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Two drugs commonly used to treat type 2 diabetes were shown to more effectively maintain target blood sugar levels than other common medications, according to new research. The findings offer up more insight on long-term management of the chronic disease.
In a new, large clinical trial supported by the National Institutes of Health, researchers compared four common type 2 diabetes drugs: liraglutide and insulin glargine U-100, two injectable medications; and sitagliptin and glimepiride, two oral medications. The drugs were taken in conjunction with metformin, a medication also used to treat type 2 diabetes.
The two injectable medications performed best, when used in combination with metformin, in helping people maintain their targeted blood sugar levels for the longest amount of time.
Though none of the drugs "overwhelmingly outperformed" the other drugs, researchers say the study still offers necessary and helpful information on how to better manage type 2 diabetes in the long term.
“This study was designed to provide health care providers with important information on how to guide the long-term management of type 2 diabetes,” lead study author Henry Burch, MD, program director for the division of diabetes endocrinology, and metabolic diseases at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), said in a news release. “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.”
The new findings come from the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study, which launched in 2013 and was conducted at 36 different study centers throughout the U.S. The results were recently published as a pair of papers in the New England Journal of Medicine (NEJM).
For the the trial, researchers aimed to compare the four most common FDA-approved type 2 diabetes treatments at the time. Dr. Burch and his team looked at 5,047 people living with type 2 diabetes. Study participants came from a diverse pool of racial and ethnic groups, which included 19.8% Black participants and 18.6% Hispanic or Latinx participants. Everyone in the study was already on a regimen of metformin for their diabetes treatment.
Participants were placed randomly into one of four groups—one for each of the trialed medications.
Individuals who were given the injectable treatments were able to maintain their blood sugar levels for a longer period of time, albeit "modestly." According to study authors, people on those injectable treatments were able to maintain their blood sugar targets for about six months longer than those on the oral medication sitagliptin, the least-effective drug in the trial. Those findings held true regardless of sex, ethnicity, race, or age.
“The two injectable medications studied in GRADE appeared to provide blood glucose control for a longer period of time than the oral medications studied in GRADE,” Dr. Burch told Health.
However, recent treatment advancements may throw these findings slightly out of whack.
“Since the start of GRADE agents in another class of oral diabetes medications known as SGLT-2 inhibitors have been approved and made widely available," said Dr. Burch. "Given the timing of the release of these newer agents, they were not included in the GRADE study, so it is not known how they would have compared with injectable therapies.”
In addition to the effectiveness of the four treatment options, the study also looked at the medications' effects on developing diabetes-related cardiovascular disease, along with drug side effects.
The injectable medication liraglutide came out on top here as well: participants who took that medication were less likely to develop cardiovascular disease than others, and they lost more weight on the treatment.
“Liraglutide additionally resulted in greater weight loss and perhaps offered some protection from cardiovascular events as compared to the other three medications,” Utpal Pajvani, MD, PhD, associate professor of medicine in the division of endocrinology at Columbia University, told Health. “These data suggest that of these medications, liraglutide is the most effective, although the magnitude of effect was not particularly game-changing.”
Additionally, severe hypoglycemia (severely low blood sugar), was generally uncommon throughout the study, though it was seen more often in patients who took the oral medication glimepiride.

“One of the more interesting findings was that insulin therapy was one of the two therapies associated with better blood glucose control, without markedly increasing the risk of hypoglycemia or body weight," said Dr. Burch. Those two concerns, he added, often delay the use of insulin therapy in clinical practice.

Though the study found two medication that can effectively manage blood sugar levels for longer periods of time, it also highlighted the challenges people living with diabetes face in maintaining their recommended target levels.
According to study authors, though blood sugar levels decreased during the study, nearly 75% of the participants were able to maintain the blood glucose target for more than four years.
"It is currently quite challenging for patients to maintain optimal glucose levels on a combination of metformin and a single additional diabetes medication," said Dr. Burch. "Many patients require more than one type of diabetes medication added to metformin to maintain control."
Despite the fact most of the trial participants were unable to hit these blood sugar benchmarks, Dr. Pajvani believes the outcome might have been different if the study used the more current and commonly prescribed versions of GLP1 class of medications—the injections administered daily or weekly for diabetes treatment—that came out after the research started. 
“In fact, in head-to-head randomized controlled trials comparing liraglutide, the one used in this study, with newer agents—dulaglutide (Trulicity) and semaglutide (Ozempic)—the newer agents provide far better blood sugar control, and significantly more weight loss,” Dr. Pajvani said. “The vast majority of my current GLP1 prescriptions are for one of the newer agents.”
“This was not the fault of the study investigators, as these newer drugs were not available at trial design and onset," said Dr. Pajvani. "But nevertheless, as a consequence of the improved efficacy data of the newer medications, the study data presented here really do not inform the choice that most patients and their physicians currently have."
It’s also worth noting that type 2 diabetes is a chronic, progressive disease in large part because one’s resistance to the effects of insulin increases as a person gets older and with weight gain, Dr. Pajvani said.
“That means that escalation of therapy is often necessary to maintain optimal blood sugar levels,” he added. 
Moving forward, Dr. Burch said the GRADE study will further examine how a person’s body responds to diabetes medications and what can be done to best treat diabetes moving forward. 
Next, researchers intend to look into an “in-depth genetic analysis” that’s designed to figure out “whether heterogeneity at the genetic level can contribute to variable responsiveness to individual diabetes medications,” Dr. Burch said.
Ultimately, it’s crucial that individuals who are impacted by diabetes work closely with their health provider to “identify the regimen that works best and is tolerated best for their individual needs,” Dr. Burch said.
“Overcoming clinical inertia, which is the tendency to stick with a regimen that is not working, goes hand in hand with working closely with the health care team to identify the optimal regimen and to not stop striving to achieve target results,” Dr. Burch explained. 
A big part of the puzzle involves healthy lifestyle changes. Dr. Pajvani said adopting a healthy lifestyle “is the best approach” to preventing the onset of type 2 diabetes and is especially important for those already diagnosed who are working to manage their blood sugar levels. 
He added that people “should be as active as possible and maintain a healthy diet.” These two factors combined can make all the difference in reducing that insulin resistance set off by aging and weight gain.
For his part, Dr. Burch added that a healthy diet and exercise can play a big role in also controlling other conditions that often go hand in hand with diabetes—controlling other cardiovascular risk factors like high cholesterol and high blood pressure.


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