In 2012, the American Diabetes Association and the European Association for the Study of Diabetes published a position statement on the management of hyperglycemia in patients with type 2 diabetes. “This was needed because of an increasing array of anti-hyperglycemic drugs and growing uncertainty regarding their proper selection and sequence,” says Silvio E. Inzucchi, MD. “However, the 2012 document was less prescriptive than prior consensus reports because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications.”

Recently, the American Diabetes Association and the European Association for the Study of Diabetes requested an update to the position statement that incorporates new data from recent clinical trials. Dr. Inzucchi, who served as co-chair to the 2015 update, notes that the writing group focused on areas where revisions were suggested by a changing evidence base rather than developing an entirely new position statement. He adds that the most recent position statement should be viewed as an addendum to the previous full account that was released in 2012.

A Patient-Centered Approach

Previous position statements have recommended individualizing treatment targets and strategies when managing type 2 diabetes. According to the update, patient-centered care and shared decision making continue to be a focus for the management of hyperglycemia in type 2 diabetes. “Glycemic targets should be personalized based on a variety of factors.” says Dr. Inzucchi. These include those that are potentially modifiable factors, such as patient attitudes, resources and support systems, and those are usually non-modifiable factors, such as disease duration, life expectancy, prevalent comorbidities, and established vascular complications. Personalization is necessary to balance the benefits of glycemic control with its potential risks. The adverse effects of glucose-lowering medications—particularly hypoglycemia—must be taken into account, along with the patient’s age and health status, among other factors.

Guidance on Drug Therapy

The position statement notes that treatment for most patients with type 2 diabetes should begin with lifestyle changes and patient education, with metformin monotherapy being added at diagnosis or soon thereafter unless contraindicated. “If the A1C target is not achieved after about 3 months, clinicians should consider one of the six treatment options combined with metformin,” Dr. Inzucchi says. These agents include a sulfonylurea, a thiazolidinedione (most notably pioglitazone), a dipeptidyl pepidase 4 (DPP-4) inhibitor, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a glucagon-like peptide 1 (GLP-1) receptor agonist, or basal insulin.

“The position statement provides clinicians with the pros and cons of using the six classes of drugs that we have at our disposal based on current evidence,” says Dr. Inzucchi (Figure). “Newer therapies like SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists have different mechanisms of action and should be considered for use at various stages of type 2 diabetes depending on patient, disease, and drug characteristics. Ultimately, the goal of the position statement is to help clinicians reduce glucose concentrations while minimizing side effects, especially hypoglycemia.” According to the update, the newest class, the SGLT2 inhibitors, are now endorsed as second-line therapy. These drugs are somewhat unique in that they may be used at any stage of disease, given that their mechanism of action—to induce glucosuria—is entirely independent of insulin secretory capacity. Earlier concerns that thiazolidinediones may increase the risk of bladder cancer have been allayed by subsequent research, and pioglitazone is now available as a generic drug at a substantially lower cost.

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The position paper notes that, in light of recent evidence from a large clinical trial which implicated the DPP4 inhibitor saxagliptin in increasing heart failure hospitalization rates, this class of glucose-lowering drugs should be used cautiously, if at all, in patients with preexisting heart failure until more safety information becomes available. Basal insulin should be considered in patients who are unable to achieve target glucose levels taking three anti-glycemic agents. The statement also underscored the emerging role of basal insulin plus a GLP-1 receptor agonist. This combination might be considered over the addition of prandial insulin due to equal or even slightly superior efficacy as well as weight loss and lower risk of hypoglycemia.

Other Considerations

The position paper emphasizes the importance of taking into account comorbidities that are frequently encountered in patients with type 2 diabetes in order to optimize treatment strategies. Common comorbidities include coronary artery disease, heart failure, renal and liver disease, dementia, and an increasing propensity to develop hypoglycemia. “Importantly, clinicians should consider the costs and complexity of multiple combination therapies,” adds Dr. Inzucchi. “We should always consider whether less costly generic products could be used.”

More long-term data are anticipated regarding the cardiovascular impact of glucose-lowering therapies over the next few years, and Dr. Inzucchi says this information will further assist clinicians in optimizing care. “We need studies that might provide better guidance for physicians on what to do after initiating lifestyle interventions and metformin. As we conduct more head-to-head drug comparisons and cost analyses with new drug options, there is hope that we’ll be able to improve our efforts to personalize diabetes care and enhance long-term treatment outcomes.”