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Patient Preference and Adherence 2016:10 1299–1307
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REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/PPA.S106821
Poor medication adherence in type 2 diabetes:
recognizing the scope of the problem and its key
contributors
William H Polonsky
1,2
Robert R Henry
2,3
1
Behavioral Diabetes Institute, San
Diego,
2
University of California,
San Diego,
3
Center for Metabolic
Research, VA San Diego Healthcare
System, San Diego, CA, USA
Abstract: At least 45% of patients with type 2 diabetes (T2D) fail to achieve adequate glycemic
control (HbA1c 7%). One of the major contributing factors is poor medication adherence.
Poor medication adherence in T2D is well documented to be very common and is associated
with inadequate glycemic control; increased morbidity and mortality; and increased costs
of outpatient care, emergency room visits, hospitalization, and managing complications of
diabetes. Poor medication adherence is linked to key nonpatient factors (eg, lack of integrated
care in many health care systems and clinical inertia among health care professionals), patient
demographic factors (eg, young age, low education level, and low income level), critical patient
beliefs about their medications (eg, perceived treatment inefficacy), and perceived patient burden
regarding obtaining and taking their medications (eg, treatment complexity, out-of-pocket
costs, and hypoglycemia). Specific barriers to medication adherence in T2D, especially those
that are potentially modifiable, need to be more clearly identified; strategies that target poor
adherence should focus on reducing medication burden and addressing negative medication
beliefs of patients. Solutions to these problems would require behavioral innovations as well
as new methods and modes of drug delivery.
Keywords: glycemic control, HbA1c, hypoglycemia, medication adherence, psychosocial,
type 2 diabetes
Introduction
The prevalence of type 2 diabetes (T2D) is at epidemic proportions worldwide,
1,2
and
the incidence and prevalence of T2D continue to increase (Figure 1).
3,4
Indeed, the
worldwide prevalence of T2D is expected to increase from 382 million individuals
(2013) to 417 million individuals by 2035.
1
This is of critical concern because T2D
represents the largest budget item in many health care systems,
5,6
primarily due to
the high rates of morbidity and mortality associated with the disease.
7–9
Even worse,
it has been well documented that this cost burden has been inexorably growing
worldwide.
10
A key contributor to the remarkably high rates of morbidity and mortality is chronic
poor metabolic control, especially poor glycemic control.
7
Although a wide array of
options are now available for treating T2D, including several new pharmacological
classes of drugs that are included in the current American Diabetes Assocation/Euro-
pean Association for the Study of Diabetes (ADA/EASD) and American Association of
Clinical Endocrinologists (AACE) recommendations,
11,12
~50% of patients with T2D fail
to achieve adequate glycemic control (glycated hemoglobin [HbA1c] 7%).
13,14
Using
data from the National Health and Nutrition Examination Survey, targets for glycemic
Correspondence: William H Polonsky
Behavioral Diabetes Institute,
PO Box 2148, Del Mar, CA 92014, USA
Tel +1 760 525 5256
Email whp@behavioraldiabetes.org
Journal name: Patient Preference and Adherence
Article Designation: Review
Year: 2016
Volume: 10
Running head verso: Polonsky and Henry
Running head recto: Poor medication adherence in type 2 diabetes
DOI: http://dx.doi.org/10.2147/PPA.S106821
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Polonsky and Henry
control (HbA1c) were achieved by only 55.5% of participants
during 2009–2010.
15
A number of factors contribute to poor
glycemic control, including lack of integrated care in many
health care systems, clinical inertia among health care provid-
ers, and poor patient adherence to self-care recommendations.
Among them, it is evident that poor medication adherence
looms large.
16
This article reviewed the magnitude of the
problem of poor medication adherence, the impact of poor
adherence on long-term outcomes and health care costs, and
the key contributors to poor medication adherence. In addition,
the barriers and challenges that patients with T2D and their
health care providers face regarding medication adherence are
reviewed and the potential future approaches for enhancing
long-term adherence and persistence are highlighted.
Scope of the problem
Much of the evidence regarding poor medication adherence
in diabetes is based on retrospective or observational studies
that collect data from claim databases using a broad range
of definitions. Consequently, the reported incidence of poor
medication adherence in patients with T2D ranged widely
from 38% to 93% owing to widely different methodological
approaches.
17–19
For the purposes of this article, we focused on
one of the more common metrics and definitions of accept-
able medication adherence, eg, a medication possession ratio
(MPR) of 80% over the period of observation.
20
A review of
studies found that among patients with diabetes, hypertension,
and dyslipidemia, only 59% had MPR 80%.
17
An analysis
of 238,000 patients with T2D from the MarketScan data-
base reported adherence rates (MPR 80%) of 47.3% with
dipeptidyl peptidase-4 inhibitors, 41.2% with sulfonylureas,
and 36.7% with thiazolidinediones (Figure 2).
18
Similarly,
a recent meta-analysis of 40 studies in which patients tak-
ing oral antidiabetic drugs found that medication adherence
rates were suboptimal, with only 67.9% of patients having
an MPR 80%.
21
Another commonly used metric is medication persistence.
Unfortunately, definitions vary even more widely here.
Persistence is often defined as no gap in prescription drug
supply for at least 30 days, although in some studies the defi-
nition is extended to 60–90 days. Other researchers have
defined persistence on the basis of the proportion of patients
who discontinue treatment, which may include discontinu-
ation for lack of efficacy, side effects, patient preferences,
and other causes. In total, the body of current findings can
be difficult to interpret. In one recent meta-analysis that
included randomized clinical trials of patients with T2D,
persistence rates ranged from 41% to 81% and discon-
tinuation rates ranged from 10% to 61% over a 12-month
follow-up.
21
According to the MarketScan database, 47% of
238,000 patients discontinued therapy (last day of drug prior
to a 60-day gap) over a 1-year follow-up.
18
A retrospective
study of 1,321 patients with T2D treated with liraglutide
(Novo Nordisk A/S, Bagsværd, Denmark) reported that 60%
were persistent with therapy (no 90-day gap) over a 12-month
period, but only 34% were adherent (MPR 80%).
22
Among
40,000 patients with T2D, persistence (no 30-day gap)
over a 12-month follow-up ranged from 27% to 32%.
23
A retrospective analysis of persistence (time to discontinu-
ation prior to 60-day gap) with different oral or noninsulin
injectable agents for T2D reported an overall discontinuation
rate of 52.2% over 12 months.
24
In total, despite the wide range of definitions, there is rela-
tively broad agreement across studies that problematic medi-
cation adherence and/or persistence is far from uncommon in
T2D and may affect at least half of the population, if not more.
Figure 1 Prevalence of diagnosed diabetes among adults 20 years old from the
NHANES of 1988–1994 and 1999–2010.
Note: Data from a previous study.
4
Abbreviations: NHANES, National Health and Nutrition Examination Survey;
BMI, body mass index.
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Figure 2 Percentage of patients discontinuing therapy (60 days without drug) with
oral hypoglycemic drugs during a 1-year follow-up of patients initiating therapy.
Note: Data from a previous study.
18
Abbreviation: TZD, thiazolidinedione.
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Poor medication adherence in type 2 diabetes
Of note, however, most of the studies cited above are limited,
given the nature of claim databases, to those patients who had
at least an initial prescription filled for the new medication. The
risk of poor medication adherence may be higher once con-
sideration is given to those who fail to fill a first prescription.
In one study that tracked new prescriptions written electroni-
cally over a 12-month period for 75,000 patients, 31.4% of
new prescriptions for diabetes drugs were never filled.
25
This
problem, often referred to as primary nonadherence, may be
particularly relevant among patients who are refusing to initi-
ate insulin or other injectable hypoglycemic therapy, typically
due to injection phobia, inconvenience, poor patient–physician
communication, and/or negative patient perceptions.
26
Consequences of poor medication
adherence
Poor adherence is associated with inadequate glycemic control,
increased use of health care resources, higher medical costs,
and markedly higher mortality rates.
16,27,28
Among 11,000
veterans with T2D who were followed up for at least 5 years,
poor medication adherence (MPR 80%) was significantly
(P0.001) associated with poor glycemic control (HbA1c
8%).
16
The National Health and Wellness Survey of 1,198
patients with T2D found that each 1-point drop in self-reported
medication adherence (using the Morisky Medication Adher-
ence Scale) was associated with 0.21% increase in HbA1c,
as well as 4.6%, 20.4%, and 20.9% increase in physician,
emergency room (ER), and hospital visits, respectively.
28
Most importantly, poor medication adherence in T2D
has also been linked to increased mortality. For example,
among 15,984 patients from general practices in the UK who
were treated with an oral antidiabetic agent, poor medica-
tion adherence and missed clinical appointments were each
independently associated with a significant (P0.001)
1.6-fold increase in all-cause mortality.
7
Similarly, Ho et al
8
reported a significant association between poor medication
adherence in T2D and all-cause mortality over time (odds
ratio 1.8; P0.001).
Finally, poor medication adherence results in increased
costs of T2D outpatient care, ER visits, hospitalization, and
managing T2D complications.
6,29
An analysis of adherence
to medications used to treat diabetes, dyslipidemia, and
hypertension estimated that the direct cost of poor adherence
was $105.8 billion in 2010 across 230 million patients, which
represented $453 per adult.
6
The pharmacy and administra-
tive claim databases of CVS Caremark were used to assess
the impact of medication adherence on hospital days, ER
visits, and outpatient visits.
29
The annual medical spending
per patient with diabetes was projected to decrease by $4,413
for all adults and by $5,170 for those at the age of 65 years
or older when MPR was 80%. A systematic review of the
economic impact of medication adherence and/or persistence
on the overall cost of T2D care found that the average total
annual cost per patient ranged from $4,570 to $17,338, and
medication adherence was inversely associated with total
health care and hospitalization costs.
30
Improved medication adherence has the potential to sig-
nificantly impact T2D health care costs. Patients with T2D
who evidenced an improvement in medication adherence had
a 13% reduction in the risk of hospitalization or ER visits,
while a 15% increase in hospitalization and ER visits was
associated with worsening adherence over time.
31
Based on this
analysis, improved adherence was projected to save $4.7 bil-
lion annually, while reduced incidence of poor adherence was
projected to save $3.6 billion annually. Egede et al
27
compared
a large group of poorly adherent Veterans Administration (VA)
patients (5-year MPR of 58%) with a similar large group of
adherent VA patients (5-year MPR of 93%) and found that the
poorly adherent group had a 37% lower pharmacy cost and a
7% lower outpatient cost over the 5-year period (likely asso-
ciated with a decreased use of health care resources), but the
inpatient cost was 41% higher. Annual cost savings in the range
of $661 million–$1.16 billion were projected in the VA system
by improving adherence in the poorly adherent group.
In total, it is apparent that addressing problematic medi-
cation adherence in the T2D population offers the potential
for dramatically reducing costs and improving care and
outcomes for patients.
Key contributors to poor
medication adherence
Studies based on large claim databases have identified key
demographic factors, such as younger age, lower education
level, and lower income, that are associated with poor medica-
tion adherence in T2D,
24,32
but it may be of greater importance
to identify those critical factors that are potentially modifi-
able. In total, the available body of data points to six key fac-
tors: perceived treatment efficacy, hypoglycemia, treatment
complexity and convenience, cost of treatment, medication
beliefs, and physician trust. It should be noted that many addi-
tional factors have been described in the extant literature (eg,
depression, forgetfulness, and limited diabetes knowledge),
but we suggest that it is these six factors that may be the most
critical as well as the most amenable to change:
1. Perceived treatment efficacy: Patients are more likely
to be adherent to medication regimens when they have
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Polonsky and Henry
some tangible sense that the prescribed medication is
contributing to some positive and relatively immediate
outcomes.
33
Indeed, in numerous studies across a wide
variety of chronic illness conditions, there is a consistent
finding that medication adherence is associated with per-
ceived need.
34
The more firmly the patients believe that
the prescribed medication is actually necessary, the more
adherent they are likely to be. Consider, for example, that
among 477 patients with T2D starting on any new class
of diabetes medication, self-reported medication adher-
ence over 6 months was associated with greater weight
loss (3 kg: 29.9% adherent vs 24.2% poorly adherent)
and with a greater likelihood of attaining HbA1c goal
(7.0%: 47.5% adherent vs 32.7% poorly adherent).
35
These data may suggest that realization of patients that
improvement is occurring (and that this may be due, at
least to some extent, to their medications) contributes to
their willingness to continue with their medications in a
more reliable manner.
2. Hypoglycemia: A cross-sectional study of patients with
T2D treated with metformin and a sulfonylurea agent
found that patients reporting moderate or worse symp-
toms of hypoglycemia had poorer medication adherence
vs those with no or mild hypoglycemia (MPR 80%:
46% vs 67%, P0.01).
36
Among T2D participants in a
recent survey, 56% had experienced hypoglycemia and
had higher HbA1c levels than in those with no reported
hypoglycemia (Figure 3).
37
Finally, a claims database
was used to evaluate the impact of hypoglycemia-
related events on costs and discontinuation rates among
212,000 patients with T2D.
38
During a 6-month interval,
the risk for medication discontinuation was significantly
(P0.0001) greater among those with a hypoglycemic
event vs those with no reported hypoglycemia. It is
noteworthy that even a single hypoglycemic event may
contribute to greater fear of hypoglycemia in patients
with T2D,
39
and hypoglycemic fear, in turn, may con-
tribute to poorer medication adherence as the patient
chooses to keep his/her blood glucose levels in a higher
range where further hypoglycemic events will be less
likely.
40
The choice of medication(s) will, of course, have
a major impact on the risk of hypoglycemia. However,
even in the case of sulfonylureas, the actual likelihood
of hypoglycemic problems may be influenced by the
dosage prescribed, prescription errors, and/or how well
or poorly the patient understands and follows medication
directions.
3. Treatment complexity and convenience: Not surpris-
ingly, medication adherence and persistence become
more challenging when the treatment itself is perceived
as more difficult, onerous, or burdensome.
41
In their
comprehensive review of 76 studies, Claxton et al
42
found
that the prescribed number of doses per day was inversely
associated with medication adherence; indeed, the mean
adherence across studies decreased progressively from
79% with a once-daily dose to 51% with a four times
daily dose. Several recent reviews have confirmed these
findings, with adherence rates for patients with chronic
diseases, including T2D, found to be significantly
lower for any medication regimen requiring more than
once-daily dosing (79%–94% once daily vs 38%–67%
three times daily; P0.05).
43,44
Beyond the influence of
dosing schedules, recent data suggest that the overall
complexity of the T2D medication regimen predicts
adherence, with greater complexity contributing to poorer
adherence.
45
Similarly, the convenience or complexity of
medication delivery devices can influence adherence. For
example, in retrospective analyses of insulin pen vs vial
and syringe use in T2D samples, improved persistence
and adherence, improved glycemic control, and lower
rates of hypoglycemia were reported in the insulin pen
groups.
46–49
4. Cost of treatment. Out-of-pocket costs for medications
have been consistently associated with problematic
adherence across treatment conditions.
50
Higher out-
of-pocket costs for antidiabetic medications in particular
are linked to poorer adherence.
32,51
To illustrate, patients
with T2D receiving a low-income subsidy for Medicare
Part D were found to have lower out-of-pocket costs and
Figure 3 Percentage of patients with low, medium, or high adherence to antidiabetic
medication based on the MMAS score according to the occurrence of recent hypo-
glycemic episodes.
Notes: *P0.05 vs never hypoglycemia. Data from a previous study.
37
Abbreviation: MMAS, Morisky Medication Adherence Scale.
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Poor medication adherence in type 2 diabetes
better medication adherence than those not receiving the
subsidy.
52
5. Medication beliefs: Many patients hold markedly negative
or highly skeptical beliefs about their prescribed medi-
cations, often fearing that the long-term risks outweigh
any likely benefits.
26,53
Numerous studies have examined
the impact of this “necessity-concerns framework”;
although – as noted above – while believing that one’s
medications are necessary is associated with adherence,
there is a consistent finding across the studies to date
that patients’ concerns about their medications are more
strongly linked to adherence than their beliefs in the
necessity of those same medications.
54
In patients with
T2D, such concerns about the possible negative impact of
medications are associated with poor adherence
55
as well
as reluctance to initiate new medications, both orals
56
as
well as injectables.
57,58
6. Physician trust: Adherence to hypoglycemic medications
59
as well as antidepressant medications
60
has been linked
to patients’ trust in their physicians. In a conceptually
similar vein, Kerse et al
61
found that primary care patients’
sense of “concordance” with their physician (feeling that
their needs during medical visits had been heard and
addressed) predicted medication adherence over time.
In a large multinational survey, Polonsky et al
62
found
that ratings of patients with T2D on the overall quality
of communication with their physicians at the time of
diagnosis were linked to adherence to current hypogly-
cemic medications. To highlight the potential influence
of physician trust, a small study by Piette et al
63
reported
that the association between medication adherence and
out-of-pocket costs is minimized among those patients
who report high trust in their physicians.
Of note, while the available data focus solely on the
critical value of trust in the physicians, it seems likely that
trust in other key health care professionals with whom
the patients have ongoing contact may also be similarly
potent in influencing medication attitudes and behaviors.
Therefore, we hope to see future research examining how
medication adherence is affected, for example, by trust in
community pharmacists (whose clinical practice role in
the US has been expanding in the recent years) and trust
in nurse specialists in the UK (who play a central role
in the diabetes care system of National Health Service).
In summary, these data suggest that modifiable factors
influencing T2D medication adherence fall into two broad
categories: treatment burden (eg, complexity and conve-
nience, out-of-pocket costs, and hypoglycemia risk) and
treatment-related beliefs (eg, perceived treatment efficacy,
medication beliefs, and trust in one’s health care providers).
To address problematic adherence, it would therefore seem
likely that effective strategies might target one or both
of these domains. However, what is known about what
really works?
Interventions to address poor
medication adherence
While numerous methods to address poor medication adher-
ence across disease states have been developed and tested,
including educational programs, disease management pro-
grams, intensive behavioral support, medication reminders,
and special packaging, long-term, sustained reductions in the
rates of poor adherence have been difficult to achieve.
64,65
Recent literature reviews focusing specifically on T2D-specific
medication adherence interventions have led to similarly
disappointing conclusions; in those cases where benefits are
apparent, the magnitude of intervention effects is typically
small and/or of limited duration.
66–70
A closer examination of
the wide variety of intervention contents revealed no single
form of intervention to be consistently effective for improving
adherence,
71
though multifaceted interventions were found to
be more effective than single-strategy approaches,
66
and as
observed in one recent review, interventions targeting medica-
tion side effects might be of particular value.
67
Descriptions of the specific T2D interventions are often
inexact, making it difficult to determine which of the key
modifiable factors, if any, are being targeted. For example,
educational and/or behavioral support interventions are
described as central pillars in the majority of adherence
interventions, especially in the complex interventions consist-
ing of multiple strategies, but exactly how these operate or
what obstacles are being targeted are typically not specified.
In total, we speculate that most interventions to date have
focused within the broad category of reducing treatment
burden – focusing primarily on the problem of medication
behavior rather than medication attitudes. Indeed, we know
of no study that has directly examined the potential impact of
addressing dysfunctional medical beliefs, perceived treatment
efficacy, or any other aspect of patients’ treatment-related
beliefs. One of the keys to future advances in addressing
problematic medication adherence, especially primary
medication adherence, may be through better physician
communication regarding benefits and risks of treatment,
addressing patients’ treatment concerns, engaging in shared
decision-making, and providing and/or supporting self-
management training.
26
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