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Evidence-Based Diabetes Management September 2013
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Improving Patient-Centered Care in Diabetes With Comparative Effectiveness Research
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Improving Patient-Centered Care in Diabetes With Comparative Effectiveness Research

Douglas K. Owens, MD, Wade Aubry, MD, Roy Beck, MD, Joshua Benner, MD, Jan E. Berger, PharmD, Michael E. Chernew, PhD, Felicia Forma, BS, Dana P. Goldman, PhD, William H. Herman, MD, Rebecca Killion,
The complexity of glycemic management in type 2 diabetes mellitus (T2DM) has increased dramatically in the past 15 years. In 1995, the drugs available for treatment of T2DM were insulin and sulfonylureas. Since then, 9 new drug classes have become available, significantly increasing the number of clinical options for physicians and patients. The expanded treatment options currently available, in turn, have produced more opportunities for individualized, patient-centered treatment approaches, while creating additional challenges. For example, among T2DM patients, there is substantial heterogeneity in clinical outcomes and patient preferences regarding which health outcomes and treatment effectsmatter to them most. For the physician who seeks an approach that maximizes an individual patient’s likelihood of responding favorably to treatment while optimizing other considerations (eg, quality of life, functional ability, healthcare spending), the challenge is made greater by an insufficient evidence base to inform clinical decision making.

At a minimum, such an evidence base would include data on the comparative effectiveness of various treatment options—both overall and for specific subgroups of patients—as well as data on patient preferences that drive treatment decisions and, often, health outcomes. Comparative effectiveness research (CER) plays an important role in generating evidence for patients, physicians, and payers; it is increasingly conspicuous in discussions about optimizing patient-centered care for T2DM. CER compares the benefits and harms of alternative treatment options to determine “what works best for which patients under what circumstances.”1 By also assessing utilization and costs, CER can provide a foundation for cost-effectiveness analysis,2 an important approach for identifying high-value health care.3

The hallmark of CER is the comparison of clinically relevant alternative diagnostic or management strategies in representative clinical practice populations. With its multiple treatment  alternatives and heterogeneity of patient outcomes, T2DM management is well-suited to this type of research. Accordingly, CER is increasingly used within the diabetes arena. For example, a form of CER was used to evaluate available drug therapies for T2DM.4 However, without an economic evaluation or measurement of comparative clinical effectiveness in real-world settings, the findings are limited. In another example, a major pharmaceutical company developed its phase III clinical trials program using CER. Drawing on insights of an expert panel, the company developed a clinical research approach to provide clinical and economic data once the trials were completed, with a particular focus on enhancing liraglutide’s entry into the market and integration into formularies.5

Finally, a recent comprehensive review of randomized control trials (RCTs) and observational studies by the Agency for Healthcare Research and Quality (AHRQ) identified several gaps in the

evidence on the effectiveness of oral agents for T2DM. These gaps will limit clinicians in providing patient-centered care.6,7

Comparative Effectiveness Research Working Group

To better understand how CER may be used to help improve patient-centered T2DM care, we convened a multidisciplinary working group that included patient representatives as well as a range

of experts in: diabetes care, technology assessment, pharmacology, health economics, evidence synthesis, systematic reviews, clinical decision making, guideline development, epidemiology,

clinical trials, and public policy. The group considered the following questions:

1. What are the limitations in the available evidence for patient-centered T2DM care in diabetes?

2. What outcomes are important to patients and, therefore, should be included in studies of diabetes management?

3. How should RCTs be modified to improve the evidence base for patientcentered care?

4. How should observational studies be designed to improve the evidence base for patient-centered care?

The working group made recommendations, by consensus, for how CER could be used to improve the evidence base for patient-centered diabetes care in order to make results of future diabetes management studies more useful. The final recommendations are summarized here.

Limitations of the Evidence Base for Patient-Centered Diabetes Care

The working group highlighted 5 gaps in the evidence base for T2DM patient-centered care: (1) limited evidence on long-term and patient-reported outcomes; (2) the nonrepresentativeness of patient populations and clinical settings— particularly in clinical trials; (3) the dearth of systematic data on patient subgroups; (4) the insufficient attention paid to social, cultural, and economic factors that influence care; and (5) the comparatively few direct comparisons among alternative treatment strategies. We discuss each in turn.

Limited Evidence Regarding Long- Term and Patient-Reported Outcomes

The comparatively little evidence on long-term outcomes is striking: many outcomes important to clinicians and patients are not tracked or reported. The AHRQ review, for example, found insufficient evidence to conclude that alternative T2DM treatments result in improvements in total mortality, cardiovascular mortality or morbidity.6,7 No study in the AHRQ analysis addressed retinopathy. Only 3 studies evaluated neuropathy, and these had significant methodological flaws.6,7 The working group also noted a lack of postmarketing surveillance, which limits the likelihood of identifying adverse events. Another limitation of the available evidence identified by the working group is the comparatively little attention  paid to results that patients find most important, which we call “patientcentered outcomes.” The working group highlighted the importance of outcomes such as satisfaction with care, functional ability, and quality of life. Other outcomes that may be significant to patients include therapeutic side effects (such as weight gain and hypoglycemia), convenience, and cost. Patient- centered outcomes are important because they can influence adherence to care, among other things. Adherence is particularly challenging when patients may not fully believe in the value of the prescribed medications or if they find the regimens difficult to follow. To prevent long-term complications, diabetes care also often includes treating patients who are asymptomatic.

Nonrepresentativeness of Patient Populations and Clinical Settings

It is well understood that for purposes of methodological rigor, statistical power, and regulatory requirements, randomized controlled trials frequently are conducted with highly selective patient samples. For example, patients with a variety of comorbidities, poor  adherence, or limited access to healthcare often are ineligible for clinical trials. Yet these are the patients most likely to pose management challenges in a clinical setting. Among the 166 studies examined by AHRQ, information was insufficient on patients with varying levels of cardiovascular and renal risk, with comorbid conditions, and the elderly.7 Finally, few studies report the recruitment methods used, making it impossible to judge how representative the trial population is likely to be. For example, trials that recruit from large urban teaching hospitals might cover different patient populations than trials based in community clinics. In addition, trials that recruit through physicians might draw different patients than those recruiting using more direct methods to access patients. It is often difficult to know how these various approaches affect the sample-frame of the study.

There is also wide agreement regarding the comparative “artificiality” of clinical trial settings. In terms of a more specific gap in the evidence base for T2DM care, a concern raised by the working group is the vigilant monitoring, support, and follow-up patients receive in a clinical trial compared with the reality of the “real-world” setting, which may contribute to differences in the effectiveness of a given therapeutic intervention. Furthermore, few trials report the study settings, which makes it difficult to assess how the results apply to individual practices.7

Dearth of Systematic Data on Patient Subgroups

Clinical trial participants always vary in terms of demographics, comorbidities, disease states, and other potentially significant dimensions. When the variation in treatment response is substantial in a trial, the overall result might not be applicable to all enrolled patients. Yet trials often are not large enough to permit meaningful analyses of subgroups.8

Pooling data from subgroup analyses is one way to overcome this limitation.9 Such research underscores the importance of assessing and reporting results of therapies in clinically important subgroups, in part to enable pooling of subgroup results from different studies.

Increasingly, large health plan databases allow for rudimentary comparisons of outcomes and costs.10-12 These analyses can serve as hypothesis-generating tools for more detailed economic and clinical analyses of best practices for patient care. For example, Onur and colleagues used a large commercial US healthcare data source to study the effectiveness of adding rapid-acting insulin to basal insulin therapy (with or without concomitant oral agent therapy).13 Both overall and diabetes-related healthcare costs were reduced. These results suggest that rapid-acting insulin in this population can improve glycemia and perhaps health, but meaningful numbers are small, rates of hypoglycemia unknown, and optimal patterns for dosing and administering rapid-acting insulin unknown.

Insufficient Attention Paid to Social, Cultural, and Economic Factors That Influence Care

Differences in education, patient-physician relationships, income, and cultural norms can all influence patient management, but are not often addressed in RCTs or observational studies. Treatment plans, for example, must account for such cultural and social factors as food insecurity, economic hardship, or even the celebratory role of food in many cultures. Beliefs about alternative approaches to health (use of herbal products and supplements) also should be considered.

Comparatively Few Direct Comparisons Among Alternative Treatment Strategies

Finally, the working group noted that, in view of the vast number of treatment alternatives now available, there are a number of important comparisons among alternative treatments that have not been systematically examined to date.7 For example, there are few good studies of comparative effectiveness and safety of 2 drug combinations or of monotherapy and combination therapy involving meglitinides, dipeptidyl peptidase- 4 (DPP-IV) inhibitors, and glucagon- like peptide-1 agonists with other first-line diabetes medications. There are also few comparisons with a basal or premixed insulin added to metformin or thiazolidinediones.7 The absence of some key treatment comparisons limits the ability of clinicians to determine the best treatment alternative for patients and to provide patient-centered care. However, the working group recognized that even if head-to-head trials were available, care for specific patients must be individualized.

Key Recommendations

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