Achieving specific glycemic goals is widely recognized as a means of substantially reducing morbidity in type 2 diabetes. As such, the effective treatment of hyperglycemia is the foundation of treatment strategies. The expansion of available glucose-lowering medications developed to supplement traditional therapies (eg, insulin, sulfonylureas, and metformin) has increased the number of treatment options available to manage this condition. This magnifies an already challenging undertaking for physicians who are trying to determine the most appropriate treatment route.
A consensus statement by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) was developed to help guide healthcare providers in choosing the safest and most appropriate interventions in the management of hyperglycemia. Originally published in the August 2006 issue of Diabetes Care, the consensus statement has since been updated twice based on the availability of new interventions and compelling evidence to establish their clinical role in diabetes management. In January 2008, an update to the algorithm was released, specifically addressing safety concerns of thiazolidinediones (TZDs). The most recent update, published in the January 2009 issue of Diabetes Care, includes further data on TZDs and also highlights new classes of medications for which more clinical data and wider experience are now available.
“Diabetes is the largest epidemic worldwide,” says David M. Nathan, MD, lead author on the consensus statement, “and emerging drugs and treatment continue to cause uncertainty among clinicians as they determine how to manage the metabolic aspects of the disease. Addressing such uncertainty was the genesis of our consensus algorithm. The statement is based on best available data on the effectiveness of lowering A1C and considers safety, tolerability, patient acceptance, and the cost of interventions. It’s intended to be a practical guideline for practicing physicians.”
Modifying the Consensus Algorithm
In the latest iteration of the guidelines, the consensus algorithm for the medical management of type 2 diabetes was simplified (Figure). “The tier 1 algorithm consists of well-validated core therapies, which are preferred for most patients with type 2 diabetes,” says Dr. Nathan. “Interestingly, metformin, sulfonylureas, and insulin—the most established and cost-effective drugs—have also been shown to be the most effective medications to achieve glycemic targets.”
In tier 1, metformin is recommended as the initial pharmacologic therapy to be added to lifestyle interventions at the time of diagnosis due to its: effect on glycemia; absence of weight gain or hypoglycemia; tolerability; and cost-effectiveness (Table). The statement recommends that metformin be titrated, as tolerated, to its maximally effective dose at 1 to 2 months. In the event that this combination does not achieve and sustain glycemic goals, ADA and EASD experts recommend that insulin or sulfonylureas be added within 2 to 3 months of initiation of therapy. TZDs are no longer recommended as a treatment option at this stage and have been demoted to tier 2 to (“less well validated therapies”) where the use of glucagon-like peptide-1 (GLP-1) agonist may also be found. The downgrading of pioglitazone (rosiglitazone is no longer recommended) is primarily due to the increasing data that TZDs may potentially cause fluid retention and congestive heart failure, as well as bone loss and osteoporosis.
The tier 2 algorithm consists of less well-validated therapies that should be considered in selected clinical settings. “Tier 2 was primarily developed because we acknowledged that there are patients with hazardous jobs, such as policemen and bus drivers, for whom hypoglycemia is particularly dangerous,” explains Dr. Nathan. “For such patients, physicians needed alternate treatment options that don’t cause hypoglycemia, a potential side effect of both insulin and sulfonylureas. In these patients, adding a GLP-1 agonist or TZD to metformin is recommended.”
More Research & Experience Required
The amylin agonists, α-glucosidase inhibitors, glinides, and dipeptidyl peptidase-4 inhibitors are not included in the two tiers of preferred agents in the algorithm. This decision was based on their lower or equivalent overall glucose-lowering effectiveness compared with the first- and second-tier agents and/or to their limited clinical data or relative expense. Additionally, many are not well tolerated due to gastrointestinal symptoms. However, the authors do state that these interventions may be appropriate choices in selected patients.
“The long-term consequences of type 2 diabetes can be extensive for patients and their caregivers as well as create significant economic costs,” says Dr. Nathan. “Much of the morbidity associated with long-term microvascular and neuropathic complications can be considerably reduced by interventions that achieve target glucose levels. Our hope is that our consensus statement will help guide physicians managing what is a very complicated chronic disease to reach that goal.”
David M. Nathan, MD, has indicated to Physician’s Weekly that he has received research grants for investigator-initiated research from Sanofi-Aventis.
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