The study was launched the same month as the first US approval of a sodium-glucose co-transporter 2 inhibitor, and the failure to include a drug from this class was viewed by a commentator as a weakness of GRADE.
With so many choices in type 2 diabetes (T2D) care, the question in recent years has been: After metformin, what’s next?
If maintaining glycated hemoglobin (A1C) levels over time is the primary consideration, then the best options are liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), or insulin, a mainstay of diabetes care that has seen many evolutions since its discovery 100 years ago.
Those are the preliminary findings of GRADE (Glycemia Reduction Approaches in Diabetes: a comparative effectiveness study), funded by the National Institutes of Health and presented late Monday during the 81st Scientific Sessions of the American Diabetes Association.
GRADE, conceived a decade ago as T2D incidence soared and more than a dozen new drugs had reached the market, had several strengths over earlier trials, starting with its head-to-head comparisons of T2D therapies from different classes. As lead study author David Nathan, MD, director of the Diabetes Center, Massachusetts General Hospital, and professor of medicine, Harvard Medical School, noted, there’s typically little incentive for industry to fund such trials, and thus, clinicians are left with little data to guide a precision medicine approach to diabetes care.
The trial also stands out for its duration and diversity. Patients were treated for an average of 5 years and a maximum of more than 7 years. The study population was 20% Black and 18% Latino—far more diverse than many industry-sponsored trials—and more reflective of how T2D disproportionately affects minority groups.
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” Nathan said in a statement. “We believe these results will provide value to both patients and their providers when deciding which medication is needed to meet their appropriate blood glucose target, and we are encouraged that these findings can be applied to a very diverse range of patients.”
“Comparative effectiveness trials like GRADE are essential in helping people make decisions about how to best manage and treat chronic diseases like type 2 diabetes,” Henry Burch, MD, project scientist for the study from the National Institute for Diabetes and Digestive and Kidney Diseases, added in the ADA statement. “NIH supports GRADE and studies like it to help people with type 2 diabetes make informed choices between medications based on individual patient needs and the characteristics of the medications.”
However, GRADE has some faults. Launched in 2013, it sought to compare several commonly used drug classes when combined with metformin: sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, insulin, and GLP-1 RAs. The study launched the same month as the first US approval of a sodium glucose co-transporter 2 (SGLT2) inhibitor; these drugs have become blockbusters and mainstays in clinical guidelines, not only for managing A1C but also preventing related cardiometabolic events, such as heart failure hospitalization and kidney failure. In fact, some experts call for using SGLT2 inhibitors and GLP-1 RAs together for the most at-risk patients, even skipping metformin altogether.
There was some consideration to adding an SGLT2 inhibitor to GRADE, but the idea was scrapped, a fact that commentator David Matthews, professor emeritus of the University of Oxford, viewed as an unfortunate gap.
As a Forbes commentator noted in 2013, the design of GRADE meant NIH spent millions to compare various T2D therapies’ primarily for their ability to control A1C—a question that by itself would no longer pass muster at the FDA, based on regulatory standards put in place after 2008. After the blockbuster glucose-lowering drug rosiglitazone was suspected of causing heart attacks, the FDA created a landmark guidance for cardiovascular outcomes trials. These large studies, intended to guarantee drug safety, have revealed how some therapeutic classes offer additional benefits and have permanently reshaped T2D care.
However, as investigator John B. Buse, MD, PhD, of the University of North Carolina presented, GRADE did gather data on cardiovascular events for each therapy, although only 91% of the events have been adjudicated; thus, the description of the results as “preliminary.”
Design and Results From GRADE
GRADE enrolled 5047 patients with T2D. Patients were at least 30 years old, with an average age of 57 years and an average disease duration of 4 years. Patients had A1C levels of at least 6.8% but not higher than 8.5%. Approximately 1250 patients were randomly assigned to each of 4 medications: a sulfonylurea, Amaryl (glimepiride); a DPP-4 inhibitor, Januvia (sitagliptin); Lantus (insulin glargine); and Victoza (liraglutide).
The study examined the ability of the medications, used with metformin, to keep A1C below the guideline-recommended level of 7%. The primary outcome was the time to the first A1C of 7% at a quarterly visit; a secondary outcome was the time to the first A1C of 7.5%. Protocols called for adding insulin if patients had sequential A1C readings of 7.5% or higher.
Results showed that liraglutide and insulin were most effective in controlling A1C:
A secondary end point examined which therapy allowed the highest share of patients to keep their A1C below 7.5%. Results showed insulin glargine allowed 61% to keep A1C below this level compared with 54% for liraglutide, 50% for glimepiride, and 45% for sitagliptin.
Results were similar for men and women, across age groups, and across major racial and ethnics groups. The one distinguishing factor in results was baseline A1C, according to the investigators.
Liraglutide offered the best weight loss benefits in addition to glycemic control, although it did cause nausea and vomiting, bloating, and diarrhea, which are known effects of the GLP-1 RA class. In GRADE, 60% taking liraglutide had these effects compared with 50% on average with the other drugs.
Buse, in presenting the cardiovascular data analyzed thus far, said liraglutide was associated with a lower risk of “any CVD,” a composite that includes major cardiovascular events, unstable angina, hospitalization for heart failure, transient ischemic attacks, and revascularization. Individual outcomes for these components only favor liraglutide, and drug-by-drug comparisons are not yet available.
Glimepiride was associated with a higher risk of low blood glucose than the other therapies.
The results will be published at a later date, and additional subgroup analyses are planned.