Diabetes Drugs: Does Class Matter?

When a patient is diagnosed with type 2 diabetes, the American Diabetes Association (ADA) and other leading expert organizations recommend counseling on dietary modifications, increased physical activity and diabetes self-management education (DSME). If medical treatment is necessary, then metformin is usually the drug of choice for first-line therapy.

If a patient cannot meet treatment targets with metformin, diet and exercise, however, the question of what to do next is more complex.

Today, endocrinologists have a wide range of novel agents in their armamentarium. Recently approved agents belong to several different drug classes, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose transporter-2 (SGLT-2) inhibitors.

With all of these new agents, a clinical conundrum exists: Currently, there is no consensus on optimal second-line pharmacotherapy in patients with type 2 diabetes.

“The choice of which agent to prescribe is a matter of clinical judgment, experience, patient profile, tolerability, adverse effects, pre-existing conditions, local formulary and other factors. Physicians are encouraged to individualize the goals, intensity and therapeutic armamentarium based on patients’ characteristics, risk profile and informed preferences,” said ADA President-Elect, Samuel Dagogo-Jack, MD. 

Dr. Dagogo-Jack, who is also professor of medicine and the director of Endocrinology, Diabetes and Metabolism at the University of Tennessee Health Science Center in Memphis, said GLP-1 receptor agonists, SLGT-2 inhibitors and DPP-4 inhibitors differ in their chemistry, pharmacokinetics, pharmacodynamics and mechanisms of action. The agents are also different in terms of their tolerability profiles, routes of administration and costs.  

“Clinical differences also exist with regard to blood glucose efficacy, changes in body weight, blood pressure, adverse effects and other measures. The three classes share a low risk of hypoglycemia when agents are used in monotherapy,” Dr. Dagogo-Jack told Endocrinology Advisor.

Endocrinologist Howard Baum, MD, assistant professor of medicine and a specialist in the Division of Diabetes, Endocrinology and Metabolism at Vanderbilt University in Nashville, said clinicians today must rely on trial data that were used to get these various agents approved. But currently, there is a lack of scientific data to support a specific medication over another in determining a patient’s drug regimen after inadequate control with metformin.

“We certainly have more drugs than ever, but whether it is going to represent an advantage is truly not known yet. It is good to have new options, but whether it is a new era remains to be seen,” said Dr. Baum.

GLP-1 Agonists

At present, the FDA has approved four GLP-1 receptor agonists, including exenatide (Byetta, Bydureon), liraglutide (Victoza), dulaglutide (Trulicity) and albiglutide (Tanzeum).

Dr. Baum said researchers have compared exenatide with liraglutide and the findings were rather surprising.  The study suggested that once-daily liraglutide and once-weekly exenatide both led to improvements in glycemic control, but there were greater reductions with liraglutide.¹

“From the initial studies, it appeared that exenatide extended-release lowered HbA1c more than liraglutide. A head-to-head study, however, showed the opposite,” Dr. Baum said in an interview with Endocrinology Advisor.

“The interesting thing about this study is that the FDA-approved prescribing information would indicate that Bydureon is a more potent agent than Victoza, though this head-to-head study showed the opposite. This lets us know that we have to be careful about comparing the efficacy of different agents that are not studied head-to-head in the same trial.”

GLP-1 agonists help produce more insulin when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. These agents also reduce the rate at which the stomach digests foods and empties, thus reducing appetite.