New Data Emerges for Managing Type 2 Diabetes

Volume 20, Issue 1

When it comes to therapies for type 2 diabetes, metformin has remained the preferred first-line therapy for over a decade. This reflects the relatively favorable side effect profile for this agent vs other oral therapies, as well as its efficacy in lowering A1c.

When considering add-on therapy to metformin, the SGLT2 inhibitors have quickly established the class as a preferred second-line therapy for any patient with cardiometabolic risk factors. Liraglutide and other GLP-1 agonists have also set that class apart from other oral agents with respect to lowering the risk of major adverse cardiovascular events in patients with type 2 diabetes.

Aside from these two classes, the remaining options for add-on therapy to metformin have not been systematically evaluated. In this week’s issue of Talking Therapeutics, we explore two new papers published in The New England Journal of Medicine which shed light on the additive value of four different drug therapies to metformin in patients with type 2 diabetes.

Point 1: Parenteral Therapy Preferred for Additional Glucose Lowering

The first iteration of the GRADE trial randomized patients with type 2 diabetes, who were receiving metformin and had glycated hemoglobin levels of 6.8% to 8.5%, to receive insulin glargine, glimepiride, liraglutide, or sitagliptin. Overall, the trial showed that glargine and liraglutide were modestly more effective than glimepiride and sitagliptin at lowering A1c. Glimepiride had the highest rates of hypoglycemia, followed by insulin glargine, liraglutide, and sitagliptin. Patients on liraglutide reported the most weight loss.

Overall, the findings of this trial support the use of liraglutide as the preferred second-line agent amongst those studied, based on the combined efficacy and safety data for this trial.

Point 2: No Clear Winner for Hard Endpoints

Glycosylated hemoglobin is an important endpoint, but it’s still a surrogate endpoint. In the follow-up GRADE analysis, the authors looked at rates of hypertension, dyslipidemia, increased albuminuria or an estimated glomerular filtration rate of less than 60 mL/min, diabetic peripheral neuropathy, cardiovascular events, hospitalization for heart failure, and death.

Overall, the trial failed to identify a significant difference in rates of meaningful clinical endpoints between any of the four therapies. These findings are not unexpected given the modest reductions in A1c noted between the four drugs.

In the end, this trial leaves me convinced that the SGLT2 inhibitors are the only second-line therapy for most patients with type 2 diabetes, with all of the other agents a distant third.