A recent study showed that taking exenatide twice daily was associated with a lower risk for cardiovascular disease (CVD) events and hospitalizations compared with exenatide once monthly, liraglutide or lixisenatide.3

In the study, the researchers looked at 39,275 patients with type 2 diabetes treated with exenatide twice daily and 381,218 treated with other glucose-lowering therapies. The study indicated that patients treated with exenatide were less likely to have a CVD event than patients treated with other therapies. Those treated with exenatide also had lower rates of CVD-related hospitalization and all-cause hospitalization.2


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A separate study also suggested that a significant reduction in CVD risk factors offers a strong rationale for incorporating a GLP-1 agonist early in the management of type 2 diabetes in patients at risk for CVD.3 The researchers found that identifying the optimal candidates for GLP-1 therapy should be based on glycemic control, medical comorbidities and the presence of CVD risk factors.

They also theorize that GLP-1 agonist therapy may have a role in patients with prediabetes and CVD risk factors.3

SGLT2 Inhibitors

Currently, there are three SGLT2 inhibitors — dapagliflozin (Farxiga), canagliflozin (Invokana) and empagliflozin (Jardiance) — approved by the FDA in the United States and at least five others in clinical development (ipragliflozin, tofogliflozin, remogliflozin etabonate, and ertugliflozin). 

These agents prevent the reabsorption of glucose from the kidneys back into the blood. This leads to increased glucose in the urine and reduced glucose levels in the blood.

A study published in The Lancet Diabetes & Endocrinology suggests that empagliflozin might be an effective and a well-tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycemic control on metformin.4

In this study, investigators compared the efficacy and safety of empagliflozin with the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. The study included 1,549 patients who were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780). 

The researchers found that empagliflozin was noninferior to glimepiride and both were similar in terms of adverse events. However, empagliflozin was associated with significantly fewer hypoglycemic events, as compared with glimepiride (2% vs. 24%).

“Depending on the patient and depending on the coverage by the third party payer, there may be one or more drugs that may be better for an individual. They all engender weight loss, but some do a little bit better than others. The side effect profiles are similar in general. The main side effect is nausea and some drugs are better than others, but what I found is that some patients can tolerate some agents better than other,” said Past-President of the Endocrine Society Robert Vigersky, MD, who is the Director at the Diabetes Institute at Walter Reed National Military Medical Center in Bethesda, Maryland.

He said there have not been a lot of head-to-head trials, and no particular agent has stood out as an optimal second-line therapy after metformin. Moreover, real-world results vary as well, with Dr. Vigersky saying he sees patients who respond to one medication but not to another.

DPP-4 Inhibitors

DPP-4 inhibitors block the breakdown of GLP-1 and increase the incretin effect in patients with type 2 diabetes. They have been associated with significant reductions in HbA1c levels and no weight gain, according to Dr. Vigersky.

“The DPP-4 inhibitors all tend to work about the same. They don’t engender any hypoglycemia,” Dr. Vigersky told Endocrinology Advisor. “In terms of side effect profile, these drugs are quite well tolerated and they seem to work better in older individuals than younger individuals, although we don’t know why that is.”

Another factor to consider when selecting which agent to use is quality of life, according to Past-President of the American Heart Association (AHA), Robert Eckel, MD. Some agents are longer acting and therefore require fewer treatments while others combine two medications into one pill, which simplifies treatment regimens. These are key issues in determining which agent may be best as second-line therapy for a particular patient.