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GLP-1 RA, Insulin Glargine Outperform DPP-4 Inhibitors and Sulfonyulreas in GRADE Study

Results of the GRADE Study suggest use of GLP-1 receptor agonists and insulin glargine U-100 outperformed sulfonylureas and DPP-4 inhibitors for glycemic control in people with type 2 diabetes.

Results of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded study, which compared the 4 aforementioned classes as add-ons to metformin, indicate use of liraglutide and insulin glargine were associated with a greater ability to help achieve and maintain target glycemic control in people with type 2 diabetes, but no material differences were observed for incidence of microvascular complications or death.

“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” said Henry Burch, MD, NIDDK’s project scientist for GRADE, in a statement. “This is an integral step toward precision medicine for diabetes care, as these results can now be used in the decision-making process for each individual patient in light of their levels of glucose control, how well the medications are tolerated, and the person’s other health considerations.”

Launched in 2013, the Glycemic Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study was created with the intent of comparing 4 medications approved by the FDA at the time as add-ons to metformin for improving glycemic control and reducing risk of adverse outcomes. multicenter, parallel-group, comparative effectiveness clinical trial conducted in 36 medical centers in the US, the study followed 5047 participants diagnosed with type 2 diabetes at or after the age of 30 years for a mean of 5.0 years.

Those identified for inclusion were randomized to sitagliptin, liraglutide, glimepiride, or insulin glargine U-100 as add-on therapies to metformin. Overall, the 5047 participants identified for inclusion had a mean age of 57.2±10.0 years, 63.6% were men, and 65.7% identified as White. The mean duration of diabetes at stud entry was 4.2±2.7 years, the mean BMI was 34.3±6.8 kg/m2, and the mean HbA1c was 7.5±0.5%. A total of 1263 received insulin glargine, 1254 received glimepiride, 1262 received liraglutide, and 1268 received sitagliptin. Investigators pointed out thiazolidinediones were not included as a result of safety concerns at the time and SGLT2 inhibitors were not included as they had not yet been approved.

The primary glycemic outcome of interest was achieving an HbA1c of 7.0% or higher and the secondary glycemic outcome of interest was a confirmed HbA1c greater than 7.5%. The GRADE Study Research Group also conducted analyses assessing microvascular and cardiovascular outcomes. Outcomes of interest related to these analyses included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml/min/1.73m2 , diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, major adverse cardiovascular events, and death.

Upon analysis, results suggested there with significant differences in the cumulative incidence of HbA1c levels of 7.0% or greater between the study arms (P <.001). Incidence rates per 100 patient-years were 26.1, 26.5, 30.4, and 38.1 for liraglutide, insulin glargine, glimepiride, and sitagliptin, respectively. Further analyses indicated these trends persisted when examining the secondary outcome of incidence of an HbA1c level greater than 7.5%. Investigators pointed out no material difference were observed with respect to the primary outcome based on sex, age, or racial/ethnic group.

When examining risk of microvascular and cardiovascular outcomes, results suggested there were no material differences observed for the study’s interventions for the development of hypertension, dyslipidemia, or microvascular outcomes. Investigators noted there was no significant differences in risk of MACE, hospitalization for heart failure, cardiovascular death, or all-cause mortality based on study arm. Investigators highlighted small differences were observed for the rate of cardiovascular disease, with rates of 1.9, 1.9, 1.4, and 2.0 per 100 patient-years in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively.

“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,” said GRADE study chair David M. Nathan, MD, director of the Massachusetts General Hospital Diabetes Center, Boston, in the aforementioned statement. “We still have more work to do, such as evaluating other interventions and treatment combinations to help people with type 2 diabetes achieve long-term glucose control.”

These studies, “Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes” and “Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes,” were published in the New England Journal of Medicine.