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Jonas D, Van Scoyoc E, Gerrald K, et al. Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Feb.

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Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report [Internet].

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Introduction

Diabetes mellitus (diabetes) is a chronic and insidious disease affecting more than 23 million Americans, about 8% of the population.1 Of those diagnosed, 90% to 95% have type 2 diabetes, while 5% to 10% have type 1 diabetes. Type 1 diabetes is characterized by autoimmune destruction of beta cells of the pancreas resulting in absolute insulin deficiency. Type 2 diabetes encompasses a heterogeneous group of disorders characterized by slow progressive loss of beta cell function and mass leading to variable degrees of insulin resistance, impaired insulin secretion, and increased hepatic glucose production. Higher glucagon levels relative to insulin also plays a significant role in the pathogenesis and management of type 2 diabetes.

The 2010 American Diabetes Association treatment guidelines recommend a hemoglobin A1c (HbA1c) goal of <7% in nonpregnant adults in order to prevent adverse microvascular outcomes.2 The guidelines acknowledge that less stringent goals may be appropriate for certain populations. Insulin is the standard treatment for type 1 diabetes. Pharmacologic options for type 2 diabetes include sulfonylureas, biguanides, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs, combination products, and insulin. Because of the progressive nature of diabetes, practitioners and patients often experience challenges in reaching and sustaining American Diabetes Association goals. In fact, it is estimated that more than 50% of persons with type 2 diabetes will require more than one oral hypoglycemic agent after 3 years of diagnosis and approximately 70% will require combination oral therapy with or without insulin 6 to 9 years from diagnosis.3

Newer Diabetes Medications

Within recent years, several new antihyperglycemic agents have been approved: pramlintide, exenatide, liraglutide, sitagliptin, and saxagliptin (Table 1). These agents offer mechanisms of glycemic control beyond that of “traditional” oral agents and insulin by targeting alternate gluco-regulatory receptors and hormones such as amylin, GLP-1, glucose-dependent insulinotropic peptide (GIP), and DPP-4. For the purposes of this report, we consider the following to be “newer diabetes medications”: amylin agonists, DPP-4 inhibitors, and GLP-1 agonists. Amylin is a neuroendocrine hormone co-secreted with insulin from beta cells in response to elevated blood glucose concentrations and complements the actions of insulin. GLP-1 and GIP are secreted by L-and K-type cells in the intestinal tract in response to a combination of endocrine and neural signals initiated by the entry of food into the gut. Secretion of GLP-1 and GIP enhance insulin release. Both endogenous GLP-1 and GIP are rapidly degraded by the proteolytic enzyme DPP-4.

Table 1. Characteristics of included drugs.

Table 1

Characteristics of included drugs.

Thiazolidinediones

There are 2 thiazolidinediones approved for prescription use in the United States and Canada, rosiglitazone maleate (Avandia®), which has restrictions on its use described below, and pioglitazone hydrochloride (Actos®) (Table 1). A third thiazolidinedione (troglitazone) was removed from the market in 1999 due to adverse hepatic effects. Pioglitazone is approved in the United States and Canada for use in adults for the treatment of type 2 diabetes, either as monotherapy or in combination with insulin, metformin, or sulfonylurea when diet, exercise, and a single agent does not result in adequate glycemic control. In September 2010, the US Food and Drug Administration (FDA) restricted access for rosiglitazone (Avandia®) and combination products that contain rosiglitazone due to an increased risk of cardiovascular adverse events. The FDA required that GlaxoSmithKline develop a restricted access program for rosiglitazone under a risk evaluation and mitigation strategy, or REMS.4 Under the REMS, rosiglitazone will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other drug in this class. Current users of rosiglitazone who are benefiting from the drug will be able to continue using the medication if they choose to do so. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. Health Canada has added similar restrictions for rosiglitazone, which is now only indicated in patients with type 2 diabetes where other medications are either inappropriate (due to intolerance or to contraindications) or do not result in adequate glycemic control (as monotherapy or in combination).5 Prior to initiation of rosiglitazone, there must be adequate documentation that the patient meets the eligibility criteria for rosiglitazone treatment, patients must be counseled on the risks (including cardiovascular) of treatment with rosiglitazone, and have written informed consent from the patient for treatment with rosiglitazone. Additionally, the Canadian Product Monographs for rosiglitazone and combination products containing rosiglitazone have been updated to reflect the restrictions and new boxed warnings have been added. Boxed warnings for all included medications are in Appendix A.

The mechanisms of action of thiazolidinediones in lowering plasma glucose among persons with type 2 diabetes are thought to include the following: increase in insulin sensitivity, decrease endogenous glucose production and postprandial gluconeogenesis, increase fasting and postprandial glucose clearance, and have beneficial effects on beta-cell function.6 The glycemic effects of thiazolidinediones are thought to be mediated by binding to the peroxisome proliferators-activated receptor (PPAR) gamma receptors. These receptors are expressed in the liver, heart, adipose tissue, skeletal muscle, and smooth muscle, and endothelial cells of the vasculature of the kidneys and the gut.7

Dual therapy and Fixed-dose Combination Products

For this report, we’ve included 5 fixed-dose combination products (FDCPs) approved for the treatment of type 2 diabetes. These include 2 products that combine metformin with a thiazolidinedione, 2 that combine a sulfonylurea with a thiazolidinedione, and 1 that combines metformin with a DPP-4 inhibitor (Table 1). In addition to the 5 FDCPs, we’ve included studies of the individual components of those FDCPs when used together but in separate pills—we refer to this as “dual therapy” throughout the review.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix B and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. In addition, efficacy studies frequently exclude patients who have comorbid disease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures. Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of study results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The goal of this report is to compare the effectiveness and adverse event profiles of newer medications, TZDs, and combinations (Table 1) in the treatment of diabetes. The RTI-UNC Evidence-based Practice Center developed preliminary key questions to identify the populations, interventions, outcomes of interest, and eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project website for public comment. A group of clinicians specializing in treating patients with diabetes were consulted for clinical insight into the proposed key questions. The draft was reviewed and revised by representatives of the organizations participating in the Drug Effectiveness Review Project. Revision took into consideration input from the public and from clinical advisors and the organizations’ desire for the key questions to reflect populations, drugs, and outcome measures of interest to clinicians and patients. These organizations approved the following key questions to guide the review for this report:

  1. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus?
  2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus?
  3. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions, obesity), or other medications (drug-drug interactions) for which newer diabetes medications, TZDs, and drug combinations (administered as combination products or dual therapy) differ in efficacy/effectiveness or frequency of adverse events?

The majority of this report focuses on type 2 diabetes mellitus. Studies enrolling subjects with type 1 diabetes are only included for one of the medications, pramlintide. Further details of the inclusion/exclusion criteria used to answer these key questions, including specific populations, interventions, comparisons, outcomes, and study designs, are provided in the methods section of this report.

Copyright © 2011, Oregon Health & Science University.
Bookshelf ID: NBK54205
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