Study reveals which type 2 diabetes drugs are most effective

After Neda Rasouli, MD, professor at the University of Colorado School of Medicine, and a team of national researchers published a study in 2022 comparing the effectiveness of four common drugs for type 2 diabetes, they decided to dig deeper into the data to determine which drugs were better than the others.

The results of these secondary analyses have recently Published as 10 articles Diabetes CareRasouli is First author of these papers He is also a co-author on other papers that will provide more details about the differences between the four drugs — insulin glargine, liraglutide, glimepiride and sitagliptin — and help healthcare professionals decide which drug will work best for their patients.

This study Glucose Lowering Approaches in Diabetes: Comparative Effectiveness (GRADE) StudyThe GRADE study is a nationwide clinical trial that was conducted from 2013 to 2021. The GRADE study had more than 5,000 participants and was conducted at 36 clinical centers across the United States, including the CU Anschutz Medical Campus.

Rasouli, vice chief of the Division of Endocrinology, Metabolism and Diabetes and director of the CU Diabetes and Endocrinology Clinical Trials Program, was principal investigator at CU sites, including the Rocky Mountain Regional Veterans Affairs Medical Center.

“With the increasing prevalence of obesity and diabetes, it's really important to answer the question of what is the best drug to treat people with type 2 diabetes,” Rasouli says. “One difference between these four drugs is cost, so we need to investigate which ones are better than the others and whether there is enough data to support changes in treatment guidelines.”

The need for GRADE studies

is more than 38 million About 90-95% of people in the U.S. have type 2 diabetes, a disease that leads to high blood sugar levels because the pancreas doesn't produce enough insulin or the body's cells don't respond properly to insulin.

People with diabetes who keep their blood sugar levels in a near-normal range (also known as having glycemic control) generally have a much lower risk of developing complications like heart disease or kidney disease, Rasouli explains. But maintaining control can be difficult.

“Type 2 diabetes is a progressive disease that over time leads to a deterioration in blood sugar control due to dysfunction of beta cells, the main cells that produce insulin,” Rasouli said.

To help these patients control their blood sugar levels, they are usually prescribed metformin, a blood sugar-lowering diabetes drug, but many eventually reach a stage where metformin no longer controls their blood sugar levels.

“Because diabetes is progressive, most patients who take metformin for five to 10 years will need a second line of treatment,” Rasouli said. “Before the GRADE study, there was a lack of head-to-head studies comparing which drug was more effective and which drug improved glycemic control the most. That was the main goal of the study.”

The GRADE study compared four commonly used drugs for diabetes treatment in combination with metformin: insulin glargine, liraglutide, glimepiride, and sitagliptin. The results of the study, published in 2022, showed that: New England Journal of MedicineStudies have shown that combining liraglutide and insulin glargine with metformin helps patients achieve and maintain target blood glucose levels for a longer period of time compared to glimepiride and sitagliptin.

Examining beta cell function

After these initial results were published, GRADE investigators continued to analyze the data and look at other aspects of diabetes treatment. This further analysis led to the publication of 10 additional papers, one of which was lead authored by Rasouli.

Rasouli's paper compares the long-term effects of four drugs in addition to metformin on insulin sensitivity and beta cell function. Research shows that beta cell function gradually declines by about 5-10% each year, leading to worsening blood sugar control. Therefore, any drug that can preserve beta cell function would be extremely valuable.

“We found that liraglutide showed a significant improvement in beta-cell function during the first year, but then there was a more rapid decline in beta-cell function compared to the other groups,” she says. “We saw some short-term improvement with liraglutide, but unfortunately the long-term effects were not sustained.”

At the end of the study, liraglutide was associated with better beta cell function compared with other drugs, in the following order: liraglutide, sitagliptin, insulin glargine, and glimepiride.

“However, none of these drugs were able to halt the loss of beta cell function,” she says, “which indicates a gap in knowledge and the need for better interventions to preserve beta cell function and maintain glycemic control in the long term.”

So, which medication is the best option?

There's no one-size-fits-all solution, Rasouli explains, but the GRADE study results provide valuable information to health care providers about the different effects each drug may have.

“The best medicine will vary from patient to patient, which is why we need to develop better tools to personalize the treatment of complex diseases like diabetes,” she says.

For example, the GRADE study surprised Rasouli by proving that insulin glargine is safe and effective as a second-line treatment for type 2 diabetes, and it has been well-received by patients.

“Insulin is usually a last resort, used when patients have failed all other treatments,” she says. “GRADE has shown that as a second-line treatment, insulin is a slightly better option for maintaining blood sugar control and is not associated with the highest risk of hypoglycemia (low blood sugar levels). However, insulin is associated with weight gain.”

The advantage of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is that it not only has beneficial effects on glycemic control, but is also associated with weight loss and does not present a risk of hypoglycemia unless used in combination with other medications that may cause hypoglycemia, she explains.

“When you look at the overall effect on glycemic control, weight, and hypoglycemia, liraglutide is more effective than insulin,” Rasouli says, “but the cost of these medications is an issue, given that insurance coverage for these medications is not widespread. These GLP-1 receptor agonists (which also include Ozempic, Trulicity, and Maunjaro) are among the most expensive medications currently available.”

“If we lived in a utopia where cost was not an issue and everyone could get the drugs they wanted, I think the GLP-1 class is likely to be the drug of choice for many people,” she added.

Continuing research

The GRADE researchers' work isn't done yet. Rasouli says there is still a lot of data from the study that needs to be explored. One area of ​​research Rasouli hopes to continue is pursuing interventions that improve beta cell function over the long term.

“Interventions that can preserve beta cell function should be the focus of future treatments,” she says.

Rasouli leads the CU Diabetes and Endocrinology Clinical Trials Program, which aims to provide patients with innovative testing of new drugs targeting diabetes, obesity and their metabolic complications. Overall, she hopes the GRADE study will increase recognition that diabetes is a progressive disease and that earlier, more intensive and personalized treatment should be the goal.

“Ultimately, we need to help these patients maintain their blood sugar targets and prevent future diabetes complications,” she says.

“Once the disease progresses and complications arise, there's no going back. I think the most important message to take from GRADE is to be aggressive in treating type 2 diabetes from the very beginning.”