Therapy-related strategies to improve adherence to diabetic medications

by S. Rasheeqa Ismail, Malaysia; S. Tsoli and R. Chowdhury, United Kingdom

Department of Public Health and
Primary Care, University of
Cambridge, Cambridge
Diabetes & Endocrine Unit
Cardiovascular, Diabetes
& Nutrition Research Centre
Institute for Medical Research
Stergiani TSOLI, MPhil
Department of Population Health
Faculty of Epidemiology and
Population Health, London School
of Hygiene and Tropical Medicine

Objective: To determine the efficacy of various therapy-related strategies in improving adherence to diabetic medications. Design: Systematic review and meta-analysis of prospective interventional studies. Data sources: Medline, Embase and Cochrane electronic databases, supplemented by searching the reference lists of relevant studies. Study selection: Randomized controlled trials in adults (age >18 years) with either type 1 or 2 diabetes mellitus and on existing diabetic medications (defined as any oral antidiabetic medication and insulin) that evaluated the effects of therapy-related strategies on subsequent changes in medication adherence compared with usual care or equivalent. Data extraction and analysis: Two investigators extracted data and a consensus was reached with involvement of a third. Study-specific effect estimates were combined using random-effects metaanalysis. A systematic narrative review was performed for the studies that could not be quantitatively synthesized. Results: Our search strategy retrieved 1364 unique citations, of which 14 were included in this review. We evaluated 15 different interventions from these 14 studies, including 9 multifaceted interventions and 6 single-intervention programs. The most common intervention was personalized education counseling (10 out of 15 interventions). Other interventions included automated system (2 studies), pictorial (2 studies), and drug labeling strategies (1 study). Adherence was measured using self-report tools in 11 studies, while 3 studies used medication counts–related tools, and 1 used interviews. In the quantitative synthesis, therapy-related interventions significantly improved adherence to diabetic medication (6 trials; 929 participants; 590 events; pooled relative risk, 1.218; 95% CI, 1.07-1.386; I2=0). Since there were significant differences in measurement tools and reporting across the studies, only a subset could, however, be included in the meta-analysis. Among those studies not included in the meta-analysis, a 1- week intervention did not result in a significant difference in adherence between the 2 study groups. However, for interventions lasting at least 6 weeks, a significant difference was reported. Conclusion: Available intervention studies on various strategies to improve adherence to diabetic medications generally show significant positive effects of therapy-related interventions on medication adherence. Similarly, pharmacy- and technology-based strategies also tend to benefit adherence substantially. However, the number of available trials is low and their quality is generally poor.


High diabetes prevalence worsened by a lack of medication adherence
Diabetes mellitus, principally type 2, remains a major public health challenge worldwide. Poorly controlled diabetes mellitus leads to a wide array of complications including diabetes-induced renal dysfunction, retinopathy, and peripheral and autonomic neuropathies as the key microvascular complications of diabetes.1 The overwhelming disease burden and the extensive complications associated with diabetes are further worsened by a lack of medication adherence, which is becoming increasingly common globally. An emphasis on adequate adherence to diabetes therapy is, therefore, crucial given the deaths and poor quality of life brought about by diabetes and its complications.2

Lack of adherence and associated detrimental impact on health
Adherence is defined as “the extent to which a person’s behavior— taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health care provider.”3 Adherence includes initiation of the treatment, implementation of the prescribed regime, and discontinuation of the pharmacotherapy.4 Worldwide, a substantial proportion of people do not adhere adequately to oral antidiabetic agents,5,6 with good adherence to sulfonylureas and metformin reported to be only 31% and 34%, respectively.7

Adherence to oral antidiabetic agents has been reported to have an inverse association with glycemic control,8 which subsequently leads to the development of microvascular and macrovascular complications of diabetes and altered lipid metabolism.9 In addition, patients with uncontrolled diabetes demonstrate a higher probability of developing depressive mood disorders.10 A lack of adherence to oral antidiabetic agents has been shown to lead to a 39% increased risk of allcause mortality and a 38% increased risk of hospitalizations, compared with adherent patients.11 The inverse relationship of medication nonadherence has also been observed with total annual health care costs,12 especially inpatient costs.13

Objective of the present review
Given the widespread problem of nonadherence to oral antidiabetic agents and its likely impact, an earlier World Health Organization statement emphasized that increasing the efficacy of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatment.3 However, existing trial evidence on the benefits of different types of available therapyrelated strategies to improve adherence is inconsistent and should be systematically reviewed. Therefore, we aimed to synthesize all available evidence to review the impact of different interventions on improving adherence to diabetic medications.


Data sources, search strategy, and eligibility criteria
Medline, Embase, and Cochrane Central electronic databases were searched systematically for relevant published articles (date of last search: May 3, 2017). Our search strategy combined terms related to the intervention (eg, oral diabetic agents, insulin) and outcomes (eg, medication adherence, compliance), without any language restriction (see Supplementary Table I, online only). We searched for studies that evaluated the effects of adherence-enhancing strategies compared with usual care or equivalent in adult participants (age> 18 years) with either type 1 or 2 diabetes mellitus, taking any diabetic medication. Diabetic medications were defined as any class of antidiabetic medications (ie, metformin, sulfonylureas) and insulin.

Study selection
We included randomized controlled trials that (i) followed patients prospectively, (ii) evaluated therapy-related interventions that promoted medication adherence, and (iii) had assessed medication adherence using commonly known measurement tools. Direct measurement tools were defined as directly observed therapy and measurement of levels of medicine, metabolites, or biologic markers in the blood. Indirect measurement tools were defined as patient questionnaires, self-reports, pill counts, rates of prescription refills, and electronic medication monitors.14 Potential eligible articles were identified by two reviewers through screening of titles and abstracts. Full texts were retrieved for articles that satisfied all the selection criteria. The reference lists of the articles selected and of relevant reviews on the topic were searched for additional publications.

Data extraction
A predesigned data extraction form was used to extract relevant information. Two reviewers piloted the data extraction form for a sample of the included papers until an agreement was reached among reviewers. The extracted data included information on study size, study design, baseline population, country of study, duration of follow-up, duration of diabetes mellitus, type(s) of diabetes mellitus medication used, description of intervention and control, frequency of intervention, medication adherence scale, definitions of good adherence, and values of adherence. When available, effects of good adherence— such as changes in HbA1C—were obtained.

Data synthesis and analysis
Effect estimates (expressed as relative risk, RR) were calculated for subsequent changes in medication adherence and were based on the proportion of participants with good adherence (≥80% adherence or equivalent),15,16 irrespective of the measurement tool used. Summary RRs were calculated by pooling the study-specific estimates using a random-effects meta-analysis that allows for between-study heterogeneity. All statistical tests were two-sided and used a significance level of P<0.05. Analyses were performed using the statisti- cal package, STATA release 11 (Stata- Corp, College Station, TX, USA). Where appropriate, a narrative review of the included studies was performed when quantitative synthesis could not be done due to either significant heterogeneity or unavailability of the relevant data among included studies.

Figure 1. Search strategy for studies included
in the review.

Assessing the risk of bias and quality of evidence
The risk of bias in the included studies was assessed using the Cochrane Collaboration tool for randomized controlled trials.17 Seven possible sources of bias were evaluated with this tool: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The quality of evidence of our outcomes was assessed using the GRADE Working Group framework (Grading of Recommendations, Assessment, Development and Evaluations Working Group) and presented in the form of a “Summary of findings” table. The GRADE working group defined quality of evidence based on five factors: risk of bias across all studies, consistency of the effects across all included studies, directness of the outcome measured, precision of the effect estimates, and publication bias. We assessed the presence of publication bias using funnel plots, plotting precision against the effect size. We performed Egger’s test to quantify asymmetry.18


Studies identified
We retrieved 1364 unique citations through our electronic database search. We retained 200 articles for further evaluation following our initial screening based on titles and abstract. Our search flowchart and reasons for exclusion are presented in Figure 1. In total, 14 articles were finally eligible to be included in this review. While a narrative review was performed for all of the included studies, given the substantial methodological heterogeneity and differences in the ways outcomes were reported, only six articles could be combined for quantitative synthesis.

Adherence achieved by therapy-related strategies
There were fourteen studies that evaluated the effects of therapy- related strategies on diabetes medication adherence.19-32 The baseline characteristics of the included studies are presented in Table I and there were no significant differences. The median follow-up of the included studies was 6 months (minimum 1 week, maximum 12 months). While all the included studies included participants with type 2 diabetes mellitus, none of the studies targeted solely participants with type 1 diabetes mellitus.

Table I. Summary of baseline characteristics of included studies.
Abbreviation: IQR, interquartile range.

Table II. Details of the interventions of the included studies.

There were 15 different therapy-related interventions in the 14 included studies (Table II), of which 9 were multifaceted interventions and 6 were single intervention programs. The most common intervention was personalized education counseling (10 out of 15 interventions). Ten studies included health care professional interventions that were mostly led by a pharmacist, two involved automated system interventions,20,26 two were based on pictorial27,28 and one on drug labeling strategies31 to improve medication adherence.

Eleven studies measured adherence using self-report tools, three used medication counts–related tools, and one used interviews (Table III, page 295). The adherence rates of the two study arms are presented in Table III. In three studies, baseline adherence was not reported. In the quantitative synthesis, therapy-related interventions significantly improved adherence to diabetic medication (6 trials; 929 participants; 590 events; pooled relative risk, 1.218; 95% CI, 1.07-1.386; I2=0)20-22,25,26,29 (Figure 2, page 295). The quality of evidence was moderate.

Assessments of study quality and risk of bias
None of the included studies had a low risk of bias in all seven domains (Supplementary Table II, online only). Participant bias was not clearly reported in all of the included studies. There was also unclear demonstration of reporting bias in all of the included studies. Funnel plotting for the studies included in the meta-analysis produced a symmetrical funnel plot (Supplementary Figure 1, online only). However, in view of the rather small number of studies included in the funnel plot (n=6), this may be inadequately powered to distinguish chance from true asymmetry.17 Egger’s asymmetry test of associations, nonetheless, was not significant (P=0.164). The quality of evidence of the association between therapy-related strategies and medication adherence was presented in the form of a “Summary of findings” table (Supplementary Table III, online only). The overall quality of evidence was graded as moderate. The quality of evidence was downgraded two levels because of: (i) serious risk of bias (blinding of outcome assessors was not reported in 3 out of 6 studies and absent in 2 out of the 6 studies; and the method of randomization was unclear in 2 studies); and (ii) indirectness (indirect measure of the outcome in all studies).

Table III. Table of characteristics of the included studies.
Abbreviations: OR, odds ratio; NS, not significant; NR, not reported; aIntervention (officer leading the program); bDuration of intervention in months, unless otherwise
stated; cPercentage of good adherence, unless otherwise stated; dMean score (standard deviation); eMean change in score (standard deviation); fDifference in end of
intervention between intervention and control study arms.


Summary of the key findings
The current review of available intervention studies on various strategies to improve adherence to diabetic medications demonstrates a moderate, but significant, effect of therapy related interventions in improving medication adherence.

Similarly, other interventions (such as pharmacy- and technology- based programs) also improved the level of adherence to diabetic medications substantially, but these benefits were particularly observed in interventions lasting more than 6 weeks. Nonetheless, the overall number of trials available in each of these intervention groups and their quality were generally inadequate.

Figure 2.
Effect of
on improving

Comparison with other reviews
A number of reviews have evaluated different types of interventions to improve medication adherence, but a measure of true effect could not be established.33 Although education counseling is potentially important for optimal adherence, studies linking education counseling to improved adherence in literature are also generally scarce and often inconclusive, with an earlier review reporting significant improvements in adherence in only 2 intervention studies.34

Pharmacological intervention remains a key component of effective diabetes management, which perhaps explains why a large number of trials are based on pharmacist-based interventions. Pharmacists can educate their patients about the proper use of medications, screen for drug interactions, explain monitoring devices, and make recommendations for ancillary products and services. This also enables them to potentially increase the communication between health care providers and patients, implement multidisciplinary programs, and recommend treatment regimens with easier dosing.35 With their clinical training, pharmacists have been seen to positively impact health outcomes and empower patients to actively manage their health.36 While patient counseling remains the most common form of pharmacist-based intervention to improve medication adherence, there are various forms of pharmacist-based interventions, and there seems to be no conclusive evidence of any specific intervention being superior to the rest (principally owing to the somewhat poor quality of existing studies37). A recent review reported generally significant improvements in adherence rate with pharmacist interventions in 5 studies.38

Furthermore, an earlier small prospective cohort study reported an improvement in medication adherence with the additional support of a diabetes nurse educator (29 participants; odds ratio, 6.6; 95% CI, 1.0-55.7).39 Other interventions, such as intense monitoring and sending of periodic cell phone messages, did not show any statistically significant impact on improving medication adherence (8 interventions; standardized mean difference, 0.22; 95% CI, 0.05-0.49).40 Multifaceted interventions (ie, those addressing more than one adherence factor) were comparatively more effective in improving adherence to diabetic medications and overall glycemic target in patients with type 2 diabetes mellitus compared with single strategies.41

Strength and limitations of the current review
The strengths and limitations of the present review deserve careful consideration. Although the present review is based on an extensive literature search and systematic synthesis of available evidence, as for any systematic review, publication bias remains a possibility. This is of particular concern for a number of articles in which full texts were not available and for the grey literature, which could not be searched. Additionally, the quality of evidence in the retrieved studies was generally poor, owing principally to the variability of measurement tools used in the different studies, the indirectness of the methods of adherence assessment, the multiple components of the interventions, and the insufficient quality of studies in general. Self-report was the most commonly used tool to evaluate medication adherence,42 making interpretation of the findings complicated since patients often tend to underreport a lack of adherence in order to avoid disapproval from their health care providers.43 Therefore, findings from studies measuring adherence with self-reporting instruments should be considered with some caution.

Implications for future research and practice
There is a clear need for standardized methods of adherence assessment and reporting, as well as larger scale and better quality studies to assess the efficacy of these methods to improve diabetic medication adherence reliably. To reduce the possibility of reporting bias, the study protocols of all new trials should be published. It is also essential that randomized trials clearly state the presence or absence of blinding—with reasons— involving various parties in the study. Since there appears to be no clear ideal instruments to reliably measure medication adherence, using multiple tools might capture individual adherence levels to diabetic medications with greater precision. Additionally, future studies should also explore medication persistence to diabetic medications, which remains largely under addressed in the prevailing literature. Finally, although these methods have a generally significant positive effect on adherence, individual patient needs should still be considered when formulating an intervention plan to improve adherence.


Available intervention studies on various strategies to improve adherence to diabetic medications show generally significant positive effects of therapy-related interventions on improving medication adherence. Similarly, pharmacy and technology-based strategies also tend to benefit adherence substantially. However, the number of available trials is low and their quality is generally poor. ■

Acknowlegements. The authors would like to thank the Department of Public Health & Primary Care at the University of Cambridge and the Director General Of Health Malaysia.

Keywords: adherence; diabetes; systematic review; therapy-related strategy

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