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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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Summary

Strength of Evidence (SOE)

Most of the evidence was limited to adult populations. Most of the included studies evaluated intermediate outcomes, such as HbA1c or weight. Very few studies reported health outcomes and few studies were longer than 6 months. For the amylin agonists, DPP-IV inhibitors, and GLP-1 agonists, we found no studies that focused on health outcomes as primary outcomes. Some studies of these drug classes reported some health outcomes such as all-cause mortality or number of people with macrovascular disease among secondary outcomes or adverse events, but overall evidence was generally insufficient to determine how medications in these classes compare with other treatments for their impact on health outcomes. Here we summarize some of the main comparative findings for the most commonly reported outcomes and the related strength of evidence (SOE). A more detailed summary of findings is presented in Table 71.

Table 71. Summary of the evidence by key question.

Table 71

Summary of the evidence by key question.

For the newer diabetes drugs (pramlintide, sitagliptin, saxagliptin, exenatide, and liraglutide), all of the included medications were efficacious for reducing HbA1c compared with placebo. For reduction in HbA1c, pramlintide was similar to rapid acting insulin analog when added to insulin glargine or detemir (low SOE); sitagliptin monotherapy was less efficacious than metformin or glipizide monotherapy (low SOE); sitagliptin was not significantly different than rosiglitazone when either was added to metformin (moderate SOE); and there was no comparative evidence for saxagliptin (insufficient SOE). One head-to-head trial comparing exenatide with liraglutide reported a slightly greater reduction in HbA1c with liraglutide (between group difference −0.33%, 95% CI −0.47 to −0.18, low SOE). For reduction in HbA1c, exenatide was similar to glibenclamide (low SOE), rosiglitazone (low SOE), and insulin (with both groups also receiving oral diabetes agents, moderate SOE). Liraglutide-treated subjects had greater reductions in HbA1c than subjects treated with glargine (low SOE), rosiglitazone (low SOE), or sitagliptin (low SOE), and similar or greater reductions than those treated with glimepiride (insufficient SOE).

For weight, pramlintide, exenatide, and liraglutide (doses of 1.2 or greater) appear to cause weight loss compared with placebo. Sitagliptin and saxagliptin are likely weight neutral. Most studies evaluating weight change were 6 months or less and it is uncertain whether weight loss is sustained long-term. Rates of hypoglycemia were lower with sitagliptin than with glipizide (moderate SOE), with liraglutide than exenatide (low SOE), and with liraglutide than glimepiride (high SOE). Hypoglycemia rates were similar to placebo for sitagliptin and saxagliptin (low SOE) and were similar between exenatide and insulin (moderate SOE). Rates of gastrointestinal side effects were higher with exenatide and liraglutide than with comparators.

For the TZDs, the available evidence indicates that pioglitazone and rosiglitazone are not statistically significantly different in their ability to reduce HbA1c (moderate SOE). Further, there were no significant differences in ability to reduce HbA1c between either TZD and sulfonylureas or metformin (moderate to high SOE). Both TZDs increase the risk of heart failure (high SOE), edema (high SOE), and fractures in women (moderate SOE). The risk of hypoglycemia is reduced with TZDs when compared with sulfonylureas; the risk is similar to the risk with metformin (high SOE). Both TZDs cause a similar degree of weight gain to that caused by sulfonylureas (moderate SOE). Although rosiglitazone now has restricted access due to an increased risk of cardiovascular adverse events, we found no evidence of increased all-cause mortality or cardiovascular mortality with pioglitazone; some studies suggest reduced risk of all-cause and cardiovascular mortality with pioglitazone (low SOE).

For the FDCPs, we found no head to head trials that compared HbA1c control between any 2 FDCPs (insufficient SOE). Therapy with Avandamet®, Avandaryl®, Actoplus Met®, or dual therapy with metformin and sitagliptin produced statistically significantly greater reductions in HbA1c compared to monotherapy with any of their respective components.

Limitations of this Report

As with other types of research, the limitations of this systematic review are important to recognize. These can be divided into 2 groups, those relating to applicability of the results (addressed below) and those relating to methodology within the scope of this review. Methodological limitations of the review within the defined scope included the exclusion of studies published in languages other than English and lack of a specific search for unpublished studies.

Unfortunately, for many drugs, there are few or no effectiveness studies and many efficacy studies. As a result, clinicians must make decisions about treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. An evidence report indicates whether or not there is evidence that drugs differ in their effects in various subgroups of patients, but it does 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 are decisions that must be informed by clinical judgment.

In the context of developing recommendations for practice, evidence reports are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of the intervention are based on strong evidence from clinical studies. By themselves, they do not tell you 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 not true. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policies. Additional criteria include acceptability to physicians or patients, the potential for unrecognized harms, the applicability of the evidence to practice, and consideration of equity and justice.

Applicability

The applicability of the results are limited by the scope of the Key Questions and inclusion criteria and by the applicability of the studies included. Many studies included narrowly defined populations of patients. Minorities, older patients, and the most seriously ill patients were often underrepresented.

Pramlintide: Applicability to General Populations with Type 1 Diabetes

The methods for recruiting study subjects were not reported in the included trials of pramlintide, and subjects likely represent a highly selected population: Primarily white, middle-aged men and women with mean baseline HbA1c ranging from 8.1% to 9.0% and diabetes of 16 to 21 years duration. None of the patients had significant cardiovascular or renal disease or problems with gastrointestinal motility. Data regarding baseline comorbidities, disease severity, and existing microvascular disease such as retinopathy or neuropathy were not reported. The population included highly motivated subjects who were willing to add 2 to 4 injections to their daily regimen and who rigorously self-monitored blood glucose over the course of the study. Study settings were not reported, but they were likely to have been outpatient clinics.

Pramlintide: Applicability to General Populations with Type 2 Diabetes

No included trial evaluated the effects of pramlintide in patients whose type 2 diabetes was inadequately managed on combination prandial and basal insulin therapy with or without oral agents. Two studies evaluated pramlintide in patients using fixed-dose insulin. One trial used flexible dosing for insulin glargine only and 1 compared pramlintide with flexible rapid acting insulin analog (RAIA; lispro, aspart, or glulisine) in addition to flexible basal insulin (glargine or detemir).22 Hence, results have limited applicability to the broader population using more commonly prescribed insulin regimens.

US Food and Drug Administration-approved dosage of pramlintide for type 2 diabetes includes initial therapy of 60 mcg/meal and maintenance therapy of 120 mcg/meal. Three trials examined the 120 mcg dosage.22, 24, 25 The third included trial was a dose-ranging study that did not use a 120 mcg dose but did include a 75 mcg dose which may be used in clinical practice.26

Overall, patients included in these 3 trials represent a highly selected population: mainly white, middle-aged men and women with mean baseline HbA1c between 8.2% and 9.3% and diabetes of 11–13 years’ duration. None of the patients had significant pulmonary, cardiovascular, renal, neurologic, or hematologic diseases or problems with gastrointestinal motility. The study populations probably included highly motivated subjects who desired to achieve optimal glycemic control through the additional 2–4 injections added to their usual regimens of insulin and oral hypoglycemic agent over 16–52 weeks of participation in a trial. Study setting also was not reported in any of the included trials; subjects likely were evaluated in outpatient clinics.

Sitagliptin and Saxagliptin: Applicability to General Diabetes Populations

Patients enrolled in the sitagliptin and saxagliptin trials represented a highly selected population: primarily white, middle-aged, obese adults with moderately elevated baseline HbA1c (< 9%) and diabetes for less than 10 years. These populations were further selected during long dose-stabilization and run-in periods, where only persons with > 75% adherence to placebo went on to randomization. Moreover, these trials did not provide much baseline information on comorbidities and other characteristics and laboratory values that would enable inference about the applicability of study findings to general diabetic populations. The available data appear to be limited to persons with diabetes without related comorbidities and who are highly motivated.

Exenatide: Applicability to General Diabetes Populations

The studies identified for this review are rather homogeneous, relatively small, and may be rather selected, thus applicability to broader diabetes populations may be limited. Study subjects were homogeneous across studies for age, sex, and baseline HbA1c in both the placebo- and active-control trials. Significant comorbidities were excluded in placebo-controlled studies reporting that characteristic69–71 and comorbidities were not mentioned in 3 of the 4 active-control trials.62, 64, 65

Most studies reported only the number of subjects randomized, and randomization occurred in all placebo-controlled trials after a run-in of injected placebo. In other words, the number of potential study subjects who did not tolerate twice daily injections and who were therefore not included in the study was usually not reported. Open label extension studies were of highly selected populations who completed the primary study and who volunteered to continue (or start if on placebo) exenatide.

Liraglutide: Applicability to General Diabetes Populations

The studies identified for this review are rather homogeneous, relatively small, and may be rather selected, thus applicability to broader diabetes populations may be limited. Study subjects were homogeneous across studies for age, sex, duration of diabetes, and baseline HbA1c in both the placebo- and active-control trials. Significant comorbidities were excluded in the placebo-controlled studies reporting that characteristic.

Studies Currently Being Conducted

We identified no trials in progress that would meet inclusion criteria for this review that would potentially change conclusions.

Copyright © 2011, Oregon Health & Science University.
Bookshelf ID: NBK54204
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