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Researchers are launching a large-scale comparative effectiveness trial that will help determine which of the top type 2 diabetes drugs are best for glycemic control.
The aim of the GRADE trial (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is to help clinicians make the best clinical decisions when it comes to choosing from the "considerable armamentarium of glucose-lowering medications," David Nathan, MD, of Massachusetts General Hospital, and colleagues reported online in Diabetes Care.
"GRADE is designed to provide a comprehensive comparative effectiveness study that will help to determine how to treat type 2 diabetes," Nathan told ľֱ via email. "It will include not only metabolic outcomes, but other outcomes that are important to healthcare providers and especially to patients, such as adverse effects, tolerability, safety, and cost."
Nathan added that the study "will be long enough to be meaningful in a chronic disease such as type 2 diabetes" and also aims to identify individual patient factors "that are associated with response to and failure of medications with the goal of determining which approaches are likely to work best in which people."
Researchers have long cited a dearth of head-to-head-to-head comparative studies of all of the medications available for type 2 diabetes, which has led to challenges in developing treatment algorithms.
Some groups, in fact, have stepped away from specific algorithms for pharmacotherapy, including the latest guidance from the American Diabetes Association and the European Association for the Study of Diabetes.
The GRADE trial is a pragmatic, parallel-group, unmasked clinical trial that will enroll 5,000 patients who have been recently diagnosed with type 2 diabetes and have a glycated hemoglobin (HbA1c) of 6.8% to 8.5%. Researchers expect the trial to run for a mean observation period of nearly 5 years.
It will focus on four main classes of drugs as add-ons to metformin therapy: sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin. The researchers said these were selected from the 10 classes of available agents (aside from metformin) because they are the agents most commonly used in combination.
Thiazolidinediones (TZDs) were not included in the trial. The class has been plagued by various problems, including cardiovascular risks with rosiglitazone (Avandia) and bladder cancer risks with pioglitazone (Actos).
The primary outcome is the time to primary treatment failure, defined as an HbA1c of 7% or higher, with secondary outcomes including microalbuminuria and clinical cardiovascular disease.
Other long-term metabolic outcomes will include the need for the addition of basal insulin after reaching an HbA1c higher than 7.5% and the need to implement an intensive basal/bolus insulin regimen. The drugs will also be compared with respect to adverse effects, tolerability, quality of life, and cost-effectiveness, the researchers said.
"GRADE results should not only help practitioners to choose the medications that are the most appropriate with regard to metabolic control and patient-centered outcomes," they wrote, "but should also provide insights to allow individualization of treatment."
Disclosures
The GRADE study will be supported by the National Institute for Diabetes and Digestive and Kidney Diseases.
The researchers reported relationships with Abbott, Amylin, Andromeda, AstraZeneca, Bayhill Therapeutics, BD Research Labs, Boehringer Ingelheim, Bristol-Myers Squibb, Catabasis, Cebix, Diartis, Elcelyx, Eli Lilly, Exsulin, Genentech, GI Dynamics, GlaxoSmithKline, Halozyme, Hoffman-La Roche, Johnson & Johnson, LipoScience, Medtronic, Merck, Metabolic Solutions Development Company, Metabolon, Novan, Novella, Novartis, Novo Nordisk, Orexigen, Osiris, Pfizer, Rhythm, Sanofi, Spherix, Takeda, Tolerex, TransPharma, Ventas, Verva, Intarcia Therapeutics, Janssen, and Receptos.
Primary Source
Diabetes Care
Nathan DM, et al "Rationale and design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)" Diabetes Care 2013; DOI: 10.2337/dc13-0356.