What's Best for Diabetes After Metformin? GRADE Outdated at Outset

Mitchel L. Zoler, PhD

June 30, 2021

Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter US trial that randomized just over 5000 patients.

The GRADE trial ran for roughly 5 years at 36 US centers and was designed to answer the question of which is the best second-line agent for patients with type 2 diabetes already taking metformin. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions. 

The comparison included two oral medications — the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin — and two injectable medications — insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.

The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.

During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were lowest, at 67%, among patients randomized to insulin glargine, 68% for those maintained on liraglutide, 72% for patients taking the sulfonylurea glimepiride, and 77% in those taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University in Rockville, Maryland.

Too Soon for Take-Aways, or Are the Data Already Obsolete?

"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," noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.

Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.

"We undertook this study to fill a gap in the guidelines," said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. "I would like to have all the results in...before I comment on how the guidelines should change."

"The metabolic data are solid, but the cardiovascular disease data are preliminary," warned Nathan.

But that didn't stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.

"A pleasant surprise was the performance of basal insulin," he said, calling the findings "a vindication" for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.

Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. "Based on the results, guidelines should say that you add insulin early on," he observed.

A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Kahn, an endocrinologist and professor at the University of Washington in Seattle.

Rosenstock, director of the Dallas Diabetes Research Center in Texas, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.

The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it "is justifiable to put them on the same level as other agents?"

Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, UK — while congratulating the investigators on certain aspects of the study — said it ultimately fell short because it didn't include an arm with an SGLT2 inhibitor.

"We should kick the authors for missing out on SGLT2 inhibitors," Matthews said. "The omission means that the GRADE data are already obsolescent."

In reply, Nathan admitted "we feel bad we did not include" an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial's organizers.

Oral SGLT2 inhibitors were not "well-established drugs" for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.

They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.

Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure, and too US-centric to be generalizable elsewhere.

A Study With Lots of Data

The roughly 5000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, A1c was in the range of 6.8%-8.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2.

The trial included a run-in period during which metformin therapy was titrated to the maximum tolerated dose, between 1000 and 2000 mg/day; patients were then randomized to one of the four agents as add-on treatment. The latter were titrated to achieve A1c < 7% up to the maximally tolerated dose, and the primary outcome was reached when treatment failed, that is, A1c rose to 7% or higher.

Both liraglutide and insulin glargine also performed well on many of the other numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.

The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.

Mean doses of the second-line agents after 4 years of treatment were 38.8 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin. 

A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.

For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina School of Medicine in Chapel Hill.

For each of the other two main cardiovascular endpoints — MACE and hospitalization for heart failure — liraglutide had a numeric advantage over the other three drugs but failed to reach significance. 

Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.

And, Nathan emphasized, the cardiovascular disease data are still considered preliminary.

Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)

And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin, but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years on treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.

Four Drugs Performed Equally Well for Some Outcomes

Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.

The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.

But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.

GRADE received no commercial funding. Wexler has reported serving on data monitoring committees for Novo Nordisk. Buse has reported being a consultant for and holding stock in numerous companies. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi, and has received research support from numerous companies. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Lachin and Nathan have reported no relevant financial relationships.

ADA 2021 Scientific Sessions. Presented June 28, 2021.

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

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