Recommendations for Improving Adherence to Type 2 Diabetes Mellitus Therapy-Focus on Optimizing Oral and Non-Insulin Therapies

Adherence to therapy in patients with type 2 diabetes mellitus is contingent upon a number of variables, including variables specific to the patient, to the provider, and to the treatment. While treatment selection will involve consideration to maximize effectiveness and minimize side effects, the physician must also take into account the priorities and preferences of each individual patient. For some patients, the risk of weight gain may exert a significant influence on adherence, while for others the risk of hypoglycemia or the cost of medications may be more important factors. It is incumbent upon physicians to discuss these issues with patients and to develop a patient-centric treatment plan to achieve optimal adherence and therapeutic outcomes. The nature of the clinical setting can also influence the likelihood of patient adherence to treatment. A multidisciplinary team approach to diabetes management has been shown to improve outcomes and to have a neutral or beneficial effect on costs. The treatment plan itself plays an additional role in the likelihood of a patient adhering to treatment. Less complex treatment regimens with fewer pills are associated with higher rates of adherence, as are fixed-dose combinations for those patients requiring combination therapy. Frequency and timing of dosing are also important aspects of adherence, as once-daily dosing is associated with higher rates of adherence than twice-daily dosing for anti-hyperglycemic medications.

(Am J Manag Care. 2012;18:S49-S54)

The effective management of type 2 diabetes mellitus (T2DM) is a multifaceted effort involving lifestyle interventions (eg, diet and exercise) and, for most patients, drug therapy. Regardless of the intervention made, adherence is critical to achieving treatment goals. In fact, a connection between adherence to medications and glycated hemoglobin (A1C) has been shown: when adherence increases, A1C decreases. Higher adherence likely leads to better treatment effectiveness.¹ Yet despite the importance of adherence to achieving treatment goals, there is room for improvement with regard to the current level of adherence to treatments among patients with T2DM.² Focusing on drug therapy, in patients taking oral medications for glycemic control, the rate of adherence has been reported to be as low as 65%.³

The challenges to patient adherence to prescribed treatment for T2DM are multiple and varied, may be mutually reinforcing, and may be difficult to overcome. Among the many reasons for nonadherence in T2DM, the most common ones relate to fear of treatment side effects (particularly weight gain and hypoglycemia), needle anxiety (for injectable therapies), inconvenience or complexity of a prescribed treatment regimen, inaccessibility to treatment arising from cost or formulary issues, and poor levels of patient knowledge about the use and importance of therapies for glycemic control.^4-10

Oral and injectable non-insulin therapies represent a broad array of treatments and drug classes which are commonly used before insulin is initiated. Strategies to improve adherence to oral and injectable non-insulin therapies must address each of the areas of potential adherence deficit, and these can range from the relatively straightforward—eg, optimizing therapies to avoid or minimize side effects, prescribing medications with easier-to-use formulations and simpler dosing schedules—to more complex approaches that may require changes in the way T2DM is treated by clinicians as well as cooperation on the part of third-party payers. The potential benefits of achieving higher rates of treatment adherence in T2DM include improved patient outcomes and cost savings.^11,12 This article will focus both on the potential causes of poor adherence in T2DM and strategies to improve adherence to oral and injectable non-insulin therapies. Potential causes for poor adherence to insulin therapy in patients with T2DM along with strategies for improving adherence will be discussed in the third article in this supplement.¹³

Impact of Patient-Related Factors on Adherence to Drug Therapy

A key therapeutic challenge in managing T2DM—and one with particular relevance to adherence—is the need to balance therapeutic efficacy with tolerability. The dual goals of achieving A1C target and avoiding or minimizing side effects that may impact tolerability and promote poor adherence need to be taken into consideration when formulating a treatment plan for patients with T2DM. The situation is complicated by the fact that unlike certain other diseases, in which disease management and therapeutic intervention may occur during a discrete period of time of illness, the task for patients with T2DM of achieving glycemic control is usually one that extends for the duration of a patient’s life. Ultimately, the patient is responsible for the day-to-day management of T2DM, including adherence to lifestyle changes as well as medications. Psychosocial factors can weigh heavily on patients and have a meaningful impact on the likelihood of treatment adherence. An international study of patients with diabetes and their providers found that between two-thirds and three-fourths of providers reported that their patients had psychosocial barriers that interfered with their adherence to therapy.¹⁴

Among the barriers to adherence in T2DM, patient fear of side effects such as weight gain, increased risk of cardiovascular events, and hypoglycemia are among the most influential factors. The frequency of these side effects, and their impact on adherence, is illustrated by a survey of 2074 patients with T2DM receiving at least 1 oral antidiabetic drug (OAD) and no insulin therapy.¹⁵ Nearly 72% of respondents had experienced a tolerability issue in the 2 weeks prior to the survey and half had experienced more than 2 tolerability issues in that time. Symptoms related to hypoglycemia were the most common, affecting 57% of patients with T2DM, while other common issues included constipation and/or diarrhea (28%), headaches (26%), weight gain (23%), and fluid retention (21%). A limited but statistically significant correlation was observed between the number of tolerability issues experienced by a patient and their likelihood of nonadherence to treatment (r = 0.20; P <.01). Moreover, for every additional tolerability issue experienced by a patient, the risk of medication nonadherence increased by 28% (P <.01).

The confluence of efficacy, side effects, and adherence was explored in the Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study, an observational study conducted in 6 European countries. RECAP-DM included patients who had failed metformin monotherapy and subsequently added a sulfonylurea or thiazolidinedione to their existing metformin therapy.⁹ The study sought to evaluate the relationships between the occurrence of hypoglycemia, patient satisfaction with treatment, and poor adherence. Data from 1709 patients with T2DM participating in the study showed that within the previous 12 months, 38% of patients receiving combination therapy had experienced hypoglycemic symptoms. Moreover, only 28% of patients were found to be below the International Diabetes Federation A1C goal of 6.5%. Compared with patients who had not experienced hypoglycemic symptoms, those who had experienced them rated the efficacy, convenience, and satisfaction with treatment significantly lower, and also gave a lower rating to the side-effect profile of their regimen (all P <.0001). Patients with hypoglycemic symptoms were also significantly more likely to report barriers to treatment adherence (eg, being bothered by medication side effects). The impact of hypoglycemia on glycemic management is further reflected in the fact that patients with more severe hypoglycemic events were less likely to be at A1C goal (Table). The authors suggest that reducing the incidence and severity of hypoglycemic events might help improve treatment adherence and glycemic control.

In reality, the challenge of balancing efficacy and tolerability in T2DM treatment is even more complex since successful disease management should also take into account the perceptions and preferences of the patients themselves. In an ideal world, patients would prefer those treatments that were the most measurably effective and tolerable. However, patients may have different priorities and may also be influenced by factors that they themselves underestimate as being influential on their adherence behavior. For example, in a 2009 survey patients with T2DM in the United States and the United Kingdom receiving OADs were asked a series of questions, the purpose of which was to determine the influence of treatment effectiveness and side effects on adherence to therapy.⁷ Subgroup analyses revealed several key differences in priorities. For example, weight gain was twice as important to women compared with men, while for those without a college education, cardiovascular risk was the most important factor.

Newer medications may help address medication-related weight gain. Glucagon-like peptide-1 (GLP-1)-receptor agonists represent a newer generation of medications for glycemic control that have the advantage of being associated with moderate weight loss, which might be expected to lower the risk of nonadherence.¹⁶ However, it is not clear how patients will balance the lower risk of weight gain against fears of self-injection or the costs of this class of medications. Nonetheless, it may be an appropriate option for patients who are concerned about weight gain.

In summary, the calculation necessary to achieve maximal treatment efficacy and adherence while minimizing side effects is a nuanced one that requires evaluating the benefits and limitations of particular treatments along with an understanding of the preferences and inclinations of the patients who must take them.

Practitioner-Related Factors in Treatment Adherence

If patients are to adhere to treatment, and treatment outcomes are to be optimized, it is important that treatment be customized to individual patients and modified to meet their evolving clinical requirements. There are currently about 10 different classes of antihyperglycemic agents on the market (depending on the classification scheme used), including agents administered orally or parenterally (including injectables); each class has its own advantages and disadvantages.¹⁷ The emergence of a diverse armamentarium of treatment options for diabetes provides additional tools for clinicians; however, the diversity of treatment options can make the management of T2DM more complex and difficult, particularly in the primary care setting where time is short and the clinical agenda is long. Additionally, gaps in knowledge of diabetes management among some primary care physicians contribute to the clinical challenges of managing T2DM.¹⁸ Improvements both in continuing medical education for physicians who manage patients with T2DM and in educational initiatives for patients who have T2DM can help address these gaps in knowledge.

Other factors beyond knowledge gaps influence the success of diabetes treatment. The Diabetes Outcome Study, which examined factors that were associated with poorer A1C control in primary care clinics, found that single-specialty practices were more successful than multispecialty practices, solo practices, and academic settings in achieving glycemic targets. The same study also found that practices that included nurse practitioners or physician assistants were more successful in helping patients meet their A1C targets.¹⁹

It may, ultimately, be the case that the best solution for achieving clinical outcomes for patients with diabetes involves the use of multidisciplinary treatment teams. Multidisciplinary teams have been repeatedly shown to improve outcomes and have typically demonstrated beneficial or neutral effects on costs.^20,21 Scanlon et al compared the impact of multidisciplinary teams on diabetes outcomes and costs in a Medicaid- and Medicare-enrolled patient population. Significant improvements were observed for A1C, body mass index (BMI), and blood pressure among patients with higher baseline levels for each of those variables, while no significant differences were seen in treatment costs compared with patients not receiving treatment from a multidisciplinary team.²⁰ An Australian study by Zwar et al found that the implementation of multidisciplinary care in patients with T2DM resulted in significant reductions in A1C (from 8.3% to 7.8%; P <.001) for those patients who had A1C levels greater than 7%, and also significantly increased adherence to outcomes guidelines for A1C, blood pressure, and total cholesterol (all P <.01).^22,23

A different approach was taken in a French study which evaluated the utility of a multidisciplinary team intervention by 1) providing a group of 73 volunteer general practitioners who treated T2DM with an 8-page guideline booklet for the appropriate treatment of T2DM and 2) conducting 2 subsequent audits of outcomes. The first audit, conducted in the year following the provision of guidelines, found generally poor guideline adherence and subpar patient outcomes, including inadequate screening for complications, underestimation of the role of education, and insufficient control of hypertension.²⁴ After the first audit, a multidisciplinary team was given the task of evaluating the clinical deficits it observed and making recommendations for their improvement. Recommended interventions for improvement included the implementation of educational programs and the creation of protocols for screening and treating retinopathy, nephropathy, and foot complications. The following year, a second audit was conducted which demonstrated that the interventions had resulted in significant improvements, including decreases in A1C levels, reductions in foot complications, increases in prescription of antihypertensive medications, and reductions in severe complications.

It should be noted that physicians themselves recognize the need for a multidisciplinary team approach to the treatment of diabetes, and also recognize the challenges that a single practitioner faces when treating diabetes.²⁵ Thus, success in optimizing outcomes would appear to be at least partially contingent on the structure of the clinical setting in which T2DM is treated and on the diversity of clinical expertise involved in the provision of care.

In addition to the strategies already discussed, programs that incentivize providers for quality improvements (eg, pay-for-performance [P4P] programs) also have the potential to impact patient adherence. Given the importance of adherence to achieving treatment goals and the current levels of adherence to treatment for T2DM, financial rewards or penalties tied to clinical outcomes may provide additional motivation for providers to help improve patient adherence to treatment for T2DM. Providers may help encourage adherence by several means, including educating patients regarding the consequences of hyperglycemia and the importance of adherence to lifestyle modifications as well as medications, and selecting medications that have favorable side effect profiles and convenient dosage and administration requirements.

Foels and Hewner evaluated the effect of a quality improvement initiative combining P4P with physician education on the percentage of patients with diabetes meeting specific process and outcome measures (eg, date and value of A1C) and physicians’ scores on composite adherence to guidelines (scored on a 10-point scale). Patient records and physician adherence to guidelines were evaluated in 6-month cycles; the results were discussed with physicians to help identify opportunities for improvement. The physician education component of the program focused on helping physicians formulate a systematic approach to the care of patients with T2DM. From the first cycle to the ninth cycle, the proportion of patients achieving an A1C less than 7% increased from 39.0% to 53.5%, and physicians’ scores on composite adherence to guidelines increased from 4.3 to 6.2.²⁶

To investigate the effect of a P4P program on how frequently patients with diabetes received certain quality-of-care interventions, and the relationship between receipt of these interventions and the likelihood of hospitalization, Chen et al conducted a longitudinal study of patients enrolled in a preferred provider organization between January 1, 1999, and December 31, 2006. Patients who had a claim for at least 2 A1C tests and 1 low-density lipoprotein cholesterol (LDL-C) test during 1 year were considered to have received quality care. Patients who saw physicians participating in the P4P program were significantly more likely to receive quality care compared with patients who saw physicians not participating in the P4P program (odds ratio, 1.16; 95% confidence interval [CI], 1.11-1.22; P <.001). Patients who received quality care were significantly less likely to be hospitalized in the following year compared with patients who did not receive quality care (incident rate ratio, 0.80; 95% CI, 0.78-0.83; P <.001).²⁷

Impact of Medication Formulations and Administration on Adherence

Factors related to the medications themselves can also influence adherence. A greater number of daily doses of medication or a more complex regimen involving more than 1 medication can decrease adherence.^28,29 A large-scale study based on data from a pharmacy claims database for a large MCO compared rates of adherence in nearly 17,000 patients with T2DM whose disease was poorly controlled on metformin or on a thiazolidinedione, and who switched to oral rosiglitazone-metformin combination therapy either as a fixed-dose combination (FDC) or loose-pill combination (LPC) regimen.¹⁰ Patients switching to the FDC were found to have significantly better improvements in treatment adherence measured by medication possession ratio (MPR) compared with those who switched to LPC (—12.4% vs –4.6%; difference in MPR improvement = 7.8%; P <.001). Similarly, a retrospective analysis of data from 2 very large health plan databases found improved adherence in patients switching from sulfonylurea or rosiglitazone monotherapy to rosiglitazone/glimepiride FDC compared with a switch to sulfonylurea/rosiglitazone LPC therapy.³⁰

A 2011 systematic literature review analyzed studies of oral FDC therapies and LPC therapies in patients with T2DM to determine the relationship between particular formulations and adherence, patient satisfaction, and treatment costs.³¹ Based on an analysis of 7 studies, the authors observed that among patients initiating combination therapy, FDC therapies were associated with adherence rates 10% to 13% higher than those seen with LPC therapies. Switching from monotherapy to LPC therapy resulted in a 10% drop in adherence, compared with a 1.5% drop in adherence for those switching from monotherapy to FDC therapy (P <.001). Switching from LPC to FDC therapy was associated with adherence increases ranging from 3.5% to 12.4%. The authors further found that 4 out of 5 randomized controlled trials showed greater patient satisfaction with FDC therapy, while limited data suggested that FDC therapies were associated with cost savings.

The number of pills, however, may exert a smaller influence on adherence than the frequency of dosing. A study comparing once-daily dosing of glipizide oral therapy with twice-daily dosing found a 60% adherence rate for the former compared with 52% for the latter (P <.027) despite the fact that the once-daily regimen required the administration of more pills at the time of dosing.³² The influence of frequency of dosing was also the subject of a retrospective observational study from the United Kingdom that compared adherence to immediate release (IR) versus sustained release (SR) metformin in patients with T2DM. IR metformin is dosed at least twice daily, while SR metformin is dosed once daily. The investigators found that switching from IR to SR metformin was associated with an increase in adherence from 62% to 81% (P <.0001).³³ One adherence-related benefit of the metformin SR formulation is its potential to reduce the gastrointestinal side effects that impact many patients who take metformin, since gastrointestinal side effects result in high rates of discontinuation.

Currently available GLP-1 agonists include liraglutide, which requires once daily injection at any time of the day regardless of timing with meals, and exenatide, which requires twice-daily injection within the 60 minutes preceding the morning and evening meals.^34,35 Longer-acting GLP-1 agonists, requiring only 1 injection per week, are currently in development, and a form of exenatide requiring only 1 injection per week was approved by the FDA in January 2012.^36,37 The impact of weekly versus daily injections on adherence remains to be determined.

Conclusion

Adherence to therapy in T2DM is influenced by many variables, including treatment side effects and medication formulations. Practitioner-related factors such as the structure of the clinical setting and the particular personnel employed for disease management also impact outcomes. Adherence is also influenced by patients’ preferences and priorities. Formulation of a highly effective treatment regimen to which the patient can be adherent should include discussion with the patient regarding treatment effectiveness, side effects, dosing regimen, and costs upon treatment initiation. As patients typically will require treatment intensification, it is important that clinicians also discuss effectiveness, side effects, and costs of therapy when adjusting the treatment regimen. It is, furthermore, advisable for physicians to educate their patients with T2DM about the consequences of hyperglycemia and key strategies for effective disease management, in addition to apprising patients of expected patterns of therapy escalation, the importance of blood glucose monitoring, and the necessity of maintaining regular appointments in order to achieve glycemic control.

Because of the complexity of diabetes and its comorbidities, a multidisciplinary team approach to managing diabetes is likely to be the most effective one and has been shown to be cost effective or cost neutral. Achieving adherence in order to optimize outcomes within the strictures of cost controls requires cooperation between patients, providers, and third-party payers so that proven treatment strategies can be fully and properly implemented. Author affiliation: Pharmacy Quality Alliance, Fairfax Station, VA.

Funding source: Funding for the development of this supplement was provided by Novo Nordisk.

Author disclosure: Dr Nau reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; supervision.

Address correspondence to: David P. Nau, PhD, Pharmacy Quality Alliance, 9687 South Run Oaks Dr, Fairfax Station, VA, 22039. E-mail: dnau@PQAalliance.org.

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