The clinical and economic consequences of medication nonadherence in patients with diabetes



by M. B. Schauerhamer
and C. McAdam-Marx, USA

Marisa B. SCHAUERHAMER,
PharmD

Carrie MCADAM-MARX, PhD, RPh
Department of Pharmacotherapy
& Pharmacotherapy Outcomes
Research Center, University of Utah
Salt Lake City, Utah, USA

Diabetes is a highly prevalent disease with significant health and economic burdens. Fortunately, good diabetes control through lifestyle changes and medication therapy can help avoid costly complications. Despite this evidence, adherence to diabetes therapies, including medications, is suboptimal. As medications are a cornerstone of diabetes therapy, medication nonadherence has a significant impact on health outcomes and costs with poor medication adherence associated with worse glycemic outcomes, higher health care utilization, and higher costs. Furthermore, barriers to adherence are many and complex. Thus, there is an opportunity to improve diabetes related costs and outcomes using effective methods to improve adherence. Population-level interventions include programs that reduce the cost of prescription medications to patients, such as medication assistance programs and value-based insurance design, as well as automatic refill and reminder programs. Patient-specific interventions include adherence education, use of daily pill reminder boxes, text message reminders, and direct medication management and education from a pharmacist or other health professional. While population-level targeting and support programs are important, the complexity of adherence behaviors and diversity of barriers warrant an individualized and multidisciplinary approach to improve adherence and to reduce the risk of costly diabetes complications.

It is estimated that, worldwide, 415 million individuals have diabetes,1 including 29.1 million in the United States (US) alone,2 with 1.4 million adults newly diagnosed each year in the US.3 Common downstream diabetes complications when diabetes is not controlled include hypoglycemic or hyperglycemic events, heart disease, stroke, blindness, kidney disease, diabetic neuropathy, and lower-limb amputations.4 These complications result in increased health care utilization and health care costs and increased risk of death.4

Fortunately, good management of glycemia and related comorbidities such as hypertension and dyslipidemia can reduce the risk of poor outcomes.5 However, it is estimated that almost half of patients with diabetes in the US fail to achieve a recommended glycemic control target as measured by a hemoglobin A1c (HbA1c) value of <7.0%.6 While many factors contribute to poor glycemic control, one known reason is poor adherence to recommended lifestyle modifications and prescribed treatments.

Despite the known benefits of diabetes medication therapy, adherence to diabetes medications is suboptimal. Studies suggest that adherence to oral diabetes medications ranges from 38.5% to 93.1%.7-9 It is inherent that poor adherence to prescribed treatments contributes to poor outcomes, which in turn affects diabetes- related costs. To assimilate evidence specifically around medication adherence, this article reviews the current data around barriers to medication adherence and the effect of medication nonadherence on clinical outcomes, health care utilization and costs in patients in the US with diabetes.

Methods

A literature search was conducted in June 2016 to identify studies reporting on adherence barriers and studies reporting outcomes associated with nonadherence in diabetes. There were no limits on dates of publication for reviewed articles. For these searches, the following terms were used: (1) “‘barriers’ AND ‘diabetes’ AND ‘adherence’”; and (2) “adherence, medication[MeSH Terms] AND diabetes mellitus[MeSH Terms] AND (health care costs[MeSH Terms] OR outcomes).” Studies were included if they were in English, conducted in adult patients in the US, assessed self-reported adherence barriers, and were not review articles. The review was limited to studies conducted in the US because differences in health care payment models and systems across countries may influence medication adherence and the effects on health care outcomes and costs. Only adults were included because the barriers and nonadherence effects on glycemic control may differ in pediatric patients, who predominantly have type 1 diabetes. We included cohort studies for the cost outcome assessment to limit the risk of bias that may come from assumptions made in modeling studies.

Results

♦ Barriers to medication adherence
The literature search for barriers to medication adherence identified 491 articles for title and abstract review. After title and abstract review, 35 articles were eligible for full-text review, and of these, 11 studies met all criteria for inclusion in this review. (Figure 1)

Figure 1. Barriers to adherence study inclusion flowchart.

The most prevalent medication adherence barriers reported in the identified studies were forgetfulness (7.4% to 66.7% of respondents in each study), costs (5.8% to 48.2% of respondents in each study), comorbidities (48.7% to 57.3% in each study) and traveling, being away from home, or being too busy (16.2% to 55.6% in each study) (Table I).10-20 In patients reporting barriers to insulin use, the top 3 reported barriers were interference with physical activities, traveling, or lifestyle (16.2% to 43.3% reporting in each study), injection site reactions or pain (28.6% reporting), or being too busy (18.9% reporting).17,18

Several studies included in this review reported data on specific patient populations including those with HIV,14 different race and ethnic groups,10,11,14 and patients who use Veterans Affairs health centers.<supS13 Studies by race and ethnicity suggest that cost barriers to adherence may be associated with race and ethnicity. A study evaluating barriers in Mexican Americans, non-Hispanic Whites, and Vietnamese Americans with diabetes found that 53.2% of Mexican Americans reported taking less medication than prescribed due to cost versus 27.2% of non-Hispanic Whites and 27.5% of Vietnamese Americans.15 The authors speculate that these differences are driven by having health insurance because more non-Hispanic Whites (97.2%) and Vietnamese Americans (99.5%) have health insurance by commercial, Medicare, or Medicaid providers than Mexican Americans (60.2%) (P<0.001). However, the authors state that having health insurance does not eliminate all perceived financial barriers to adherence.

Other common barriers identified in a separate study of 58 Latino patients included forgetfulness (66.7%) and lack of help to remember to take medications (55.6%), carelessness about taking medication (55.6%), being too busy or forgetting (55.6%), and running out of pills (55.6%).12 In a third, small study of 9 underserved Hispanic patients, the top 4 specific barriers were cost (22%), no refills (20.3%), forgetfulness(11.9%), and use of complementary and alternative medication (10%).11 The differences between these studies may be due to the small number of participants and differences in baseline characteristics and survey methods.

Table I (continued on next page)•••

Table I. Barriers to medication adherence (including insulin)*.
Abbreviations: coef, beta-coefficient; HbA1c, hemoglobin A1c; PDC, proportion of days covered; SD, standard deviation; T1D, type 1 diabetes; T2D, type 2 diabetes;
TAPS, Tool for Assessing Patients’Stressors. *Only barriers that had 10% or more of the population reporting were included in this table.

The top barrier to medication adherence mentioned by patients with HIV and hypertension or diabetes participating in focus groups was untreated substance abuse and mental health issues.14 In a separate focus-group study of patients with diabetes in the Veterans Affairs system, the main barriers to adherence were concerns about the quality of pharmacy services, communication issues, and lack of education and support around specific medication regimes.13

♦ Adherence and health outcomes
♦ Overview of adherence measures

Adherence is synonymous with medication compliance and refers to whether and how patients follow prescriber instructions regarding timing, dosage, and frequency of taking their medication(s).8 Adherence can be assessed using self-reported adherence or administrative data. Validated methods of self-reported adherence commonly used in research and found in this literature search were the Morisky Medication Adherence Scale (MMAS)21 and the Medication Adherence Report Scale (MARS).22 The MMAS is available in a 4- or 8-question format. Depending on the responses to the questions, patients are either scored as having low, medium, or high adherence. The MARS-5 is a different scale with 5 questions with 5 possible responses for each question (scale of “always true” to “never”). The maximum score is 25, which represents the highest adherence.23 Other self-report adherence scales include the Drug Attitude Inventory24 and the Brief Adherence Rating Scale.25 While self-reported adherence can capture data that reflects patient medication-taking behaviors and distinguish between intentional and nonintentional nonadherence, self-reported adherence is subject to recall and reporting bias.

Administrative data can overcome these biases by using objective data of medication dispensing. The medication possession ratio (MPR) and proportion of days covered (PDC) are common methods used to assess adherence using administrative data.8,26 Neither of these methods are preferred over the other or considered to be the “gold standard” for measuring medication adherence.27 The PDC and MPR differ in the way they are calculated, but both can be used to assess adherence to an individual drug or a drug class. The MPR is a ratio of the number of days supplies were dispensed for (numerator) to a specified time frame, such as 1 year (denominator). In calculating the PDC, the numerator is the total number of days covered by the medication. The denominator is the number of days from the date of first dispensing to the last dispending date plus the days supplied over the study time frame. In both cases and across disease states, a ratio of 0.80 (or 80%) or higher is often considered adherent. There are limitations to using administrative data to determine medication adherence. Using administrative data measures medication purchasing behaviors, which do not accurately reflect whether or not the patient took the medication. Furthermore, due to inter- and intra-person variability in dosing, adherence measures based on administrative data are unreliable for estimating insulin adherence.

Medication persistence is different from medication adherence. Persistence refers to the duration from starting a medication to when it is discontinued.8 Caution should be used when interpreting persistence, as there is no standard for defining acceptable gaps in therapy, and thus gaps vary by investigator, medication type, and typical dispensing periods in the study population.8

Figure 2. Outcomes and costs study inclusion flowchart.

♦ Glycemic and health outcomes, health care utilization, and health care costs
The literature search identifying the effect of adherence on diabetes-related outcomes and health care costs yielded 48 articles for review. After title and abstract review, 14 articles were eligible for full text review (Figure 2). Of these, 4 studies assessed glycemic control,28-31 2 studies assessed health outcomes,32,33 4 studies assessed health care utilization,34-37 and 4 studies reported the association between adherence and health care costs36-39 in patients with diabetes (Table II, page 188). Adherence was measured in a variety of ways including using MPR, PDC, self-reported measures including MARS-5, or by assessing gaps using a continuous measure of medication gaps (CMG). (Figure 3, page 189)

♦ Glycemic and health outcomes
Four studies assessed the effect of adherence on HbA1c in patients with diabetes using a variety of methods for defining glucose control and measuring adherence. These studies consistently identified a relationship between diabetes medication adherence and glycemic control.28-31 In a population of Veterans Affairs patients with type 2 diabetes (n=11 272), investigators found that each percentage increase in MPR decreased the odds of having poor glycemic control (HbA1c 8.0%) by 48% (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.44-0.62).28 A study of patients with diabetes treated by providers of an integrated health system (n=477) found that adherent patients, as measured via self-reported MARS-5 scores, had a higher likelihood of attaining HbA1c<7.0% compared with patients who were not adherent (OR, 1.90; 95% CI, 1.23-2.93).29 In a follow-up study in a subset of the above population (N=166), the authors found that being adherent with either a claims-based measure of adherence (MPR≥0.8) or a self-reported measure (MARS-5=25) was associated with an increased likelihood of HbA1c goal attainment compared with those who were not adherent (MARS-5: OR, 1.59; 95% CI, 1.09-2.34; MPR: OR, 2.70; 95% CI, 1.22-5.98).30 A final pre-post study of patients in an integrated health system (n=308) found that patients with worse persistence with metformin had a modest but statistically significant increase in HbA1c of 0.14% (P<0.001) at follow-up compared with baseline.31

An association between adherence and downstream diabetes-related complications and comorbidities was identified in 2 large cohort studies of adults with diabetes.32,33 A study of patients treated with an oral diabetes medication between January 1, 2002 and June 30, 2006 (n=96 734) found that adherent patients (PDC≥80%) had lower odds of having a diabetes- related complication (amputation/ulcer, acute myocardial infarction, cerebrovascular disease, neuropathy, renal events or retinopathy) than those who were not adherent.32 A second cohort study of patients newly started on a diabetes medication (n=4708) found that those who were adherent (MPR≥80%) were significantly less likely to develop microvascular complications (neurological disorders, diabetic foot problems, retinopathy, or nephropathy) than nonadherent patients (HR=0.76; 95% CI, 0.60, 0.92).33

♦ Health care utilization and costs
The existing literature is consistent in finding that adherence is associated with improved glycemic control and avoidance of diabetes-related complications. However, the degree to which adherence also affects utilization and cost is key to understanding how poor adherence in diabetes contributes to the disease burden to health care systems, as well as in establishing the feasibility of developing adherence intervention programs. Our literature search therefore included utilization and cost studies. Of 4 studies assessing the relationship between diabetes medication and adherence using medical and pharmacy claims data, 3 identified an association between good adherence and lower utilization,34,36,37 while a fourth study did not.35

Table II. Effects of adherence on glycemic outcomes, health outcomes, and health care utilization.
Abbreviations: 95% CI, 95% confidence interval; CMG, continuous measure of medication gaps; HbA1c, hemoglobin A1c; HR, hazard ratio; MARS-5, Medication
Adherence Rating Scale-5; MPR, medication possession ratio; OR, odds ratio; PDC: proportion of days covered; T1D, type 1 diabetes; T2D, type 2 diabetes.

In insured patients with diabetes treated with noninsulin diabetes medications between July 1, 2005 and December 31, 2008 (n=135 639), patients who were adherent (MPR≥80%) had 13% lower odds (OR, 0.87, P<0.001) of being hospitalized or visiting an emergency department. This study also found that a 10% increase in MPR was associated with a 1.2% reduction in hospitalization and emergency department visits (P=0.05; 95% CI, not reported).34 A second study of patients with diabetes who were continuously enrolled in a medical and drug benefit plan between June 1997 and May 1999 (n=3260) found that higher adherence was associated with a lower hospitalization risk. Patients with low adherence (1%-19% of days in a year with medication) had a 30% risk of hospitalization while those with high adherence (80%-100% of days with medication) had a 13% risk of hospitalization (P<0.05) (OR and 95% CI not reported).36 A third study of Veterans Affairs patients using diabetes medications (n=26 051) found that being adherent (MPR≥0.80) was associated with a decreased probability of hospitalization (coefficient, –0.015; standard error, 0.003; P<0.001).37

Figure 3. Example of how to calculate the medication possession ratio (MPR)
and the proportion of days covered (PDC) to assess adherence.

A fourth study did not identify any association between adherence and utilization. In this study of patients with diabetes (n=265) who were part of a pharmacy assistance program for low-income patients in North Carolina, the association between diabetes medication adherence and hospitalization was not significant, (OR, 0.70; 95% CI, 0.32, 1.51), and nor was the association between adherence and emergency department visits (OR, 0.66; 95% CI, 0.33, 1.35).35 As the benefits of improved adherence may not be seen immediately, it is possible that the follow- up time in this study (6 months vs 12 months in the other studies) may not have been sufficient to see an effect.

Three additional cohort studies based on administrative claims data found that improved adherence is also associated with lower total health care costs (Table III).37-39 In a cohort study of Medicare HMO patients (aged ≥65 years), a 10% increase in MPR was associated with an 8.6% decrease in annual all-cause total health care costs, after adjustment for potential confounders (P<0.001).39 A second study of adult patients treated with metformin, pioglitazone, or a sulfonylurea monotherapy (n=108 592) found that nonadherent patients had $846 higher annual all-cause total costs than adherent patients (95% CI, $747-$945), after adjustment for demographic characteristics, insurance, and disease characteristics.38 This overall reduction was found despite higher medication costs for adherent patients, with unadjusted drug costs being $887 higher for metformin, $1694 higher for pioglitazone, and $592 higher for sulfonylureas (no statistical test was conducted).

In the previously mentioned study of patients with diabetes treated in the Veterans Affairs system (n=26 051),37 increasing adherence, as a continuous variable, was associated with a decrease of $170 (standard error, $70) in total costs over one year (P<0.014).37 While conclusions are consistent, the effect size difference between this and the previous study may be due to differences in the population, adherence measurement methods, and costs included in the analysis.

Table III. Effects of adherence on health care costs.
Abbreviations: 95% CI, 95% confidence interval; MPR: medication possession ratio.

Discussion

This review, which summarizes the effect of nonadherence on glycemic outcomes, health care utilization, and costs, found that good adherence is generally associated with better glycemic control and lower health care utilization and costs. Despite this evidence, and despite more general knowledge that improved glycemic control is associated with a reduced risk of diabetes-related complications,5 the rate of nonadherence to diabetes medications is suboptimal.

Thus, there is a body of evidence to support the notion that improving adherence in patients with diabetes should translate into benefits for both patients and health care systems. Yet, improving medication adherence is not straightforward. Reasons for medication nonadherence in general, and specifically for diabetes, are complex, multifactorial, and differ for each patient. Thus, there is no single best approach for addressing nonadherence across a population. Rather, interventions to address nonadherence should be individualized and target the reasons behind the behavior.40

Commonly mentioned reasons for nonadherence include forgetfulness, cost, traveling/being away from home, or being too busy. To improve outcomes and reduce costs, adherence solutions may range from simple reminder aids to personalized counseling and medication management. For instance, failing to take medications as prescribed due to forgetfulness or travel may be addressed by using daily pill reminder boxes, reminders from families or other support networks, reminder alarms or text messages, and electronic devices that remind patients to take their medications.41-43 Forgetfulness to refill medications may be addressed by automatic refills at the pharmacy.44

Cost is an important barrier to adherence, and patients with diabetes may face this challenge due to being on multiple medications for diabetes and related comorbidities. Reducing patient out-of-pocket costs through prescription drug coverage and medication assistance programs can help to reduce the cost barrier.45-47 Value-based insurance design (VBID) is an innovative approach to removing cost barriers for populations of patients with chronic conditions that have high nonadherence consequences, such as diabetes. VBID allows select, high-value medications to be available at reduced or zero copayments for patients.48 These programs have generally been shown to help improve medication adherence, although evidence is mixed on whether VBID has an impact on health care cost trends.49 High pill burden is an issue in diabetes, as adequately controlling glycemia and diabetes-related comorbidities often results in complex medication regimens. A study showed that in patients with multiple comorbidities, reducing pill burden may boost medication adherence.50 However, care must be taken not to undertreat comorbidities for the sake of improving adherence. Thus, extended-duration treatment options such as daily basal insulin and weekly GLP-1 receptor agonists, as well as fixed-dose combination products may help to reduce regimen complexity without compromising treatment.51,52

Pharmacists and other health care providers can also provide further care to improve medication adherence via comprehensive medication management (CMM).53 CMM provides individualized care to patients to ensure they are receiving appropriate care and are being treated as intended.53 CMM includes assessment of all aspects of a patient’s therapy, including optimization of treatment regimens, identifying and addressing reasons for nonadherence, identifying and helping patients avoid and/or manage side effects, appropriate dosage, and appropriate indication.54 Due to their expansive knowledge in medication therapy, pharmacists are well-suited to conduct CMM, and many studies have reported that clinical pharmacist interventions have a significant and positive impact on glycemic control and goal attainment.12,16,55-69 However, current evidence is not consistent in showing that clinical pharmacists have a significant effect on medication adherence.16,56,68,70-74 This general lack of association may be because adherence is a complex behavior, and a multidisciplinary approach to address medication adherence may be warranted, particularly for complex patients, to maintain or improve medication adherence.75

Conclusion

This review reaffirms that poor adherence to diabetes medications increases the burden of illness on patients and health care systems through worse clinical outcomes and higher health care costs. Thus, improving medication adherence has the potential to improve outcomes and reduce costs. Given that the barriers to adherence are multiple and complex, an individualized approach to addressing these barriers through education and support, reminder aids, reduced medication costs to patients, and simplifying drug regimens as appropriate, is generally warranted.■

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Keywords: adherence; barriers to adherence; diabetes; glycemic outcomes; health care costs; review