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Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations

Final Original Report

Drug Class Reviews

, MD, MPH, , MD, MPH, , PharmD, BCPS, , MPH, , MSPH, , MPH, and , MPH.

Portland (OR): Oregon Health & Science University; .

Structured Abstract


To compare the effectiveness and adverse event profiles of amylin agonists, DPP-4 inhibitors, incretin mimetics, TZDs, and certain combination products for people with type 2 diabetes and for people with type 1 diabetes for pramlintide only.

Data Sources:

To identify published studies, we searched MEDLINE, The Cochrane Library, Embase, International Pharmaceutical Abstracts, and reference lists of included studies through July 2010. We also requested dossiers of information from pharmaceutical manufacturers.

Review Methods:

Study selection, data abstraction, validity assessment, grading the strength of the evidence (SOE), and data synthesis were all carried out according to standard Drug Effectiveness Review Project methods.


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.

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.


All of the included medications were efficacious for reducing HbA1c and none of the newer medications appear to cause weight gain. Little data was available to evaluate the long-term effectiveness of the newer medications compared with more established treatments, limiting our ability to determine how to best incorporate newer medications into clinical practice.


Produced by RTI-UNC Evidence-based Practice Center, Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill. Tim Carey, M.D., M.P.H., Director.

Drug Effectiveness Review Project: Marian McDonagh, PharmD, Principal Investigator
Oregon Evidence-based Practice Center: Mark Helfand, MD, MPH, Director.

Acknowledgments: We thank Leah Williams, our publications editor, for putting this report into its present form for you to read. We also thank Patricia Thieda and Shannon Brode for assistance with data abstraction, Megan Van Noord for conducting literature searches, and Claire Baker for retrieval of articles and data entry.

We extend our appreciation to the clinical advisors listed below for their thoughtful advice and input during our research process.
Marshall Dahl, MD, University of British Columbia
Diane Elson, MD, University of Wisconsin, Madison.

Funding: The Drug Effectiveness Review Project, composed of 12 organizations including 11 state Medicaid agencies, and the Canadian Agency for Drugs and Technology in Health commissioned and funded this report. These organizations selected the topic of the report and had input into its Key Questions. The content and conclusions of the report were entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report.

Suggested citation:

Jonas D, Van Scoyoc E, Gerrald K, Wines R, Amick H, Runge T, Triplette M. Drug class review: Newer diabetes medications, TZDs, and combinations.

The purpose of Drug Effectiveness Review Project reports is to make available information regarding the comparative clinical effectiveness and harms of different drugs. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports.

Copyright © 2011, Oregon Health & Science University.
Bookshelf ID: NBK54209PMID: 21595121


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