In Korea, 20.9 percent of diabetic patients, who have a hemoglobin A1c (HbA1c) of more than 8 percent, need active insulin treatment. Of the total, however, only 8.3 percent treat themselves with insulin.
The low treatment rate explains why a more active insulin prescription is necessary for patients. The second generation of basal insulin is an option for patients who do not reach their target blood glucose after oral treatment. In this regard, Sanofi, a multinational pharmaceutical firm, has emphasized the importance of efficacy and safety of Toujeo, its second-generation basal insulin, through the BRIGHT study.
The study was released during the American Diabetes Association (ADA)’s 78th Scientific Sessions in Orlando, Fla., in June 2018. Still, the research is receiving a lot of attention as it was the first head-to-head clinical trial that compared the next generation of basal insulins.
Korea Biomedical Review met with Alice Cheng, an associate professor of endocrinology at the University of Toronto, Canada, and a primary investigator of the study, during the International Diabetes Federation (IDF) 2019. We asked about the significance of the BRIGHT study in detail and why insulin treatment is vital for diabetes patients.
|Professor Alice Cheng, the lead investigator of the BRIGHT study, explains the significance of the study and the need for early insulin treatment for diabetes patients, during the International Diabetes Federation (IDF) Conference 2019 at Haeundae Centum Hotel in Busan on Wednesday.|
Question: Although the efficacy of diabetes treatments is growing, and the portfolio of the products are more diverse than before, the prevalence of diabetes is on the rise. And there is no improvement in the proportion of patients with well-controlled blood sugar. What do you think is the reason?
Answer: If we first start with the issue of control of diabetes, although we have great tools, accessing those tools continue to be an issue. Certainly, if we look at it worldwide, not every country has access to all the tools, and even in the countries that have access, not every patient has access to those tools.
Also, even if patients have access to those tools, using it properly is an issue. And, in the case of insulin therapy, there is always a struggle to start insulin.
Regarding the increase in the prevalence of diabetes, I think that is because the world population is continuing to grow, and the genetics and lifestyle of people from different parts of the world have changed significantly.
The changes have happened in various countries, and have impacted the rates of obesity and diabetes.
Q: You participated in the BRIGHT study as the lead researcher. The study has received a lot of attention after it was first introduced in Korea. What led you to participate in the research?
A: The BRIGHT study was the first randomized head-to-head study that compared the two second-generation basal analogs, Toujeo and insulin degludec, and I chose to be involved in this study because it can answer critical clinical questions.
Whenever you have several options in a particular class, it's always nice to see how the agents compare to each other within that class. The study was also very clinically relevant as it focused on insulin naïve type 2 diabetes patients, which are the patients that I see in my office.
Therefore, I believed that being involved in the BRIGHT study was very important.
Q: Can you briefly explain what the BRIGHT study is?
A: The BRIGHT study was a head-to-head randomized trial for insulin-naïve patients with type 2 diabetes to get either Toujeo or insulin degludec, and it was a treat-to-target study, meaning that everybody was aiming for fasting glucose of 4.4 to 5.6 mg/dL.
The study went on for 24 weeks. For the first 12 weeks, we called it the titration period, where patients were encouraged to increase the insulin to reach their target.
Afterward, the second 12 weeks was called the maintenance period, where patients could still adjust the insulin. However, the majority of HbA1c reduction had already occurred in the first 12 weeks.
The study met its primary endpoint by demonstrating a reduction in blood sugar (HbA1c) levels. It was non-inferior to insulin degludec in adults with type 2 diabetes but not previously on insulin.
We also looked at hypoglycemia, and overall the two treatments had similar results. What was different was during the titration period, which is the time when the insulin dosage was increasing the most, and the glucose levels were decreasing the most.
During the 12 weeks, there was less hypoglycemia with Toujeo compared to insulin degludec.
Q: What do you think is the mechanism behind Toujeo having fewer hypoglycemia incidents compared to insulin Degludec in the dose titration period?
A: The exact reasons for that are unclear. We do not know the perfect answer to why those results were seen. However, one possible explanation is if we look at the pharmacokinetics and pharmacodynamics of the two insulins, although both of them are longer and flatter than previous generations, there are some subtle differences between them in terms of still a small peak in the case of insulin degludec.
So when we look at the time of day that the hypoglycemia events occurred in the BRIGHT study, there were no statistical analyses, so I cannot say this with certainty. When you look at the results, however, it seems that the most significant difference in hypoglycemia occurred around 12 to 14 hours after injecting the insulin.
So maybe it has to do with that small difference in the profile of the two insulins.
Q: The recent CONCLUDE study showed that insulin degludec showed a significant improvement in the incidence of nocturnal and severe hypoglycemia compared to Toujeo. Both are similar head-to-head studies, so why are there conflicting results, and how do you interpret them?
A: The study was on a different patient population and studied the two insulins on patients on basal insulin who were at risk of hypoglycemia.
Now, the primary endpoint of the study was actually the superiority of insulin degludec for symptomatic-confirmed hypoglycemia during the maintenance period. However, the primary endpoint was not met, and the results were neutral, which suggested there was no difference between the insulins for hypoglycemia.
Whenever we design a study, if the primary endpoint is not achieved, then every other endpoint we look at is only exploratory. Therefore, we cannot conclude any other endpoints.
So my interpretation of conclude is a little bit different. My interpretation is that CONCLUDE showed that there was no difference in hypoglycemia between the two insulins in the primary endpoint.
Q: Next-generation basal insulin, compared to first-generation basal insulin, is said to have led to significant improvements such as the convenience of administration and the incidence of hypoglycemia. However, do you think there is a substantial improvement in treatment in the practice setting?
A: Next-generation basal insulins have helped in a clinical sense. From a very practical perspective, it has allowed me to recommend patients for a morning dosing, as opposed to the traditional bedtime dosing.
I can offer them morning dosing as the treatments indeed are effective for more than 24 hours, and the reason I recommend morning dosing is that we want patients to self-titrate.
Also, the lower risk of hypoglycemia and some flexibility in the timing of dosage are other benefits of next-generation basal insulin.
Q: Korea is one of the countries where insulin treatment is not well done, with only about 8 percent of patients receiving insulin treatment. What is the current state of insulin treatment in Canada? Did Canada face a similar problem in the past? If so, how did you overcome the problem?
A: I think many countries around the world face a similar problem of patients being reluctant to start insulin and after starting a problem with titration.
I believe the reasons are because people's perception of insulin is incorrect.
What is interesting is that those misconceptions are the same globally and not just in Korea. A lot of those misperceptions have to do with the feeling that receiving insulin means failure or that insulin is the last resort. There is also fear of the injection.
But one of the most critical problems that need attention is the stigma around insulin. Diabetes patients are ashamed or afraid to tell their family or friends that they are on insulin.
However, these are all completely incorrect perceptions of insulin.
One of the strategies to change such perceptions is to explain it better. Insulin is a replacement therapy. To have diabetes means that the patient's pancreas is not making enough insulin, and the insulin that the patient is injecting can replace the insulin that they are missing.
So if we want natural therapy to manage diabetes, it should be insulin.
An analogy would be somebody with an underactive thyroid. If a patient's thyroid is not working, what do we do? We replace the thyroid hormone with a pill, and I've never had a patient say no to such treatment.
Regarding insulin, which is just pancreas replacement, people say no due to the misconceptions. Concerning the misunderstanding of injection, I find that when patients see the injection needle, it completely changes the mistake.
This is because their perception of the injection is a big needle that is going to hurt. When they see that the needle is very small and thin, however, it helps the patient get over their fears of the injection.
The final part I want to stress that the family and friends of diabetes patients are one of the main reasons for the misperception.
Of course, they mean well, but they say things that can increase the misconception of insulin, and that is not helpful to the patient.
Everybody should realize that sugar is the problem. So if the glucose is well controlled, their life can be the same as people with no diabetes.
Therefore, it's not about the treatment but the control of blood glucose levels.
Q: In recent years, the diabetes treatment paradigm is shifting from a step-by-step therapy to promoting insulin to patients' blood sugar from an early stage. Do you have any opinion on the matter?
A: Early treatment is the most important statement to make. When I say the early treatment of diabetes, I mean achieving all targets in diabetes –HbA1c, blood pressure and cholesterol – as early as possible after diagnosis.
The problem in the past was that we used insulin too late. In the past, we only started insulin after the patient has had diabetes for more than 20 years and already showed problems.
That was too late. The amount of benefit that patients could get from insulin was smaller, as most of them already had additional complications that spawned from diabetes.
So if we use insulin earlier, we can avoid those problems that people can get.
Q: Some have suggested that the introduction of the GLP-1 analog and the emergence of new mechanisms of oral medicine may further push back the insulin treatment. However, depending on the patient's characteristics, there will be patients who need insulin treatment. What type of patient is most useful for insulin therapy?
A: The Glucagon-like peptide-1 (GLP-1) receptor agonists and Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown to provide benefit beyond glucose such as cardiac and renal benefit. So in the right patient, they absolutely should receive the GLP-1 and SGLT-2.
However, at the same time, we have to achieve the HbA1c target as we cannot just treat one part of the problem.
So insulin is never going to go away because, as I mentioned earlier, the pancreas not working is an important part of developing diabetes, and the pancreas' function will only deteriorate as time goes by.
Therefore, everyone with diabetes is going to require insulin at some point as their pancreas function has decreased. What's good about the treatment is also that anybody can use the treatment, including children, pregnant, elderly, patients with organ damage.
Regarding the patients that I would directly prescribe insulin are those who look like they are insulin-deficient. Typically that would be the patient who has very high blood sugars and may have been losing weight unexpectedly or has a low BMI at diagnosis.
However, I will still add other therapies on top of insulin to help them achieve their target and protect their organs.
Q: Finally, are there any suggestions for the effective treatment and management of diabetes for domestic medical workers and patients? (in terms of improving awareness and increasing the use of insulin therapy)
A: The first thing I would like to say is to remind everyone when a diagnosis of diabetes is made, we have to think about the multifactorial approach. It's not just about blood sugar; it's about blood sugar, blood pressure, cholesterol, and seeing the doctor for other complications.
One of those targets is getting a patient's Hb1Ac down, and the reason why we want to do that is to reduce complications. To achieve Hb1Ac targets, we're going to need multiple therapies because multiple parts of the person's body are not working properly to allow the person's blood sugar to go high.
Insulin is one of those options as it is a pancreas replacement therapy. Taking insulin at an early stage is better than later, as patients can have a chance to prevent complications from occurring.
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