypharmacy may face challenges in adhering to their prescriptions, leading to reduced therapeutic efficacy, an increased risk of adverse health outcomes and increased healthcare costs [15,23–25]. Limited data exist on the impact of adherence to antihypertensive, antidiabetic, and statin medications in primary care. Understanding this impact is crucial for improving outcomes in patients with comorbid diabetes and hypertension, given the significant burden of these conditions in the primary care setting.
This study aimed to evaluate the impact of adherence to antihypertensive, antidiabetic, and statin medications on CVD events in individuals with both hypertension and diabetes. We hypothesized that 1) adherence to any or all of the specified medications is associated with a decreased risk of CVD events and all-cause mortality, and 2) adherence to any or all of the specified medications is associated with improvements in clinical indicators, including diastolic blood pressure (DBP), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC).
Methods
This study was reported according to the research protocol [26] and the STROBE statement (see S1 Files for details).
Ethics approval and consent to participate
The University of Toronto Health Science Center’s Ethics Committee granted ethics approval (approval number: 36065).
Setting and data sources
This study leveraged the Diabetes Action Canadian National Diabetes Repository, which contains de-identified data from over 100,000 individuals with diabetes in four Canadian provinces (Ontario, Manitoba, Quebec, and Alberta). Data were retrieved from the electronic medical records (EMRs) of consenting family physicians and nurse practitioners via regional Practice-Based Research Networks. These networks were part of the Canadian Primary Care Sentinel Surveillance Network (CPCSSN), and data management followed established CPCSSN protocols. The data for this retrospective study were accessed on March 1, 2018. During and after data collection, the authors did not have access to information that could identify individual participants. For more detailed information, please refer to the protocol paper [26].
Study design and participants
This retrospective cohort study included a cohort of 36,211 individuals aged ≥18 years who were diagnosed with both hypertension and diabetes between January 1, 2008, and June 31, 2016. To be included in the cohort, participants needed to have survived for at least 1 year after the diagnosis and have received prescriptions for antihypertensive, antidiabetic, and statin medications documented in their EMRs. Individuals who 1) had a history of CVD events (including acute coronary heart disease, stroke, and heart failure) prior to the diagnosis of diabetes or hypertension, 2) lacked information on the date of the CVD event, and 3) experienced a cardiovascular outcome before the landmark date (1 year after the diagnosis) were excluded.
Exposure and study outcomes
Medication adherence.
The exposure variable was adherence to antihypertensive and antidiabetic agents and statins in patients with both diabetes and hypertension. Previous studies have demonstrated that the proportion of days covered (PDC) is a better measure of adherence than the medication possession ratio (MPR) or modified MPR (MPRm), as it is less prone to overestimating adherence levels and more reliable in predicting the relationship of adherence with outcome in survival analyses [27,28]. Therefore, in this study, the level of medication adherence was measured using the PDC, whichwas calculated using the following formula [27]:
The PDC represents the proportion of days covered by the drug supply within the landmark period, from the initial medication dispensation to the landmark date, set at 1 year after the diagnosis of both diabetes and hypertension. For monotherapy, a PDC below 80% was considered to indicate low adherence, whereas a PDC of 80% or higher indicated high level. In scenarios involving multiple medications, high adherence was characterized by each medication achieving an 80% or greater PDC, whereas low adherence was defined as the PDC of any medication falling below 80%. Medication adherence was coded as Yes/No.
Outcomes of interest.
The primary outcomes assessed in this study were CVD events, defined by the World Health Organization (WHO) MONICA criteria. These events included acute coronary heart disease (ICD-9: 410–412, 414), stroke (ICD-9: 420–438), and heart failure (ICD-9: 428). All-cause mortality was another outcome in this study, representing the death rate calculated by considering all causes of death during the study period. Additionally, the incidence rate of the composite endpoint, including both CVD events and all-cause mortality, was calculated.
The study cohort was followed until the occurrence of the outcome, death, or end of the study (31 July 2016). The secondary outcomes were clinical treatment outcomes, including DBP, SBP, HbA1c, LDL-C, and TC.
Covariates
Demographic characteristics were identified at the date of diagnosis, including age, sex, and body mass index (BMI). Risk factors, such as smoking history and alcohol consumption history, and baseline clinical outcomes, such as DBP, SBP, HbA1c, LDL-C, and TC, were also identified at baseline. Comorbidities, including chronic obstructive pulmonary disease (COPD), depression, dementia, and Parkinson’s disease, were identified at baseline. The data on all these variables came from the Diabetes Action Canadian National Diabetes Repository. Finally, all the covariates were time-fixed.
Statistical analysis
The baseline characteristics were presented as counts and column percentages for categorical variables. For continuous variables that followed a normal distribution, the mean and standard deviation were provided. Subsequently, the incidence rate of the CVD events and all-cause mortality in the overall study population was calculated. To examine the impact of medication adherence on the primary and secondary outcomes, both univariable and multivariable Cox proportional-hazards models were employed [29,30]. Proportional hazards assumptions for the Cox model including all variables were assessed using Schoenfeld residuals. Hazard ratio (HR) estimates were considered statistically significant if the P-value was less than 0.05. The results were presented as adjusted HRs along with their corresponding 95% confidence intervals (CIs). Furthermore, the association between medication adherence and clinical outcomes (i.e., DBP, SBP, HbA1c, LDL-C, and TC) was examined using multivariable linear regression models. The statistical analyses were conducted using STATA (version 15, Stata Corp LP, College Station, Texas, USA).
Results
General characteristics of participants and medication adherence
We identified 36,211 patients with both diabetes and hypertension, with a mean age of 64.3 years (±12.5) and 47.3% being female. The mean BMI was 32.6 kg/m2 (±8.0). Most patients did not smoke (51.5%) or consume alcohol (66.5%). Approximately 5.3% of patients had the comorbidity of COPD, and 12.7% had the comorbidity of depression. Approximately 2.3% of patients had dementia, and 0.5% had Parkinson’s disease. Medication adherence to the three agents was 11.1%. More details can be found in Table 1.
CVD outcomes and intermediate clinical outcomes in the overall study population
As shown in Table 2, the incidence rate of CVD was 3.55 per 1000 patients (95% CI=3.25–3.87). The incidence rate of all-cause mortality was 10.55 (95% CI=10.03–11.08). The incidence rate of the composite endpoint (including both CVD events and all-cause mortality) was 13.82 (95% CI=13.23–14.43).
The clinical outcomes at 6, 12, and 18 months of follow-up are shown in S1 Table. Notably, the mean SBP remained stable over the 18 months, with a slight decrease from 133.46 mmHg at 6 months to 133.25 mmHg at 18 months. Similarly, DBP showed a minimal decrease, from 77.72 mmHg at 6 months to 77.28 mmHg at 18 months. The mean HbA1c levels remained consistent throughout the follow-up period, averaging around 7.03% at both 6 and 12 months, with a slight increase to 7.04% at 18 months. The mean LDL-C and TC levels showed slight reductions from 6 to 18 months. More details can be found in S1 Table.
Association between medication adherence and CVD events
Table 3 shows the univariate and multivariate aHRs (95% CI) for the effects of medication adherence on CVD events. High adherence to antihypertensive, antidiabetic, and statin monotherapy was not significantly associated with changes in the risk of CVD outcomes (aHR=0.89, 95% CI=0.70–1.15, P=0.37; aHR=0.95, 95% CI=0.76–1.18, P=0.64; aHR=0.78, 95%CI=0.58–1.05, P=0.09, respectively). Similarly, patients adherent to a combination of anti-diabetics, anti-hypertensives, and statins did not show significant differences in CVD risk to those with low medication adherence (aHR=0.71, 95% CI=0.46–1.11, P=0.13).
Association between medication adherence and all-cause mortality
As shown in Table 4, high adherence to monotherapy with antidiabetics and statins significantly reduced the risk of all-cause mortality (aHR=0.67, 95% CI=0.55–0.82, P=0.001; aHR=0.68, 95% CI=0.59–0.79, P<0.001, respectively). However, high adherence to antihypertensive medications was not significantly associated with a reduction in all-cause mortality. Similarly, patients with high adherence to a regimen combining antidiabetics, antihypertensives, and statins did not show significant changes in the risk of CVD outcomes (aHR=0.97, 95% CI=0.80–1.17, P=0.75).
Association between medication adherence and the composite endpoint
S2 Table shows the univariate and multivariate aHRs (95% CIs) for the effects of medication adherence on the composite endpoint. High adherence to antidiabetic and statin monotherapy was associated with a lower risk of the composite endpoint, including CVD events and all-cause mortality (aHR=0.81, 95% CI=0.70–0.94, P=0.01; aHR=0.79, 95%CI=0.67–0.92, P=0.003, respectively). High adherence to antihypertensive monotherapy was not significantly associated with the risk of the composite endpoint outcomes (aHR=0.91, 95% CI=0.82–1.02, P=0.10). Furthermore, patients with high adherence to combined antidiabetic, antihypertensive, and statin therapy did not experience significant changes in adverse outcomes (aHR=0.92, 95% CI=0.77–1.09, P=0.33).
Association between medication adherence and intermediate clinical outcomes
Table 5 shows the effects of medication adherence on clinical outcomes. Adherence to antidiabetic monotherapy was significantly associated with reductions in DBP, LDL-C, and TC at 6, 12, and 18 months. Adherence to anti-hypertensive monotherapy was significantly associated with reductions in DBP and LDL-C at these time points. Adherence to statin monotherapy was significantly associated with reductions in DBP at 18 months and LDL-C at 6, 12, and 18 months. In patients concurrently prescribed the three medications, high adherence was significantly associated with reductions in DBP and LDL-C at 6, 12, and 18 months.
Discussion
To our knowledge, this is the first study to explore the association between adherence to antihypertensives, antidiabetics, and statins and CVD outcomes in primary care settings. Our findings indicate that strengthening adherence to monotherapies involving antidiabetic medications and statins is associated with all-cause mortality risk reductions of 33% and 32%, respectively. However, concurrent adherence to all three medications did not significantly influence CVD risk, although it did affect intermediate clinical outcomes. This study underscores the importance of streamlining medication regimens for patients with both diabetes and hypertension, to improve adherence among those prescribed multiple drugs concurrently. This strategy may facilitate the improvement of long-term health outcomes.
We found that the adherence rate of the three studied medications (11.1%) was lower than that reported previously. For example, numerous reviews show that adherence among patients suffering from chronic diseases averages about 50% in developed countries [31]. A 5-year cohort study from Hong Kong involving 218,047 newly diagnosed hypertensive individuals, that applied the PDC metric, found that 32.9% had poor adherence (PDC<40%), 12.1% had intermediate adherence (40–79%), and 55.0% exhibited high adherence (≥80%) [32]. In South Korea, a retrospective cohort study of 65,067 patients diagnosed with type 2 diabetes mellitus showed an adherence rate (≥80%) of 34.2% using the PDC method [33]. Furthermore, in the United States, a study of 155,597 newly diagnosed hypertensive patients, aged 66 to 79 years, revealed poor adherence (PDC<40%) in 8.9%, intermediate adherence (40–79%) in 30.3%, and high adherence (≥80%) in 60.8% of patients [10]. One plausible explanation for these variations is that the previous studies primarily focused on adherence to a single medication, whereas our study examined adherence to three different medications. Previous research has consistently established a robust link between medication regimen complexity and adherence among patients with diabetes and hypertension [33–36]. Crowley et al. (2014) found a significant association between higher medication regimen complexity scores and lower adherence rates in type 2 diabetes patients [35]. Likewise, Krousel-Wood et al. (2010) demonstrated an inverse relationship between medication burden and adherence among hypertensive patients [36]. These findings highlight the need to consider the influence of regimen complexity on medication adherence.
Our study also revealed that patients adhering to antidiabetic and statin monotherapy had a reduced risk of all-cause mortality and improved intermediate clinical outcomes, which aligns with previous studies [33,34]. Our findings, along with earlier research, also highlighted an increased risk of coronary events, ischemic stroke, unstable angina pectoris, and myocardial infarction among diabetes mellitus or hypertension patients with adherence below 80%, compared to those with a PDC of at least 80% [35–37]. For instance, in a retrospective cohort study of 65,067 individuals newly diagnosed with type 2 diabetes mellitus (aged ≥40 years) in South Korea, diabetic patients with the lowest PDC (<0.2) had an elevated risk for CVD (aHR=1.41, 95% CI=1.30–1.52, P< 0.001) compared to the highest PDC group (≥0.8) [33]. Similarly, for CVD mortality with a PDC<0.20, the aHR ranged from 1.36 to 1.54 compared to that for a PDC≥0.80 [33]. Similarly, a study in the United States, which included 155,597 newly diagnosed hypertensive patients aged 66 to 79 years, observed that a PDC greater than 80% significantly reduced the risk of CVD outcomes (aHR=0.44, 95% CI=0.42–0.45), including ischemic heart disease, stroke/transient ischemic attack, and heart failure [10]. However, these studies did not explore medication adherence among patients diagnosed with both diabetes and hypertension concurrently. Our study fills this gap by showing that simultaneous adherence to three medications in patients with both conditions did not significantly reduce CVD risk but could impact intermediate clinical outcomes. The possible reason for the non-significant impact on CVD outcomes is that the complexity of the medication may influence patient adherence, thereby affecting their health outcomes. Therefore, comprehending the factors contributing to this complexity and implementing strategies to streamline regimens are imperative for enhancing adherence rates and overall patient care [38]. By incorporating approaches like combination therapy, fixed-dose combinations, medication synchronization, patient education, and medication reviews to reduce the complexity of medication regimens, healthcare providers can assist patients in effectively managing their conditions and improving medication adherence and treatment outcomes [39,40].
This study has the following strengths. First, it addressed an evidence gap by exploring medication adherence among patients diagnosed with both diabetes and hypertension and examining the synergistic benefits of adhering to multiple medications in preventing CVD events and mortality. Second, we used PDC as the measurement to define the exposure variable, medication adherence, and treated as it time-varying in the analysis. The PDC is a widely measured parameter in pharmacy claim databases and is prevalently used across studies to prevent overestimation [28]. However, it is often treated as a fixed-time variable, which may cause the nuances of changing prescription patterns over time to be overlooked [41,42]. This approach may introduce bias into the link between medication use and clinical outcomes due to variations in dosing behaviors between patients with erratic and consistent medication intake, potentially resulting in divergent clinical outcomes. To overcome this limitation, we employed a time-varying PDC method [42], which accommodates dynamic prescription patterns during the follow-up period. This approach helps to mitigate information bias arising from changes in medication regimens, such as switches or discontinuations, thereby providing a more accurate estimation of the association between medication adherence and outcomes.
Our study also has the following limitations. First, the study design carries the risk of errors and omissions. For example, CVD cases could have been incompletely captured and underestimated. Given that primary care physicians are responsible for diagnosing diabetes, hypertension, and CVD, delays in EMR inputs might have occurred. Second, while our analysis accounted for individual-level risk factors and environmental determinants, the database does not include a range of variables that could influence patients’ understanding of their treatment and daily management, such as primary language, ethnicity, health literacy, employment status, and marital status. Additionally, essential process variables, such as a patient’s involvement in treatment decision-making, disease comprehension, family and social support, and physician-patient communication regarding prescription benefits and adverse effects, are not captured in the database. Furthermore, variables from the healthcare system angle, including access to primary care and primary care models, are absent. Importantly, community health support, including treatment assistance and regular visits to general practitioners, bears significance but is not encompassed. Finally, a limitation of this study is the presence of missing data for key clinical measures, including DBP, SBP, HbA1c, LDL-C, and TC. Participants with missing data were excluded from the analysis of the association between medication adherence and intermediate clinical outcomes, which may affect the generalizability of the results. These limitations may have introduced bias into our findings.
Conclusion
Our study showed that high adherence to monotherapy with antidiabetics and statins was associated with a lower risk of all-cause mortality, and intermediate clinical outcomes. However, simultaneous adherence to the three medications did not significantly change CVD outcomes but impacted intermediate outcomes. Evidently, the complexity of medication regimens can influence patients’ adherence behaviors, consequently affecting treatment outcomes. This study underscores the significance of streamlining medication regimens for patients grappling with both diabetes and hypertension, offering a notable avenue for enhancing long-term health outcomes. Adherence to antihypertensive medications, antidiabetics, and statins needs to be improved in primary care settings. Our findings may help identify challenges to medication adherence faced by diabetic and hypertensive patients in primary care settings and support the development of intervention strategies that promote medication adherence among patients with multi-morbidities.
Supporting information
S2 Table. Cox model for effect of risk factors on composite endpoint (including CVD risk and all-cause mortality).
https://doi.org/10.1371/journal.pone.0319991.s003
(DOCX)
Acknowledgments
We would like to acknowledge the Strategy for Patient-Oriented Research (SPOR) network in Chronic Diseases, Diabetes Action Canada, North York General, as well as Tao Chen, Conrad Pow and Michelle Greiver, who gave substantial technical and administrative support for data processing. Our data source was from Diabetes Action Canada’s National Diabetes Repository.
This work has not been published previously and is not under consideration for publication elsewhere. If accepted, this work will not be published elsewhere, without the written consent of the copyright holder.
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