Valerie DeBenedette has over 30 years' experience writing about health and medicine. She is the former managing editor of Drug Topics magazine.
Lara Antal / Verywell
Most people with type 2 diabetes will eventually need more than one medication to help control their blood glucose levels. The first drug used is usually metformin, prescribed alongside changes in diet and exercise. But when it comes to which drug to prescribe next if needed, there historically hasn’t been a standard second line of defense.
Now, a large clinical trial has compared four different drugs used to control type 2 diabetes and found that two of the drugs did statistically better. However, there wasn’t more than a modest difference between all four of the drugs.
The lack of a clear frontrunner demonstrates the difficulty in finding the best way to control blood glucose levels in type 2 diabetes.

“It is very difficult to control type 2 diabetes and achieve a level of glucose control blood sugar control,” study chair David Nathan, MD, director of the Diabetes Center at Massachusetts General Hospital in Boston and professor medicine at Harvard Medical School, told Verywell. “The two medications that work the best were actually the injectable medications: insulin glargine and liraglutide.”
In the study, either insulin glargine, liraglutide, glimepiride, and sitagliptin were administered to participants already taking metformin.
“These drugs should be selected based on individual characteristics, because in fact, all of them lower the A1C (a measure of average blood sugar levels over the last three months),” Nathan said. “All the patients had a benefit.”
Researchers may not have noticed the differences in the drugs at all if the study hadn’t lasted five years, he added.
Insulin glargine
The five-year trial, known as the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study, was large, with more than 5,000 people enrolled at 36 study centers. The patients were a fairly diverse group: Roughly 20% were Black, 19% were Latinx, and the rest were White.
All participants had had type 2 diabetes for less than 10 years and had been taking metformin, but did not have strong control of their blood glucose levels, as shown by tests of A1C blood levels.  
Participants began the study with A1C levels of 6.8% to 8.5%. Under 7% is considered in control.
Each of the four drugs—liraglutide, sitagliptin, glimepiride, or insulin glargine—was used along with metformin.
Liraglutide, sitagliptin, and glimepiride help increase the body’s insulin levels when blood sugar levels are high, while insulin glargine is designed to replace the body’s insulin.
Participants who took metformin plus liraglutide or insulin glargine achieved and maintained target blood glucose levels for the longest time compared to sitagliptin or glimepiride. On average, they spent six months longer with blood glucose levels in the target A1C range, which is under 7%.
Sitagliptin was least effective in maintaining target levels. Treatment effects did not differ based on age, sex, race, or ethnicity.
GRADE was funded by the several arms of the National Institutes of Health, primarily by the NIDDK, with additional support from the National Heart, Lung, and Blood Institute, the American Diabetes Association, and the Centers for Disease Control and Prevention. GRADE had additional resources from the Department of Veterans Affairs. No pharmaceutical companies had a role in the study, but the manufacturers of the drugs donated the medications.
Still, the differences the drugs made were small. And only one in four of all the participants could keep their A1C levels in the target range over the course of the study, a statistic which Henry Burch, MD, of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) calls “unfortunately typical.”
Burch said that’s why multiple drugs are frequently required for adequate control of glucose levels, along with a healthy lifestyle through diet and physical activity.
The study findings may impact how Burch prescribes medication.
“Changes to my personal practice will involve a lower threshold for the addition of insulin therapy,” he said. “Insulin therapy (insulin glargine) was one of the two therapies associated with better blood glucose control, without markedly increasing the risk of hypoglycemia or body weight, which are two of the concerns that often delay the use of insulin therapy in clinical practice.”
Ultimately, experts say the findings of the GRADE study support existing guidance.
“These findings reinforce the American Diabetes Association Standards of Care guidelines, and in particular, suggests the importance of adding GLP-1 receptor agonists (like liraglutide) versus glimepiride or sitagliptin,” Robert A. Gabbay, MD, PhD, chief science and medical officer of the American Diabetes Association, told Verywell via email. “We hope that this will lead to greater access to GLP-1 treatments earlier in the course of disease.”
The NIDDK is keenly interested in continuing to examine what works best for type 2 diabetes at the individual patient level, Burch said.
“Knowing which patient characteristics make them most responsive to a particular medication or approach to therapy is one of the hallmarks of precision medicine,” he said.
The study shows an insulin treatment and a GLP-1 receptor agonist medication have a slight advantage when it comes to keeping A1C levels in control. Since the GRADE study began, more medications in the GLP-1 receptor agonist class have been approved. And a whole new class of drugs to treat type 2 diabetes has been approved, called the SGLT2 inhibitor class. You have treatment options.
GRADE Study Research Group. Glycemia reduction in type 2 diabetes—Glycemic outcomes. N Engl J Med. 2022;387(12):1063-1074. doi:10.1056/NEJMoa2200433
By Valerie DeBenedette
Valerie DeBenedette has over 30 years’ experience writing about health and medicine. She is the former managing editor of Drug Topics magazine.

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