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The GLP-1 agonist liraglutide (Victoza, Novo Nordisk) was the overall winner compared with three other diverse agents for treating patients with type 2 diabetes already maintained on metformin.

But while liraglutide performed better than insulin glargine, doxycycline effects in dogs sitagliptin, and glimepiride, the randomized, multicenter study of 5047 patients fell short of being the last word.

In part, that’s because the study was devoid of a drug from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, as those agents were not on the US market in 2013, when the trial began.

Results of the 5-year GRADE trial in people with type 2 diabetes already taking metformin, which was funded by the US government, were first reported at the American Diabetes Association (ADA) 81st Scientific Sessions and were published online September 21 in The New England Journal of Medicine.

The study “presents a clear and objective comparison of the advantages and disadvantages of four commonly used glucose-lowering medications,” write GRADE Study Chair David M. Nathan, MD, a professor at Harvard University and director of the Diabetes Clinical Center of Massachusetts General Hospital in Boston, and colleagues.

“These findings should help guide the choice of medications used in the treatment of type 2 diabetes,” they say.

However, the absence of an SGLT2 inhibitor in the GRADE treatment mix is a “major limitation” of the study, comment Lars Rydén, MD, and Eberhard Standl, MD, PhD, in an accompanying editorial.

Insulin and Liraglutide Cut Metabolic Failure

The trial’s primary endpoint was glycemic control, specifically the rate of on-treatment “metabolic failure,” defined as an A1c value that rose to 7.0% or higher and was confirmed at that level 3 months later.

The results showed both insulin glargine (Lantus) (dosed as needed to avoid hypoglycemia) and the GLP-1 agonist liraglutide (Victoza) (dosed to a maximum 1.8 mg/day) performed about the same and were each superior compared with the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia) (maximum dose 100 mg/day) and the sulfonylurea glimepiride (Amaryl) (maximum dose 8 mg/day).

The rate of confirmed metabolic failure was significantly reduced by 13% with insulin glargine and by 16% with liraglutide compared with the other regimens. Further statistical analysis showed no significant difference in the efficacy of insulin glargine and liraglutide.

In a second publication, the authors also report the results of secondary outcomes, including microvascular (hypertension, dyslipidemia, albuminuria, kidney function, and diabetic peripheral neuropathy) and cardiovascular (cardiovascular death, myocardial infarction, stroke, and hospitalization for heart failure).

These results showed “no material differences in any of the microvascular complications evaluated,” the authors write. But for the endpoint of any cardiovascular disease, liraglutide significantly outperformed the other three agents, reducing the relative hazard ratio by 29%.

Helping Docs Decide Which Drug Is Best for Which Patient

“With many treatment options available for type 2 diabetes, healthcare providers and patients can find it difficult to know which drug is best for which person,” commented Griffin P. Rodgers, MD, director of the US National Institute of Diabetes and Digestive and Kidney Diseases, which funded the trial.

Studies such as GRADE “help providers make evidence-based recommendations that lead to better health for their patients and for all people living with type 2 diabetes,” Rodgers said in a written statement.

In their editorial, Rydén and Standl say another limitation of GRADE is the low risk of severe hypoglycemia in enrolled patients. They also note the study design did not take into account “the concept of subtypes of type 2 diabetes” that could affect differential risks for cardiovascular and microvascular outcomes.

Despite these concerns, Rydén, a professor at the Karolinska Institute in Stockholm, Sweden, and Standl, a professor and endocrinologist at the Helmholtz Center in Munich, Germany, conclude that the GRADE results “provide support for the notion that GLP-1 agonists have a primary preventive effect” for cardiovascular events, and that early used of this class of agents “may be worth considering” for the treatment of people with type 2 diabetes.

But Rydén and Standl blunt this apparent endorsement of liraglutide and the pricey GLP-1 agonists based on the GRADE findings with a caveat.

“The data confirm that older generic or biosimilar low-cost agents will have a role in the treatment of persons with early type 2 diabetes who are at low cardiovascular risk,” and hence, because of their low risk may not need the extra cardiovascular protection demonstrated by liraglutide in GRADE.

“GRADE effectively shows which drugs worked best at achieving and maintaining blood glucose targets over time, but we need to establish even more effective strategies for the long-term maintenance of acceptable glucose levels,” summed up Nathan in a written statement.

“We still have more work to do, such as evaluating other interventions and treatment combinations,” he cautioned.

GRADE received no commercial funding. Nathan and Rodgers have reported no relevant financial relationships. Rydén has reported being a consultant for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Standl has reported being a speaker on behalf of Boehringer Ingelheim, Menarini, and Novo Nordisk.

N Engl J Med. 2022;387:1063-74; 1075-88; 1136-8.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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