Current Status of Delay in Injectable Therapy among Type 2 Diabetes Mellitus Patients in South Korea: Multicenter Retrospective Study (2015–2021)
Article information
Abstract
Background
We aimed to assess the therapeutic inertia associated with injectable therapies and the factors influencing glycemic control following these therapies in patients with type 2 diabetes mellitus (T2DM) in South Korea.
Methods
This multicenter, retrospective cohort study included 2,598 T2DM patients aged 20 to 75 years from 10 referral medical centers in South Korea. These patients had been treated with three or four oral antidiabetic drugs (OADs) and were subsequently initiated on insulin (n=1,942) or glucagon-like peptide-1 receptor agonists (GLP-1RAs, n=656) between January 2015 and December 2021. We analyzed the time to initiation of injectable therapy, changes in glycated hemoglobin (HbA1c), and associations between clinical factors and glycemic control.
Results
At the time of injectable therapy initiation, the mean HbA1c was 9.54%, with insulin users having a higher HbA1c level (9.79%) than GLP-1RA users (8.70%). The mean time from starting 3 or 4 OADs to initiating injectable therapy was 3.19 years: 53.5% of patients had started injectable therapy after 2 years, and 24.2% started after 5 years. Among insulin users, older age (P=0.004), higher body mass index (P=0.035), and lower HbA1c levels at insulin initiation (P<0.001) were associated with better glycemic control. Among GLP-1RA users, only the HbA1c level at therapy initiation (P<0.001) was a significant factor.
Conclusion
This study highlighted significant delays in initiating injectable therapies, particularly insulin, in T2DM patients in South Korea. Early initiation of injectable therapy may improve long-term glycemic control in these patients.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disorder that has rapidly emerged as a major global public health challenge [1]. Over the past few decades, the development of approximately 50 new antidiabetic agents and advancements in medical devices for glycemic control have significantly improved clinical outcomes for patients with T2DM [2,3]. Cardiovascular and renal outcome trials have also reshaped diabetes care by demonstrating the vascular protective effects of certain novel antidiabetic agents [4,5].
Despite these advancements, overall glycemic control has not improved significantly. In South Korea, the percentage of patients with diabetes mellitus and glycated hemoglobin (HbA1c) levels below 7.0% was 50.6% from 2007 to 2010 and 49.6% from 2019 to 2020 [6]. Therapeutic inertia—defined as the failure to appropriately intensify treatment in a timely manner—has been identified as a major barrier to achieving optimal glycemic control in clinical settings [7-9]. A notable issue in the Korean population is the low adoption rate of injectable therapies for T2DM management. In 2019, only 8.4% of patients were receiving insulin, and just 1.0% were treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) [6], which is considerably lower than the rates observed in other developed healthcare systems. Barriers to the uptake of injectable therapies include patient resistance to injections, misconceptions about injectable therapy, and a lack of infrastructure supporting these treatments within the healthcare system [10]. Studies consistently show that delays in transitioning from oral hypoglycemic agents to injectable therapies, when clinically indicated, worsen glycemic control and increase the risk of vascular complications [11,12].
Addressing therapeutic inertia and promoting the timely initiation of injectable therapies are critical for improving long-term clinical outcomes in patients with T2DM. This study aimed to examine delays in the initiation of injectable therapies and identify factors associated with optimal treatment implementation among patients with T2DM in South Korea.
METHODS
Subjects and study design
This multicenter, retrospective cohort study was conducted at 10 tertiary referral medical centers in South Korea. The study protocol was approved by the Institutional Review Board of the Korea University Anam Hospital (IRB number 2022AN0140) and each participating center. The requirement for informed consent was waived due to the retrospective study design. A total of 2,598 patients with T2DM, aged 20 to 75 years, who were initiated on insulin or GLP-1RAs after treatment with three or four oral antidiabetic drugs (OADs) between January 1, 2015, and December 31, 2021, were included. Patients were excluded if they had type 1 diabetes mellitus, active malignancy treatment within 1 year before initiating injectable therapy, use of medications affecting blood glucose (e.g., glucocorticosteroids) within 3 months prior to injectable therapy, temporary insulin use due to acute illness, or pregnancy. The primary objective of the study was to assess the timing and clinical context of initiating injectable therapy in patients with T2DM. This included evaluating patient characteristics, HbA1c changes before and after injectable therapy initiation, and the interval from OAD therapy to injectable therapy initiation. The secondary objectives included assessing the glycemic efficacy of injectable therapies, comparing insulin and GLP-1RA effectiveness, identifying factors associated with effective therapy implementation, and investigating factors contributing to delays in injectable therapy initiation. The overall study design is illustrated in Supplemental Fig. S1.
Data collection
Data were retrospectively collected from the electronic medical records of the 10 participating centers. The following demographic and clinical variables were included: age at the initiation of three or four OADs, age at injectable therapy initiation, sex, height, and weight at injectable therapy initiation. HbA1c levels were recorded at 6-month intervals from the initiation of three or four OADs to injectable therapy initiation, as well as at 6-month intervals following injectable therapy initiation up to December 31, 2021. In addition, laboratory variables such as C-peptide, serum creatinine, estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), aspartate aminotransferase, and alanine aminotransferase were collected. The underlying medical conditions such as atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), chronic kidney disease (CKD), and microvascular complications comprising diabetic retinopathy, diabetic kidney disease, and diabetic neuropathy were also assessed. Information on the number and type of OADs used prior to injectable therapy, including metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and thiazolidinediones (TZDs), was obtained. Insulin users were defined as patients who received insulin therapy for over 6 months, regardless of insulin type. GLP-1RA users were defined as those who received GLP-1RA therapy for more than 6 months during the study period.
Statistical analysis
Data are presented as mean±standard deviation or median (interquartile range) for continuous variables and as numbers and percentages (%) for categorical variables. Changes in HbA1c levels before and after injectable therapy initiation, both overall and specifically for insulin and GLP-1RAs, were determined using the actual mean values at each time point. Additionally, HbA1c changes following the initiation of injectable therapy were modeled using nonlinear regression analysis to obtain beta values. This analysis accounted for the time to initiation of injectable therapy (<1, 1–<3, 3–<5, 5–<7, and ≥7 years), duration of diabetes (<5, 5–<10, 10–<15, and ≥15 years), and HbA1c levels (<8.0%, ≥8.0%–<10.0%, and ≥10.0%) at initiation. To identify the factors affecting glycemic efficacy after injectable therapy, candidate variables such as age, body mass index (BMI), duration of diabetes, time to initiation of injectable therapy, and HbA1c levels at initiation were categorized. Least squares (LS) mean HbA1c values over a 5-year period for each category were then calculated and compared using a generalized linear model. A comparative analysis between early and delayed injectable therapy initiators was conducted using chi-square tests for categorical variables and t tests or Mann-Whitney U tests for continuous variables. All statistical analyses were conducted using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA), with statistical significance set at a two-sided P value <0.05.
RESULTS
Patient characteristics
The study cohort comprised 2,598 patients, including 1,942 insulin users and 656 GLP-1RA users. The baseline characteristics are shown in Table 1. Of the participants, 58.8% were men, and 41.2% were women, with no significant difference in the sex distribution between insulin and GLP-1RA users. Insulin users had a significantly lower BMI than GLP-1RA users (24.7 kg/m2 vs. 28.3 kg/m2, P<0.001). The mean age at the initiation of 3 or 4 OADs was 55.1±11.7 years, and the age at injectable therapy initiation was 58.3±11.9 years, with insulin users being older at both time points. The duration of diabetes was significantly longer in insulin users, with a median of 15 years compared to 12 years in GLP-1RA users (P=0.020).
Baseline Characteristics of Study Patients
At the time of injectable therapy initiation, insulin users had significantly higher HbA1c levels than GLP-1RA users (9.79% vs. 8.70%, P<0.001). Insulin users had a lower eGFR (76.2 mL/min/1.73 m2 vs. 85.3 mL/min/1.73 m2, P<0.001) and a higher UACR (291.4 mg/g vs. 163.9 mg/g, P<0.001). No significant difference was observed in C-peptide level between groups. Regarding comorbidities, the prevalence of CKD was significantly higher in insulin users than in GLP-1RA users (27.2% vs. 15.1%, P<0.001). However, no significant differences were observed in the prevalence of ASCVD, HF, or microvascular complications between groups. Before injectable therapy, the majority of patients (91.4%) were receiving triple OAD therapy, while 8.6% were on quadruple therapy. The use of SGLT2 inhibitors (53.0% vs. 13.7%), and TZD (53.0% vs. 13.7%) was significantly more prevalent among GLP-1RA users compared to insulin users.
HbA1c at injectable therapy initiation and time to injectable therapies from OADs
Fig. 1 shows HbA1c distribution at injectable therapy initiation. For insulin users, 87.4% had HbA1c levels ≥8.0%, with 41.6% with levels at ≥10.0%, followed by 24.2% with levels between 9.0%–9.9% and 21.7% with levels between 8.0% and 8.9%. Only 12.6% of the patients commenced insulin therapy with an HbA1c level below 8.0%. In contrast, at the initiation of GLP-1RA therapy, the most common HbA1c range was 8.0%–8.9% (34.9%), followed by 9.0%–9.9% (23.5%) and 7.0%–7.9% (22.7%). A total of 14.3% of the patients initiated GLP-1RA therapy with an HbA1c level of ≥10.0%, while only 4.6% started GLP-1RA therapy with an HbA1c level <7.0%.
Glycated hemoglobin (HbA1c) levels at the initiation of each injectable therapy. Distribution of patients according to HbA1c range at insulin initiation time (A) and glucagon-like peptide-1 receptor agonists (B).
The average interval from treatment initiation with three or four OADs to the start of injection therapy was 3.19±3.1 years. The average time to initiate insulin therapy was 3.09 years, while that for GLP-1RA therapy was 3.3 years. The distribution of time to the start of injection therapy followed a reverse J-shaped pattern (Fig. 2A), with 31.7% of patients starting injection therapy within 1 year, 14.8% within 1–2 years, and 12.7% within 7 years. Overall, 46.5% of patients initiated injection therapy within 2 years of starting 3 or 4 OADs, while 24.2% began injection therapy after 5 years. This pattern was consistent with both the insulin and GLP-1RA therapies (Fig. 2B). However, when examining data from individual institutions, not all participants exhibited the same pattern (Supplemental Fig. S2). Six of the 10 participating institutions displayed a reverse J-shaped pattern. At one institution, the highest rate of patients began injection therapy after 7 years, while at two institutions, it was the second highest.
Timing of initiation of injectable therapies following triple or quadruple combination of oral antidiabetic therapy. Distribution of patients by timing of initiation of all injectable therapies (A) and insulin or glucagon-like peptide-1 receptor agonists (GLP-1RA) (B).
Factors associated with time to injectable therapy from OADs
To further investigate the factors associated with treatment delays, we analyzed the median time from 3 or 4 OAD therapy initiation to insulin or GLP-1RA initiation according to clinical and demographic subgroups (Supplemental Fig. S3). Elderly patients aged over 65 years had shorter time to insulin therapies compared to younger patients (P=0.004). Additionally, patients receiving medical aid program had significantly longer delays for GLP-1RA initiation (P=0.033). However, comorbid medical conditions such as ASCVD or CKD were not associated with time to injectable therapies.
Trends in HbA1c after injectable therapies and factors associated with glycemic control
Fig. 3 shows the average changes in HbA1c before and after injection therapy initiation. The mean HbA1c level at the start of treatment with three or four OADs was 8.08%, which increased to 9.54% at the initiation of injection therapy (Fig. 3A). There was a mean decrease in the HbA1c level of 1.08% within 6 months of the start of injection therapy, with the mean HbA1c level after 60 months being 8.27%. Compared to GLP-1RA users, insulin users had significantly higher HbA1c levels both at the time of treatment with 3 or 4 OADs (8.16% vs. 7.83%, P< 0.001) and at the start of injection therapy (9.79% vs. 8.70%, P<0.001). However, no significant difference was observed in the HbA1c levels after 60 months of treatment (8.23% vs. 8.18%, P=0.121) (Fig. 3B).
Changes in glycated hemoglobin (HbA1c) levels before and after injectable therapies. Temporal changes in HbA1c levels before and after injectable therapy (A), insulin, or glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy (B). Modeling of changes in HbA1c according to HbA1c levels at the initiation of injectable therapy (C).
Nonlinear regression analysis confirmed that there was no significant difference in HbA1c levels between the two groups (8.15% vs. 8.16%, P=0.450) (Supplemental Fig. S4). Patient characteristics associated with the reduction in HbA1c levels after starting injection therapy were also analyzed. The time from OAD use to injection therapy (Supplemental Fig. S5) and duration of diabetes (Supplemental Fig. S6) were not associated with differences in HbA1c levels after injection therapy. However, the HbA1c level at the initiation of injection therapy significantly correlated with the post-treatment HbA1c level (Fig. 3C). When injection therapy was initiated with an HbA1c level of <8.0%, the achieved HbA1c level was significantly lower than when therapy was initiated with HbA1c levels between ≥8.0% and <10.0% or ≥10.0% (P=0.002 and P<0.001, respectively). These results were consistent when analyzed for insulin and GLP-1RA users (Supplemental Fig. S7).
To further investigate patient characteristics related to glycemic control after injection therapy, adjusted LS mean HbA1c levels (from visit 2 to the last visit) were analyzed according to each variable category (Fig. 4). In the insulin user group, older age (P=0.004), higher BMI (P=0.035), and lower HbA1c levels at insulin therapy initiation (P<0.001) were associated with better glycemic control. In the GLP-1RA user group, only the HbA1c level at the start of therapy was identified as a significant factor for glycemic control (P<0.001).
Factors associated with glycemic control after initiation of injectable therapy. Adjusted least squares (LS) indicated glycated hemoglobin (HbA1c) levels over a 5-year period categorized by patient characteristics. The factors analyzed included age, body mass index (BMI), duration of diabetes, time to initiation of injectable therapy, and HbA1c levels at initiation. Separate analyses are shown for insulin (A) and glucagon-like peptide-1 receptor agonists (GLP-1RA) (B) users.
DISCUSSION
In this retrospective study, we identified significant delays in transitioning from OADs to injectable therapies among patients with T2DM at referral centers in South Korea. The mean HbA1c at the time of insulin initiation was 9.79%, with 41.6% of patients starting therapy at levels above 10.0%. Over the 72 months preceding insulin therapy, HbA1c levels consistently exceeded 8.0%, reflecting prolonged periods of inadequate glycemic control. Despite this, 51.1% of patients delayed insulin initiation for more than 2 years, and 23.4% delayed for over 5 years while on triple or quadruple OAD regimens. GLP-1RA users exhibited similar, though less pronounced delays. These findings underscore the prolonged periods of suboptimal glycemic control despite the availability of effective injectable treatments, highlighting the need for timely intensification of injectable therapy.
This study focused on patients who transitioned to injectable therapy after triple or quadruple OAD use. Although injectable agents are occasionally introduced earlier, our findings reflect the most common clinical pathway in South Korea, where injectable therapy is typically administered after extensive OAD use. Notably, triple or quadruple OAD therapy began at HbA1c levels near 9.0%, suggesting that therapeutic inertia occurs not only at the injectable therapy stage but also during OAD management. Previous studies confirm that therapeutic inertia is a pervasive issue throughout diabetes management [7,13,14]. Previous studies have highlighted the low uptake and significant reluctance for injectable therapies in South Korea. A multinational study reported that South Korea had the lowest insulin treatment rate among 11 countries [15]. Additionally, a longitudinal analysis showed that insulin prescriptions declined from 10.5% in 2002 to 8.4% in 2019, likely due to the introduction of new oral hypoglycemic agents and increased use of combination therapies [6]. Despite these shifts, target glycemic control rates have shown little improvement. Our findings further emphasize delays in treatment intensification, increasing the glycemic burden in patients with T2DM.
Numerous studies have investigated the causes of therapeutic inertia in injectable therapies. The Delay of Insulin initiation in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycemic agents (Analysis of Patients‐ and Physicians‐related FACTORs) (DIPP-FACTOR) study, conducted across 69 medical institutions in South Korea, identified key barriers to timely insulin initiation [16]. Patient-related factors, such as fear of injections, misconceptions, and viewing injectable therapy as a last resort, are well-documented. However, systemic issues, including limited consultation time, insufficient support for patient education, and inadequate reimbursement for educational efforts, also play a significant role. Additionally, therapeutic inertia among healthcare providers—stemming from concerns about adherence, potential resistance, and lack of confidence in managing injectable therapies—further delays treatment intensification. Addressing these barriers requires systemic reforms, including enhanced healthcare infrastructure, better educational support for both patients and providers, and updated clinical guidelines to promote timely adoption of injectable therapies.
In this study, the number of patients who transitioned to insulin therapy after receiving triple or quadruple OAD therapy was approximately three times higher than those who transitioned to GLP-1RA therapy. Given that current guidelines generally recommend GLP-1RAs over insulins following oral therapy failure, this finding deviates from the recommended treatment pathway [17,18]. However, as the study period spanned from 2015 to 2021 and long-acting GLP-1RAs only became available in Korea in 2016, it is possible that their implementation required considerable time. Additionally, the lower utilization of GLP-1RAs in Korea may have been influenced by cost considerations and restrictions on insurance coverage.
We further analyzed differences in patient characteristics between insulin users and GLP-1RA users. Insulin users were older, had higher HbA1c levels, a longer duration of diabetes, and lower BMI compared to GLP-1RA users. Moreover, insulin users had lower mean eGFR and a higher prevalence of CKD. However, there was no significant difference in the prevalence of ASCVD between groups. Given that current guidelines recommend the preferential use of GLP-1RAs in patients with ASCVD, this suggests that real-world practice does not fully align with guideline recommendations [17,18]. Our findings indicate that the transition to insulin or GLP-1RA therapy in South Korea may be more strongly influenced by factors such as the severity of hyperglycemia and degree of obesity rather than the comorbid conditions.
Among insulin users, age was the significant factor associated with the time to transition from OADs to insulin therapy. Patients aged 65 years or older exhibited a shorter transition time, suggesting that younger patients (<65 years) may demonstrate greater resistance to initiating insulin therapy. In contrast, among GLP-1RA users, socioeconomic status appeared to influence treatment delay, likely due to the relatively high cost of GLP-1RAs. However, considering previous studies on clinical inertia in diabetes management, delays in initiating injectable therapy are likely influenced by more complex factors, involving both patient-related and physician-related elements [16]. Further research is warranted to elucidate these multifaceted determinants.
We analyzed factors influencing blood glucose changes after initiating injectable therapy, with the HbA1c level at therapy onset being the most significant. Patients who began insulin therapy with HbA1c <8.0% achieved a 5-year mean HbA1c of 7.59%, compared to 8.74% for those with levels >10.0%. Similar patterns were observed in GLP-1RA users. These findings highlight the importance of early injectable therapy to enhance glycemic control. Despite this, many patients fail to reach target HbA1c levels even after starting injectable therapies. For these patients, combination therapy with basal insulin and GLP-1RAs can improve glycemic outcomes and reduce hypoglycemia risk [19]. Alternatively, transitioning to a different injectable regimen, such as basal-bolus insulin or switching from GLP-1RAs to basal insulin, may be effective [4,5]. Regular monitoring and timely therapy adjustments are crucial for optimizing outcomes [20]. Lastly, improving treatment adherence through patient education and lifestyle modifications remains vital [21].
Addressing therapeutic inertia in injectable therapy requires a multifaceted approach. Enhancing perceptions of injectable treatments is crucial within both medical institutions and the public. Additionally, healthcare system improvements, including better support and education, are essential to help physicians adopt injectable therapies more effectively. Successful implementation demands sufficient time for patient counseling and education on injection techniques. However, in South Korea, limited consultation time and low reimbursement for educational efforts pose significant challenges.
This study has several limitations. First, the collected variables were limited; a more detailed analysis could include insulin types, GLP-1RAs, dosages, and hypoglycemic episodes. Second, the absence of a control group hindered a robust comparison of glycemic efficacy. Third, potential confounders, such as lifestyle factors, therapy adherence, and socioeconomic status, were not accounted for, which may have influenced the outcomes.
In conclusion, therapeutic inertia in injectable therapies, particularly insulin, remains significant, with initiation often delayed until HbA1c levels are markedly elevated. This delay, despite the strong glucose-lowering effects of injectable agents, underscores the need for strategies to overcome therapeutic inertia. Early and timely therapy intensification is crucial to prevent long-term complications from chronic hyperglycemia. A comprehensive, individualized approach that integrates clinical, patient-related, and systemic factors is essential to improving glycemic control and patient outcomes in T2DM management.
Supplementary Material
Supplemental Fig. S1.
Overall study design. HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; GLP-1RA, glucagon-like peptide-1 receptor agonist; T2DM, type 2 diabetes mellitus.
Supplemental Fig. S2.
Time to injectable therapies from 3 or 4 combination therapy of oral antidiabetic drugs according to participating centers.
Supplemental Fig. S3.
Factors associated with time to injectable therapies from triple or quadruple oral antidiabetic drugs (OADs). (A) Median time from initiation of triple or quadruple OADs to insulin therapy, and (B) median time from initiation of triple or quadruple OADs to glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy, stratified by age, sex, body mass index (BMI), presence of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), microvascular complications, and medical aid status.
Supplemental Fig. S4.
Modeling of changes in glycated hemoglobin (HbA1c) levels in insulin users and glucagon-like peptide-1 receptor agonist (GLP-1RA) users.
Supplemental Fig. S5.
Modeling of changes in glycated hemoglobin (HbA1c) levels according to time to initiation of injectable therapy: (A) <1, (B) 1–3, (C) 3–5, (D) 5–7, and (E) ≥7 years.
Supplemental Fig. S6.
Modeling of changes in glycated hemoglobin (HbA1c) levels according to duration of diabetes: (A) < 5, (B) 5–10, (C) 10–15, and (D) ≥15 years.
Supplemental Fig. S7.
Modeling of changes in glycated hemoglobin (HbA1c) levels according to HbA1c level at the initiation of insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies: (A) HbA1c < 8.0%, (B) HbA1c ≥8.0% to < 10.0%, and (C) HbA1c ≥10.0%.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
This work was funded by a grant (Jong Han Choi, 2021F-8) from the Korean Diabetes Association.
AUTHOR CONTRIBUTIONS
Conception or design: N.H.K. Acquisition, analysis, or interpretation of data: J.H.C., M.K.M., H.J.K., K.A.L., H.J.K., J.H.K., J.S.Y., S.H.K., S.C., N.H.K. Drafting the work or revising: J. H.C., M.K.M., H.J.K., K.A.L., H.J.K., J.H.K., J.S.Y., S.H.K., S.C., N.H.K. Final approval of the manuscript: J.H.C., M.K.M., H.J.K., K.A.L., H.J.K., J.H.K., J.S.Y., S.H.K., S.C., N.H.K.