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The Diabetes Educator
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Medication Taking and Diabetes

A Systematic Review of the Literature

Peggy Soule Odegard, PharmD, BCPS, CDE and Kam Capoccia, PharmD, BCPS

From the University of Washington, School of Pharmacy, Seattle.

Correspondence to Peggy Soule Odegard, BS Pharm, PharmD, BCPS, CDE, University of Washington, School of Pharmacy, Box 357630, 1959 NE Pacific Street, Seattle, WA 98195 (podegard{at}u.washington.edu).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Conclusion
 References
 
Purpose

The purpose of this systematic review is to evaluate the evidence of the challenges and barriers to medication taking (adherence) and to summarize the interventions that improve medication taking in type 1 and type 2 diabetes mellitus.

Methods

PubMed, the Cochrane Collaborative, and the Health and Psychosocial Instruments databases were used to obtain articles identified by using the MeSH headings of diabetes, medication, oral hypoglycemic agents, oral antihyperglycemic agents, oral antidiabetic agents, insulin, adherence, medication taking, compliance, fears, treatment, and electronic monitoring.

Only articles published in English between 1990 and May 7, 2007, and including individuals of all ages with type 1 or type 2 diabetes mellitus were included. Retrospective and prospective studies reporting adherence to medications using self-report, pill counts, medication possession ratios, and electronic monitoring devices were included. Database analyses of prescription records from various organizations or countries were included only if adherence to pharmacologic therapy was stated. Surveys and questionnaires assessing medication taking were also included.

The data from the selected literature was abstracted independently. The various studies were grouped together based on the type of study conducted. Studies were not included if a specific measure of adherence to medication was not used or stated. The studies are presented in 3 tables according to design.

Conclusions

Several barriers to medication taking have been suggested for those with diabetes mellitus, although well-controlled trials to confirm and resolve these barriers are limited. Diabetes educators should be aware of the common barriers to medication taking (regimen complexity of more than 1 diabetes mellitus drug or more than 1 dose daily, depression, and remembering doses and refills) and provide screening and support to their patients to resolve barriers if they exist. Further studies are needed to test specific interventions to improve medication taking in diabetes.

The prevalence of diabetes mellitus (DM) continues to increase, with more than 20 million individuals currently affected in the United States.1 The treatment of DM is complex and involves lifestyle modification to optimize nutrition and physical activity as well as the addition of pharmacologic therapy to provide needed physiologic support for insulin deficiency or for insulin resistance. Pharmacologic therapy for DM can facilitate excellent control, with the potential for normalization of hemoglobin A1C by insulin and a reduction in hemoglobin A1C of 0.5% to 2% for oral antihyperglycemic agent (OAA) therapy depending on the agent or agents used. Despite this potential benefit of pharmacologic therapy, adherence to DM medication treatments is poor, ranging from 36% to 85% adherence to oral DM medications; however, fewer patients using insulin report poor adherence.2-10

In type 1 DM (T1DM), the use of insulin is essential for physiologic insulin replacement. Oral pharmacologic therapy is not an option in T1DM; however, the way insulin is administered can be modified to best meet the needs of the patient. Pharmacologic research in T1DM has explored a multitude of options for delivering insulin including the use of injections, pump therapy, and, more recently, the ability to integrate inhaled insulin therapy into the daily injectable insulin regimen. Current research is exploring the additional role of neuroendocrine hormones such as amylin analogs in combination with insulin in the management of T1DM. Insulin dosing that most closely reflects normal physiologic insulin release (basal throughout the day with meal-time boluses) appears to have the optimal safety and efficacy profile. Studies that have explored the challenges of adhering to an insulin regimen in T1DM have identified fear of needles, social stigma, fear of hypoglycemia, education, and cost as the key factors affecting adherence.11,12

In a 2005 survey report of 1267 participants of the "Taking Control of Your Diabetes" conferences, 28.2% of individuals with DM who were not taking insulin (56% of those surveyed) indicated an unwillingness to use this therapy. The most frequently cited reasons for wanting to avoid insulin therapy included the sense of personal failure (55%), pain of injection (50.8%), effect of insulin on increasing illness severity (46.7%), permanence of therapy (45%), restrictiveness (45.2%), and problematic hypoglycemia (43.3%).13 Although rates vary based on the population studied, only 72% of patients were adherent to their prescribed insulin dose according to the Diabetes Audit and Research in Tayside, Scotland/Medicine Monitoring Unit study.14 Of note, this study of younger individuals found that adolescents (10-19 years of age) had the poorest adherence to insulin as compared with those younger than 10 years of age or those 20 to 30 years old. The lowest adherence rates correlated with the poorest glycemic control and with hospital admissions for complications related to diabetes.14 Recent studies of inhaled powdered insulin have demonstrated improved satisfaction with this form of insulin as compared with standard premeal subcutaneous injections of insulin. In a report by Gerber and colleagues,15 satisfaction, convenience or ease of use, and social comfort with therapy were all improved for inhaled over subcutaneous insulin (25%, 30%, and 10% difference in satisfaction improvement between therapies, respectively).

Historically, pharmacologic therapy for type 2 DM (T2DM) has been initiated when lifestyle modifications of nutrition and physical activity have either failed or are not producing adequate results in the lowering of A1C level. Only in individuals who seemed reticent or were unable to make a lifestyle change or in individuals who had symptomatic hyperglycemia at diagnosis was pharmacologic therapy for DM initiated at diagnosis.12 In August 2006, the American Diabetes Association (ADA) stated a change to this standard of practice with the recommendation to initiate metformin in all patients with T2DM at diagnosis along with appropriate lifestyle modifications and as long as there are no contraindications to the use of metformin.16 In addition to metformin, there are a number of pharmacologic options for the treatment of T2DM including oral agents, injected insulin, and, more recently, the incretin mimetic agents, amylin analogs, and inhaled insulin. The initiation of therapy should be based on the patient's needs, adherence challenges, and physiologic benefit of the agent (eg, metformin in an individual who is overweight). Once initiated, careful follow-up with the patient is essential to achieve and maintain diabetes control, as evidenced by an A1C of less than at least 7%.

The value of pharmacologic therapy in achieving and maintaining DM control has clearly been established. In addition to benefits for A1C, several well-designed trials have explored the benefit of pharmacologic therapy in improving avoidable and costly microvascular and macrovascular outcomes of DM.17,18 Despite a wealth of evidence demonstrating a reduction in diabetes-related microvascular and macrovascular complications with improved DM control and the availability of effective therapies, the control of DM is suboptimal in the United States.19-21 According to a report by the American Association of Clinical Endocrinologists, two-thirds of individuals studied with T2DM in the United States had not achieved glycemic control, as evidenced by an A1C level >6.5%.22 Although insulin therapy can produce a dramatic lowering of A1C level, the use of insulin was estimated in 2002 to be at 16.4%, down from 24.2% in a similar National Health and Nutrition Examination Survey (NHANES) conducted approximately 10 years earlier.23 Recently, data from the NHANES III indicated that the average A1C level for those with DM has not changed; however, the proportion of persons with an A1C of 6% to 8% has increased from 34.2% to 47% in the same cohort.24 Medication taking can be challenging for the individual with DM because of several factors, including regimen complexity (number of medications and number of doses per day), cost, and understanding of the regimen.25 At the same time, the health care system poses a threat to optimal pharmacologic treatment of DM, with corresponding challenges that include provider education, costs of therapy, insurance coverage, and adequacy of follow-up with patients. Table 1 lists the patient-, medication-, and provider-related barriers to medication taking, which are frequently discussed in the literature. The table is included to summarize the literature and to provide background. This information provides relevant background to facilitate diabetes educators' understanding of the scope of the challenge of adhering to pharmacologic therapies for DM. Identifying and understanding the barriers to medication taking are the first steps in the process of facilitating the patient's ability to successfully manage the DM self-care behavior of medication taking.


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  		Table 1 Adherence Barriers to Diabetes Mellitus (DM) Medication Use5,11-13,25,47,54-56

 

In this systematic review, the authors will explore the evidence regarding the challenges to diabetes medication taking and summarize the interventions to improve medication taking in DM. Although much of the literature on medication taking is general and can be applied to the use of any medication, diabetes or non–diabetes related, emphasis has been placed on the data that specifically address factors known to challenge diabetes medication taking to provide the most helpful information for diabetes educators. A particular focus will be placed on the evidence basis for interventions that may be useful to diabetes educators for improving the self-care behavior of medication taking.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 Conclusion
 References
 
Searching
A comprehensive literature review was conducted to identify studies or reports about the use of oral hypoglycemic agents, oral antihyperglycemic agents (OAAs), and insulin, with a focus on medication taking and adherence versus the clinical efficacy of these agents. Combinations of the terms diabetes, medication, oral hypoglycemic agents, oral antihyperglycemic agents, oral antidiabetic agents, insulin, adherence, medication taking, compliance, fears, treatment, and electronic monitoring were used to obtain articles that met these criteria. These terms were searched in PubMed, the Cochrane Collaborative, and the Health and Psychosocial Instruments databases. Only literature published in English between 1990 and May 7, 2007, and including T1DM or T2DM was included in the systematic review. Reference lists from selected review articles were used to cross-reference the available data. Follow-up searches were performed on key author names and reported DM medication taking or adherence barriers (eg, needle fears) to complete the systematic search of the literature.

Selection
The population in question includes individuals of all ages with either T1DM or T2DM using pharmacologic therapy to manage DM. Retrospective and prospective studies assessing adherence by those with DM to diabetes medications using self-report, pill counts, medication possession ratios (MPRs), and electronic monitoring devices were included. Because the focus of this systematic review is on DM, selected studies were those that addressed medication taking in the DM population with emphasis whenever possible on specific findings about DM medication taking. General studies on medication adherence were excluded. Database analyses of prescription records from various organizations or countries (health maintenance organization [HMO], pharmacy benefits organization [PBO], Medicaid, Canada, Japan, etc) were included if adherence to pharmacologic therapy was stated. Surveys and questionnaires assessing medication taking in people with T1DM or T2DM were also included. To be included, articles needed to have a description of the study design, details of the calculations used to determine adherence, and the rate of adherence or persistence with the regimen. Secondary outcomes included the impact on glucose concentrations or glycated hemoglobin (A1C).

Review articles and opinion papers on the topic of medication adherence or medication taking in those with DM were included to provide information on general barriers to medication taking in this population (Table 1). Information not obtained from controlled studies, systematic surveys, or questionnaires was excluded from use in this systematic review because of the potential subjectivity of the information. Specific information about non-diabetes-related medication adherence (eg, thyroid medication adherence) was not included to maintain clarity with regard to the literature on medication taking in those with DM. If adherence rates, or the equivalent of, were not directly measured or stated, the study or research article was also excluded.

Validity Assessment
The American Diabetes Association evidence grading system was used in assessing the available literature.26 The level of evidence (A, B, C, or E) supporting the recommendations will be included in parentheses, if applicable. This rating system was not applied to the adherence barriers studies that were reviews.

Data Abstraction
The data from the selected literature were abstracted independently and incorporated into 1 of 3 tables, depending on the type of study (ie, Table 2, retrospective; Table 3, prospective; Table 4, intervention studies designed to improve diabetes medication adherence).


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  		Table 2 Retrospective Analyses of Diabetes Medication Adherence Rates

 

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  		Table 3 Prospective Studies of Diabetes Medication Adherence Rates

 

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  		Table 4 Intervention Studies Designed to Improve Adherence to Diabetes Medications

 

Study Characteristics
Retrospective studies included data reported from HMOs, PBOs, Medicaid, and/or Medicare beneficiaries and countrywide health system plans such as those in Canada, Poland, the Netherlands, and so forth about adherence to diabetes medications. The data available included prescription records of new and refilled diabetes medications including dates of use, doses, and frequency of the medication. This information can then be linked to diagnostic codes, medical records, and laboratory data to provide outcome measures based on drug use. These retrospective analyses provide a glimpse of drug use over a given period of time. In these studies, adherence is typically measured using an analysis of refills to evaluate if there are any gaps in medication use. Table 2 includes retrospective studies that report adherence rates to DM medications.

Table 3 includes studies designed to prospectively evaluate adherence to DM medications. Two of these studies are randomized controlled trials of a once-versus twice-daily drug regimen. Three studies document adherence of an oral DM medication using a medication electronic monitoring device (MEMS) as compared with another measurement of adherence such as pill count or prescribed regimen. Patient self-report of adherence is presented in 2 studies detailing a pharmacist-administered questionnaire and a questionnaire that was mailed to the patient's home.

Table 4 includes the studies that evaluated a specific intervention aimed at improving adherence to DM medications. The interventions occur in a wide variety of settings (clinic, home-based psychotherapy, community pharmacy) and are aimed at both T1DM and T2DM. The studies are not comparable because of the vast differences in measurement techniques and outcomes assessed.

Data Synthesis
The various studies were grouped together based on the type of study conducted. Studies were not included if a specific measure of adherence to medication was not used or stated. The studies are presented in 3 tables according to design. Missing data have been left blank in the tables if they were not clearly stated in the studies.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 Conclusion
 References
 
The initial search of the literature using the terms diabetes and medication compliance or adherence produced 283 articles. Figure 1 shows the flow of literature into this systematic review. Nine articles were included as background information and did not meet the criteria for inclusion in the retrospective, prospective, or intervention reports. A total of 36 studies and surveys met inclusion criteria and are presented. Tables 2 and 3 report adherence rates to DM medications from retrospective and prospective studies, respectively. Table 4 includes 8 trials that actually tested an intervention in an attempt to improve DM medication adherence rates.


Figure 1
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  		Figure 1. Flow of systematic literature review journal inclusion. DM indicates diabetes mellitus.

 

Adherence Barriers and Outcomes of Poor Adherence
There have been several reviews or opinion papers written about medication taking in those with DM with specific emphasis on factors that challenge adherence (Table 1).5,11-13,25,47,54-56 The most commonly cited factors include regimen complexity (eg, need to split tablets, mix products), dosing frequency greater than twice daily, cost, self-confidence, education about the use of the product, depression, and adverse effects or fear of them. In an informal survey of diabetes educators in 2005, patient resistance and fear, weight gain, inconvenience, physician resistance, inadequate support, and cost were among factors suggested as barriers to using insulin.11 In a 2005 review, Rubin54 identified the patient's comprehension of the treatment regimen and its benefits, adverse effects, medication costs, and regimen complexity and the patient's emotional well-being as factors that may influence adherence in DM. These factors are similar to those reported in the general medication adherence literature. In addition to these barriers, DM treatment includes the unique challenges that preclude many individuals from starting or remaining adherent to insulin including fears of hypoglycemia, disease worsening, social stigma, and use of needles. Provider or system factors have also been identified that create barriers to the initiation of insulin therapy. These include a perceived lack of time or resources to train patients on insulin use and inadequate ability to follow-up or monitor therapy. These provider and system factors may result in clinical inertia precluding advancement of therapy to insulin, which would more effectively control glucose in selected patients and therefore reduce their risk of long-term DM complications.57,58

In those requiring pharmacologic therapy, adherence is essential for optimal DM outcomes and control. Several reports characterizing these common barriers to using medications for DM have linked worse diabetes care outcomes to poor diabetes medication adherence. In a report by Pladevall and colleagues,59 nonadherent patients had significantly worse clinical outcomes than those who were more adherent. In this study, a 10% increase in nonadherence to metformin was associated with an increase in A1C of 0.14%.59 In a study assessing adherence to DM medications in 301 patients (27% rated as poorly adherent), good adherence (determined by a score of 3 or more out of 4 possible points on the Morisky self-report medication adherence assessment) was associated with a 10% reduction in A1C (P = .0003).43 In another study of 57 687 DM patients in an HMO, those with increased DM medication adherence according to claims data analyses had fewer emergency department visits, fewer inpatient admissions, and decreased medical care costs.60 Maier and colleagues61 evaluated the use of a pocket-size tablet-dispensing device on glycemic control and observed that those using the dispenser had a significant reduction in A1C (–0.74 vs –0.53, P < .0001). In a recent retrospective cohort (N = 11 532) analysis by Ho and colleagues,62 DM patients who were not adherent (prevalence of 21.3% based on <80% proportion of days covered [PDC] for OAAs, anti-hypertensives, and statins combined) had higher all-cause hospitalization (P < .001) and all-cause mortality (P < .001) than did those who were adherent (>80% PDC).

A 2005 report identified depression as a significant factor challenging DM medication adherence, with depressed patients less likely to report and demonstrate good adherence (42% reporting good adherence vs 67% nondepressed, P = .03).55 Another study of the effects of depression on DM identified medication nonadherence rates of 24.5% for those with depression versus 18.8% for those with no major depression (P < .005).56 Chao et al63 also reported that greater depressive symptoms were associated with lower adherence to diabetes medication.

Farmer and colleagues64 surveyed 200 patients with T2DM who were 40 years of age or older using a questionnaire that measured a range of plausible beliefs about taking and the intention to take medication based on the theoretical model of planned behavior. A few examples of the behavioral beliefs in the questionnaire include "if I were to take my diabetes medicines regularly... it would help me stay well; it would keep my blood sugar under control; it would help keep my diabetes under better control; it would help me avoid having to inject insulin," and so forth. These beliefs were then correlated with a self-report medication adherence tool. Most of those surveyed strongly agreed with statements about the benefits of taking medication. These beliefs were strongly correlated with the intention to take medication regularly. Two beliefs were associated with reduced medication adherence: "changes to my daily routine would make it more difficult to take my diabetes medicines regularly" (P < .001) and "if I were to take my diabetes medicines regularly this would lead to my gaining weight" (P < .05). By using a standard questionnaire, beliefs about medication taking may provide additional information that the health care provider can use when trying to improve DM medication taking (ie, exploring weight gain concerns and how to continue taking the medicines if changes in the daily routine occur).64

Given the potential factors affecting adherence, information (such as screening for depression or using a questionnaire to assess medication taking) to identify potential adherence barriers would be useful for DM education and management.

Retrospective Analyses
Twenty-one studies evaluated adherence rates to DM medications by analyzing large databases available through HMOs, pharmacy claims, or pharmacy dispensing data. The DM medication adherence was generally defined as the percentage of drug obtained over a given period of time (quantity of medication obtained by the patient divided by the quantity needed for the given time period such as refill #30 tablets/#60 tablets prescribed to be taken/60 days would be 50% adherence) and ranged from 31% to 87% (Table 2).8-10,30,32,33-38 Another measurement of adherence use is the MPR, which is a proxy measurement of medication adherence. It is defined by the total days' supply obtained divided by the number of days between the first and last fill plus the days' supply of last claim; the higher the MPR, the higher the adherence rate.8,28,39 Some studies have reported persistence rates at 12 or 24 months. While the definition of persistence rates varies among the studies, it is generally considered to be the number of days from the date of the first prescription fill to the time of the first failure to refill the prescription, within an acceptable period of time. At 12 months, the persistence rates range from 16% to 63%.29,31,35 At 24 months, the persistence rates range from 29% to 70%.40,41

Kalsekar et al44 examined the impact of depression on adherence to OAAs in patients with newly diagnosed T2DM who were identified from a Medicaid claims database. The International Classification of Diseases, Ninth Edition, Clinical Modification codes determined the presence of preexisting diabetes in these patients. Over a 4-year period, a total of 1326 patients were identified (471 were depressed and 855 were nondepressed). Using MPRs, patients with depression had significantly lower adherence rates than those who were not depressed. After controlling for confounding factors and using multivariate analyses, depression was a significant predictor of adherence, with depressed patients being 3% to 6% less adherent to OAAs than patients who were not depressed.44

Adherence rates were measured for dosing frequency (once daily vs twice daily), monotherapy (1 drug in the DM regimen), and polytherapy (more than 1 drug in the DM regimen). Once-daily dosing had higher rates of adherence than twice-daily dosing (60.5% vs 52%, respectively).35 When compared with polytherapy or multiple DM drug regimens, monotherapy had higher adherence rates (49% vs 36%, respectively).40 The DM medication adherence also improved when switching from taking 2 different pills to a fixed-dose combination in 1 pill (71% vs 87%, respectively).8 Only 1 study evaluated insulin use (reported as 67% using premixed formulations, 74% using pen delivery, 85% with 2 injections per day, and 15% with 4 injections per day) in patients with T1DM, who had an average age of 16 years. The authors concluded that 28% of patients used less insulin than their prescribed dose (defined as a deficit in insulin days/annum and calculated from the total volume of insulin dispensed for the patient divided by the prescribed volume to be used per year).42 All other studies (Table 2) were conducted in patients with T2DM with a mean age >48 years.

It is very challenging to compare these data or make specific practice recommendations; however, these data provide some perspective to diabetes educators about medication taking in diabetes. These retrospective studies are at best a level C according to the ADA evidence grading system. The data presented in Table 2 lead us to believe that in those with DM, monotherapy with a diabetes medication dosed once a day would provide better adherence than polytherapy or twice or more daily dosing with diabetes medications. The data provided by Farmer et al64 should encourage practitioners to screen for depression.

Prospective Analyses
Adherence rates to OAAs in patients with T2DM were reported in 7 prospective studies (Table 3). Most (5/7) studies used the MEMS. This system provides a cap containing an electronic monitoring microprocessor that records each opening of the bottle. Each opening is recorded as a presumptive dose along with the date and time so that when the cap is downloaded to a computer, the data are presented in a calendar-like format. Adherence to DM medication measured by these caps ranges from 53% to 98%.2,4,6,45,46 A more robust strategy to study medication adherence is to combine assessment methods such as the MEMS method with other measures of adherence such as patient self-report, pill counts, prescribed regimens, and actual prescriber report. Mason et al2 reported an overestimate of adherence by pill counts, patient self-report, and prescriber report in comparison with the MEMS data. This may be a result of the patient's inflating his or her report of medication taking in an effort to demonstrate better disease management.

As expected and previously stated, adherence rates are higher for medications taken once daily than for those administered twice or thrice daily.4,45 Of note, Paes et al4 documented a higher rate of adherence in once- and twice-daily regimens when compared with 3 times daily but also a higher incidence of overconsumption in the once-daily group.

Two surveys were designed to assess medication adherence to diabetes-related medicines (DM medicines or DM medicines and medicines used to manage DM comorbidities such as hypertension/dyslipidemia). Grant et al47 employed a pharmacist-administered questionnaire to investigate medication use of OAAs, insulin, antihypertensive agents, lipid-lowering medicines, and aspirin and predictors of suboptimal adherence. They hypothesized that adherence rates would decrease with an increase in the total number of all medications. A total of 128 patients with T2DM from a single community health center responded to the questionnaires, with a specific adherence assessment performed by a study pharmacist for each DM or DM-related cardiovascular medicine taken. A complete medication history was obtained for the purpose of assessing the total number of medications (DM and non-DM) in the regimen. The mean age of the patients was 66 (±11.7) years, and the mean number of medications to control DM or cardiovascular comorbidities was 4.1 (±1.9). The average 7-day adherence rate was 6.7 (±1.1) days for DM medications. The adherence rates were very high and were not affected by the total number of all medications taken. A predictor of suboptimal adherence (6.1 vs 6.9 days out of 7, P < .001) was a lack of confidence in the immediate or future benefits of the DM or DM-related drug. The most common problem affecting medication adherence was side effects.47

Ciechanowski et al7 investigated the impact of depressive symptoms in primary care patients with T1DM and T2DM on diabetes self-care, adherence to medication regimens, functioning, and health care costs. Questionnaires were administered to 367 patients from 2 HMO clinics, and automated data were used to measure nonadherence. The authors defined nonadherence as interruptions in the therapy for oral hypoglycemics as defined by having a refill or subsequent prescription overdue by more than 15 days and by more than 25% of the intended duration. Twelve months of pharmacy data were used to allow for a sufficient number of refill events. Regression analyses were performed using depression symptom severity tertiles (low, medium, or high) to determine the impact of depressive symptoms on medication adherence and other outcomes. The percentage of days of oral hypoglycemic therapy interruptions were significantly greater in the high-severity tertile (more depressed) as compared with the low-severity tertile (not depressed; 14.9 days [20%] vs 7.1 days [12%], respectively; P < .05). Depressive symptoms significantly decreased the rate of adherence to DM-related medication regimens.7

The prospective trials and surveys document the actual rates of adherence to DM medications using mostly randomized controlled trials. From these data, it can be concluded that people with T2DM on oral medications have improved adherence with a once-daily dosed drug as compared to a drug dosed twice or thrice daily. People with DM who are depressed tend to have lower adherence rates than those who are not depressed.

Intervention Trials
There are many studies documenting the rates of adherence to DM medications.2,4,6,45,46 However, there is a paucity of data investigating specific interventions to improve adherence to DM medications. The studies included in Table 4 focus on the specific aim of improving adherence to DM medications. Interventions were aimed at either improving insulin use in T1DM or improving the adherence to OAAs with or without the addition of insulin in T2DM. Two studies described a pharmacist intervention of providing tailored education or pharmacologic recommendations in the hopes of improving medication adherence or reducing barriers to adherence identified in baseline study assessments.3,52 Neither of these studies demonstrated a significant improvement in medication adherence or a decrease in barriers.

Skaer et al51 investigated the effect of value-added services to medication refills of sulfonylurea therapy in 289 Medicaid beneficiaries. Subjects were randomly assigned to 1 of 4 groups: (1) control group receiving standard of care, (2) standard of care plus a mailed medication refill reminder 10 days before the refill due date, (3) standard of care plus unit-dose packaging (number of pills per dose per individual blister pack) with each prescription-refill request, or (4) standard of care plus the refill reminder and unit-dose packaging.51 Medication adherence (determined by the number of days supply of medication obtained throughout a 360-day period, the MPR) significantly improved in all 3 of the intervention groups when compared with the control group. Adherence in the group receiving the refill reminder and the unit-dose packaging significantly improved relative to the other 2 intervention groups and the control group. In addition, the patients receiving both interventions (reminders and unit-dose packaging) experienced a decrease in the use of physician, laboratory, and hospital services when compared with the control group.51 This study suggests that community pharmacies could improve medication adherence rates to sulfonylureas or possibly other oral antihyperglycemic agents with these additional services.

Three studies assessed adherence to insulin regimens in adolescents with T1DM.48-50 The interventions were either behavioral in nature (counseling sessions or home-based psychotherapy) or involved weekly telephone contact by a nurse diabetes educator. None of these interventions improved adherence to insulin regimens. However, Ellis et al50 used intensive, home-based psychotherapy and demonstrated a significant increase in blood glucose testing and a significant decrease in inpatient hospital admissions. All 3 authors call for more studies evaluating the impact of behavioral therapies on medication adherence and glycemic control in high-risk adolescents.

Rosen et al6 used MEMS to assess baseline adherence to metformin in patients with T2DM. Patients with <80% adherence were then randomized to a control group or an intervention group to receive cue-dose training. Cue-dose training involved a research assistant that reviewed the data collected by the MEMS and advised the patient to link medication taking with daily activities (eg, meal times, bedtime routine, etc). After doses were identified that were the most problematic to take, and after the patient's daily activities were reviewed, the patient was advised to use a cue or reminder to take the medication. Patients were advised on cue-dose training, and MEMS data were collected for a 4-month period. Initially, adherence gradually improved in the cue-dose training group but then worsened after the 4-month intervention ended. The effects of cue-dose training did not alter medication adherence or A1C in this study.

Unfortunately, these intervention studies do not offer well-proven strategies or tools that improve adherence to all DM medications. The only proven intervention to increase adherence to an OAA, a sulfonylurea, was in 258 middle-age adults who received a refill reminder and unit-dose packaged medication from a community pharmacy.51 More intervention studies are needed to determine the best strategy or tool to improve adherence to DM medication.


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusion
 References
 
Medication taking in those with DM can be a challenge, with adherence rates to DM medications varying from 31% to 87% in retrospective studies and 53% to 98% in prospective studies.* Adherence to DM medications has been shown not only to improve DM control through A1C reduction but also to result in improved outcomes and reduced costs of diabetes. The most common factors reported to affect medication taking in those with DM include regimen complexity (eg, more than 1 DM drug, need to split tablets, need to mix products), dosing frequency greater than twice daily, remembering doses and refills, depression, and adverse effects or fear of them. Insulin use presents a unique set of challenges including education, follow-up and monitoring, fear of needles, and regimen complexity. In addition, those patients with DM often use several other medications to treat or prevent DM comorbidities, and the use of this greater number of medications results in increased regimen complexity and challenges to adherence and may lead to selective adherence by patients. These challenges create a key opportunity for diabetes educators and others caring for those with DM. It is easy to prescribe therapies and provide basic education on medication use. However, DM care is largely based on self-management knowledge and skill, so it is imperative that patients are assessed to see what factors may be in the way of proper medication use and plans developed to overcome or avoid these barriers.

In this systematic review, the authors explored the published evidence about the factors that affect and interventions that facilitate taking DM medications. Although information is available in review or opinion paper format about medication adherence, the purpose of this systematic review was to evaluate the current evidence about diabetes medication taking, so the authors chose to focus their efforts on the current literature that provided information obtained from controlled studies, systematic surveys or questionnaires, or prospective interventions. As a result, the review was organized into 3 primary areas: (1) trials that retrospectively identified factors that affect medication taking (eg, health system database correlation studies), (2) trials that prospectively surveyed those with diabetes about challenges to medication taking (eg, surveys, phone interviews, or questionnaires), and (3) trials that implemented and evaluated specific interventions to improve medication taking in those with diabetes. While there are limitations to each of these 3 types of information, the authors elected to organize study results in this manner to provide for the most accurate comparison and reporting of findings.

A key limitation of retrospective studies is the difficulty in accurately assessing medication adherence using historical claims data when changes in patient doses occur but are not updated in the prescription database. This data flaw can result in mismatches in the medication possession ratio when adherence is assessed using the database and will result in the patient's appearing to be nonadherent.

A limitation of the prospective studies included in this systematic review is that there are few controls when using surveys or questionnaires. Survey respondents may be those patients more interested and motivated in taking diabetes medications, resulting in artificially elevated adherence assessments. In the study by Grant et al,52 an effort was made to obtain information from all eligible patients with T2DM through the use of a directed phone interview; however, these investigators noted that the inclusion criteria of an A1C test in the prior 6 months may have preselected for a more motivated sample of DM patients. In their study of frequency of dosing, Paes et al4 identified improved adherence with once- or twice-daily dosing; however, there was a potential for overconsumption by patients using once-daily dosing. An explanation for this overconsumption may be the patients' insecurity with remembering to take the medication. With DM medications that can cause hypoglycemia, overconsumption could result in a serious adverse event.4 Although once-daily dosing appears ideal to promote medication adherence, the risk of overconsumption by patients who forget if they have taken their dose should be screened for prior to therapy.

Intervention trials were separated from other prospective trials because of their specific aim both to identify barriers to medication taking and to improve or resolve these barriers. Most of the intervention trials that were included were well-controlled using a randomized trial design in patients with existing DM. Although a few studies evaluated specific interventions performed by health care providers (1 nurse diabetes educator intervention, 2 mental health interventions, and 2 pharmacist interventions) to improve adherence to diabetes medication regimens, more are certainly needed.3,48-51 In addition, more studies are needed in community pharmacies because the only intervention that improved adherence to an OAA was implemented in this setting.51 Much of the current information about medication taking and its challenges has been learned from surveys, questionnaires, provider experience, and as secondary outcomes of several diabetes treatment efficacy trials.

The Diabetes Prevention Program Research Group recently published data regarding adherence to medications for the prevention of DM. This study evaluated barriers to and strategies for medication adherence and predictors of adherence in 2155 adults with impaired glucose tolerance (ie, not overt T2DM). Participants were randomly assigned to metformin or placebo and received structured interviews by case managers to promote adherence on a quarterly basis. The case manager assessed adherence by counting the returned number of pills and calculating the adherence rate to the prescribed regimen. The overall adherence rates (defined as taking ≥80% of the prescribed dose over the time of the study) were lower in the metformin (71%) group as compared with the placebo (77%) group (P < .001). Patterns of higher adherence rates occurred in the older age groups (≥60 years) as compared with the younger group (25-44 years) and men (74%) versus women (68%) in the metformin group (P = .01); in the metformin group, the highest income group had the highest adherence rate (77%), while the lowest income group had the lowest (60%) adherence rate (P < .0001). The most commonly reported barriers to taking the medication were forgetting to take doses (22%), adverse effects (8%), and disruption of routine (8%). The odds of nonadherence were greatly increased as the participants reported more than 1 barrier. Although this study examines adherence rates to preventive medications, the results are similar to the data presented in this review. Although there was no control group in this study to measure the effectiveness of the structured interview, the interview could be conducted by any health care professional in less than 3 to 5 minutes and could identify relevant barriers to medication taking.65


   Conclusion
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 Abstract
 Methods
 Results
 Discussion
 Conclusion
References
 
Adherence to DM medications, or rather, proper medication taking, is vital for effective DM management. Several factors have been identified as causative challenges for medication taking in those with DM including regimen complexity (more than 1 DM drug, greater than once-daily dosing), depression, and remembering to take doses or obtain refills. As identified in this systematic review of the literature, more evidence to support specific interventions that will be effective in overcoming adherence challenges for DM patients and facilitate medication taking are needed. Diabetes educators are in a key position to promote medication taking by (1) recognizing potential barriers to medication adherence by screening patients, (2) implementing strategies to overcome barriers, and (3) providing follow-up assessment to ensure the ongoing medication-taking ability for their clients.


   FOOTNOTES
 
* References 4,6,8-10, 14, 30, 32-38, 40, 46, 45. Back


   References
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 Methods
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 References
 

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