Metformin, Then What? More Findings From the GRADE Study

Anne L. Peters, MD


November 03, 2021

This transcript has been edited for clarity.

Hi. I'm Dr Anne Peters. Today, I'm going to give you some updates on the GRADE study.

Just to refresh your memory, the GRADE study was first presented at the American Diabetes Association (ADA) meetings in June, and those were the preliminary results. More of the final results were just presented at the European Association for the Study of Diabetes (EASD) meeting, and in about a month or so, we'll be able to read the final manuscript. The GRADE study was designed to determine the next best therapy to add to metformin when treating an individual with type 2 diabetes.

They took individuals with type 2 diabetes on metformin alone who weren't at target. The average A1c here wasn't all that high, starting out at 7.5%. These individuals were randomized to one of four treatments, including a sulfonylurea agent, which was glimepiride; a dipeptidyl peptidase 4 (DPP-4) inhibitor, sitagliptin; a glycoprotein 1 (GLP-1) receptor agonist, liraglutide; and insulin glargine. They then were followed, and the primary endpoint was how long it took for that combination therapy to fail. The definition of failing was an A1c ≥ 7%.

Then, if the A1c rose to > 7.5%, they were continued on what they were on, and basal insulin — insulin glargine — was added and then they were followed further. If the A1c kept going up, they were switched to a more intensive insulin regimen with rapid-acting pre-meal insulin, along with the basal insulin, and the additional drug — the drug that had been added to the metformin — was stopped and metformin was continued.

In terms of baseline characteristics, I already told you that the average A1c going into the study was 7.5%. The average age of the participants was 57 years, and the duration of diabetes was about 4 years. The average body mass index (BMI), as we see in studies of people with type 2 diabetes, was elevated, at 34.3 kg/m2.

In terms of that primary outcome of reaching an A1c level ≥ 7%, they reached that most quickly with sitagliptin. Overall, 77% of the people on sitagliptin reached that outcome, 72% on glimepiride, 67% on glargine, and 68% on liraglutide.

In terms of the time to that outcome, with sitagliptin it was 1.9 years; glimepiride was 2.2 years; glargine, 2.4 years; and liraglutide, 2.4 years. There were no differences in terms of age, sex, or racial or ethnic group. The injectables, liraglutide and glargine, were more effective in the individuals with the highest baseline A1c values.

There was a low rate of severe hypoglycemia, but as expected, there was a higher rate with glimepiride at 2.3% and insulin at 1.4% than with liraglutide and sitagliptin.

At the EASD meeting, the new data were on cardiovascular outcomes. These were participants at low risk for cardiovascular events. They were younger, with a mean age of 57 years, and a diabetes duration of only 4 years. Two thirds had hypertension, one third had a low-density lipoprotein (LDL) cholesterol level > 100 mg/dL, and only 6.5% had cardiovascular disease at baseline.

After an average of 5 years of follow-up, there was a significant difference in any cardiovascular disease; this included major adverse cardiovascular events (MACE), hospitalization for heart failure, unstable angina, transient ischemic attack (TIA), or revascularization among the four therapies.

Liraglutide demonstrated a significant risk reduction in any cardiovascular disease (CVD) compared with sitagliptin and glimepiride, but not compared with glargine. However, among the four treatments, there was no significant difference in MACE, which was myocardial infarction, stroke, or cardiovascular death.

There was also no difference in hospitalization, heart failure, cardiovascular death alone, or all-cause mortality, although liraglutide was associated with numerically fewer events for all outcomes. This did not show a robust benefit in terms of cardiovascular events comparing liraglutide and the other therapies, particularly compared with insulin glargine.

Overall, additional data from the results of the GRADE trial showed that there were significant differences by baseline A1c value. Medication noncompliance leading to discontinuation of therapy was highest with glimepiride and lowest for glargine, which I found interesting. There were no significant differences in microvascular complications, albuminuria, estimated glomerular filtration rate (eGFR), or distal sensory polyneuropathy. Finally, as I discussed, the rates of any CVD were lower with liraglutide, but looking at the individual components of that outcome, there really wasn't much in terms of a difference.

This has been Dr Anne Peters for Medscape. Thank you.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California (USC) Keck School of Medicine and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts, and three books, on diabetes, and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.

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