‘Early insulin treatment and personalized goal-setting is new solution for blood sugar control’

As the number of diabetes patients in Korea increases every year, effective blood sugar control is becoming a more critical issue.

According to the “2024 Diabetes Factsheet” released by the Korean Diabetes Association, one in seven (14.8 percent) adults over the age of 30 has diabetes, and the number increases to nearly three in 10 (28 percent) for those over 65.

Of the 5.33 million people with diabetes, 90 percent are treated with oral hypoglycemic drugs, but only 6 percent are treated with insulin, and 32.4 percent are controlled with glycated hemoglobin of less than 6.5 percent, pointing to the need for more active blood sugar management.

Professor Hong Eun-gyoung of the Department of Endocrinology at Hallym University Dongtan Sacred Heart Hospital, the president-elect of the Korean Endocrine Society, has proposed a new possibility for blood sugar management. She proposed it through the TOBE study published in the April 2024 issue of the SCIE journal “Advances in Therapy.”

Hong’s team analyzed the clinical effectiveness of basal insulin Tuojeo (insulin glargine) through a multicenter study at 27 university and general hospitals nationwide from June 2016 to July 2019. The study, which included 494 adult patients with type 2 diabetes who had difficulty controlling their blood sugar with oral hypoglycemic agents and GLP-1 analogs and needed basal insulin, is notable for being the first real-world evidence (RWE) study in Korea.

The researchers divided 369 eligible participants into a general glycated hemoglobin target (HbA1c<7 percent) group and an individualized target group that considered patient conditions and followed them for 24 weeks. Individualized targets were set at <6 percent (2.3 percent), <6.5 percent (20.5 percent), <7 percent (55.7 percent), <7.5 percent (6.8 percent), <8 percent (10.2 percent), <8.5 percent (3.4 percent), and <9 percent (1.1 percent) depending on patient condition.

The results showed an average decrease in HbA1c of 1.5 percent and a 9.0 percent incidence of hypoglycemia in the overall group. 37.5 percent of the individualized goal group achieved their goal, nearly three times higher than the 13.9 percent in the general goal group. In addition, fasting glucose decreased by an average of 68.7 mg/dL from baseline, and weight only increased by 0.9 kg.

Notably, 26.1 percent of patients in the individualized target group achieved HbA1c <7 percent, a significant difference from the general target group. This suggests personalized glycemic targeting that considers the patient's condition can improve treatment success.

Korea Biomedical Review interviewed Professor Hong about the clinical significance of personalized glycemic management and its potential for changing the paradigm of diabetes treatment in Korea. The study highlights the importance of setting personalized glycemic targets for each individual diabetic patient and finding the optimal time to start insulin therapy in patients with difficult glycemic control.

Question: How has the prevalence of type 2 diabetes in Korea changed recently, and what are the clinical highlights?

Answer: The prevalence of diabetes in Korea has been steadily increasing. It rose from 11.8 percent in 2012 to 16.7 percent in 2020 and the average for men and women increased significantly. Although the increase in prevalence has stabilized somewhat since 2021, it is expected that the prevalence will increase further as diabetes is a combination of genetic predisposition and lifestyle and environmental issues.

Even more noteworthy is the fact that the prevalence of pre-diabetes, the potentially diabetic population, is 41.1 percent (30+ years old, 2021-2022 combined). Active management of pre-diabetes patients is critical to curbing the rising prevalence of diabetes.

The key to treating diabetes is glycemic control to prevent complications. However, despite the current increase in prevalence, diabetes control rates remain low. The Korean Diabetes Association recommends a glycemic control goal of less than 6.5 percent HbA1c to prevent complications. The United States uses a 7 percent goal, a conservative target based on past research. In Korea, the control rate is over 55 percent at 7 percent, but only 32.4 percent at 6.5 percent (age 30+, 2021-2022 combined). Patients who do not reach the target are at risk of various complications, which leads to increased healthcare expenditure.

The low glycemic control rate among diabetes patients in Korea is due to a combination of factors, including a lack of early aggressive treatment due to clinical inertia and delayed insulin treatment due to psychological fear of hypoglycemia. Korea has one of the lowest rates of insulin use in the world due to the negative perception and hassle of injections, yet insulin is the most effective way to treat diabetes. Current treatment guidelines recommend initiating insulin therapy after oral agents 2 and 3 have failed. Delayed initiation of insulin therapy is associated with lower rates of glycemic control and increased risk of complications, so prompt initiation of insulin therapy is essential if glycemic control is not achieved.

Q: Why did you decide to conduct the RWE study in Korea?

A: All drugs, including insulin, undergo multiple clinical studies before launching, but insulin-related studies are mainly conducted in foreign countries, and there is a lack of studies in Korean patients. Insulin glargine 300 units/mL (Tuojeo), the long-acting insulin used in the TOBE study, is the ideal basal insulin on the market today, but most of the studies have been conducted in the U.S. and Western Europe.

There are very limited studies of Tuojeo in Asians. There is only EDITION-JP, a clinical RCT study in Japanese, the ATOS Study, an RWE in various populations, including Asians; EDITION-AP, an RCT study in Asian populations, including Koreans, and the Korean Titration Study, an RCT study in Korean patients who titrate insulin daily to achieve optimal glycemic control by adjusting insulin dose according to blood glucose fluctuations and those who titrate weekly.

Against this backdrop, this study is the first to provide clinical evidence of Tuojeo's efficacy and safety in a real world setting in Korean patients.

Q: The TOBE study is designed to analyze Tuojeo's clinical performance in the Korean population while incorporating the latest diabetes guidelines, such as individualized glycemic targeting. What were some of the specific focuses of the study design?

A: This study is different from previous diabetes drug studies. While previous studies have used a blanket under-7 percent target glycemic goal to evaluate glycemic achievement, this study compares patients with individualized targets based on their clinical characteristics to patients with conventional under-7 percent targets.

Previous studies, including the UKPDS and DCCT, have shown that early and aggressive glycemic control minimizes long-term complications. However, subsequent studies of cardiovascular risk in diabetes, such as ACCORD, ADVANCE, and VADT, have shown that attempting to achieve a uniform goal may increase cardiovascular risk in high-risk groups, such as those who have already developed complications or are elderly.

Against this backdrop, the U.S. and other national guidelines recommend individualized goal setting that takes into account the patient's physical, mental, and social conditions, life expectancy, severity of comorbidities, and risk of hypoglycemia. The TOBE study echoes the importance of individualized target glycemia.

However, the study did not arbitrarily divide patients into individualized and standard targets at the outset. Due to the real-world nature of the study, some patients were not given an individualized target and were given a generic under-7 percent target. This situation allowed for a comparative analysis between the two groups, which made the study more meaningful.

Q: Glycemic control was better with individualized goals. What are its implications?

A: In the ACCORD, ADVANCE, and VADT studies, the primary reason for individualized goals was safety concerns and no improvement in efficacy was expected. However, it is noteworthy that in this study, the group with individualized targets had better outcomes on efficacy metrics such as target glycemia attainment without an increased risk of hypoglycemia. In particular, the glycemic target achievement rate in this study (37.5 percent) was higher than the achievement rate with individualized targets in the ATOS study (25.2 percent), a multi-country RWE pivotal study, further strengthening the clinical evidence for the safety of Tuojeo in Koreans with diabetes.

While individualized goal setting is time-consuming as it requires consideration of various factors, including patient age, comorbidities, and patient adherence, the study concluded that it is essential for patients to have individualized goal setting in clinical practice.

Q: It is impressive that patients who reached target glycemia had a low incidence of hypoglycemia (9.0 percent for 24-hour symptomatic hypoglycemia, 0.2 percent for severe hypoglycemia, and 1.0 percent for nocturnal hypoglycemia). Notably, the incidence of hypoglycemia was lower in the elderly patient population (6.5 percent) than in those under 65 years of age (12.6 percent), which may contribute to addressing concerns about insulin and hypoglycemia.

A: While it is difficult to eliminate hypoglycemia concerns from insulin use, it is essential to note that when insulin treatment is tailored to individualized goals and patient comfort, rather than tightening to a pre-existing glycemic goal, there is no increased risk of hypoglycemia without compromising efficacy.

It is noteworthy that Tuojeo's safety was analyzed separately in the elderly population. The incidence of hypoglycemia was low even in patients aged 65 years and older, who are typically at higher risk of hypoglycemia with insulin therapy, confirming that Tuojeo is a relatively safe insulin for use in elderly diabetes patients in Korea. Glycemic control targets are often set higher in elderly patients because they may be less able to recognize and cope with hypoglycemia and have higher rates of comorbidities. However, a glycemic goal of 6.5 percent may be acceptable for patients with no comorbidities at a considerable age, who can use therapies that minimize hypoglycemic events, and who have strong family support.

Q: Besides the change in target glycemic levels, there was a significant difference in the disease duration between those who achieved their target glycemic levels and those who did not. What does that mean?

A: Patients who reached their target glycemic levels had a significantly shorter duration of diabetes than those who did not, suggesting that early initiation of insulin therapy helps patients achieve better glycemic control. Currently, up to a four-drug combination is allowed for diabetes treatment in Korea, but it is not covered by insurance, so it is time to reconsider the cost-effectiveness of four-drug therapy. If insulin is started after using up to four drugs, it is often difficult to stop insulin because of problems with pancreatic function. In contrast, early insulin treatment may restore some pancreatic function and allow some younger patients to stop injections or control with minimal oral medications.

The difference between reaching a target HbA1c of 6.5 percent with three or more oral medications and lifestyle factors versus reaching 6.5 percent with insulin can affect long-term outcomes 10 and 20 years later. Lowering blood glucose with a combination of three or more oral medications often requires agents that stimulate the pancreatic beta cells to secrete insulin, including sulfonylureas. This puts an additional burden on the pancreas of patients with already decreased pancreatic function. Eventually, insulin treatment becomes inevitable, at which point it is difficult to proceed with aggressive insulin treatment because starting insulin treatment can further increase cardiovascular risk due to hypoglycemia.

Therefore, early initiation of insulin therapy in patients with uncontrolled glycemia on oral medications may have multiple benefits, including increased likelihood of achieving target glycemia, reduced treatment burden, and preservation of long-term pancreatic function.

Q: How do you expect your findings to change treatment strategies in clinical practice?

A: In Korea, insulin treatment is underutilized due to resistance and negative perceptions of insulin therapy. This is due to high barriers in Korea, including the negative connotation of insulin treatment as a “last resort” for patients, the need for hospitalization for treatment, and the inconvenience and pain of self-injection.

This study confirms the importance of early initiation of insulin therapy and individualized glycemic goals for diabetes management in patients with type 2 diabetes and demonstrates that basal insulin is safe to use, especially in older patients with diabetes. Based on this long-term efficacy and safety, it is expected that patients who have difficulty controlling their blood glucose with oral medications will be able to receive insulin treatment earlier and based on individualized glycemic goals.

Q: You will serve as the president of the Korean Endocrine Society for the next couple of years. What are your plans and goals?

A: During my two-year term, I plan to focus on establishing the academic value of endocrinology and laying the foundation for future training. Externally, I will strengthen communication with the government and conduct active public relations activities to help the public understand and treat endocrine diseases correctly. Internally, we will raise the self-esteem of colleagues and society members specializing in endocrinology and make various efforts to position endocrinology as a global leader.

Currently, most endocrine diseases, including diabetes, are categorized as mild in policy and public perception and are often mistaken for easily treatable conditions. As a result, the expertise of endocrinologists is underutilized, and a decline in the number of applicants for full-time endocrinology positions threatens the future of endocrinology. However, the role of endocrinologists in healthcare is often essential, such as preoperative counseling and risk assessment for patients with diabetes. Nevertheless, the current situation in which endocrine diseases are treated as minor indicates that it is time to rethink the scope of essential care.

To address this, my colleagues and I at the executive board will first reclassify the categories of mild and severe endocrine diseases and improve the current situation where even emergency acute complications such as diabetic ketoacidosis are not categorized as severe. Policy efforts will be expanded to help endocrinologists determine the severity of the disease and organize appropriate treatment based on this.

Second, we will strengthen public awareness and social contribution activities. We will promote rare diseases to improve understanding of the disease and correct misconceptions about endocrine diseases, which will lead to policy changes.

Third, we will expand the participation of non-physician members, such as nurses, dietitians, and foreign members, to strengthen the society. Through the activities of special directors and various committees, we will explore new businesses, revitalize the culture of donations to increase our society's self-reliance and create an environment that fosters pride in endocrinology among seniors and juniors.