Abstract
Background
This study aimed to evaluate the effectiveness and safety of quadruple combination therapy (metformin, DPP4 inhibitors, SGLT2 inhibitors, and sulfonylurea) in patients with high HbA1c at initial diagnosis or those who failed to achieve treatment goals.
Methods
This retrospective study included 412 diabetic patients treated with quadruple therapy at Uijeongbu St. Mary’s Hospital from January to December 2023. These patients were first diagnosed with diabetes or, due to suboptimal glycemic control, the attending physician recommended insulin therapy, but the patient refused. Patients were divided into an initial treatment group (group A) and a subsequent treatment group (group B). HbA1c levels, side effects, and regimen changes were monitored at 3- and 6-month post-treatment. Factors associated with achieving HbA1c < 7% were analyzed using logistic regression.
Results
For the total population, with quadruple therapy, the mean HbA1c decreased by -12.0 ± 15.5% from baseline, with 23.5% achieving HbA1c < 7% at 3 months. At 6 months, HbA1c decreased by 10.6%, with 21.6% achieving HbA1c < 7%. Group A achieved significantly greater HbA1c reductions at both 3 and 6 months than group B (-38.1% vs. -9.9%, P < 0.001). At 6 months, 54.5% of patients in group A achieved HbA1c < 7% compared to 18.9% in group B. Factors positively influencing HbA1c reduction included younger age, shorter diabetes duration, and initial treatment group. Minimal side effects were reported.
Conclusions
Quadruple oral hypoglycemic therapy may be a safe and effective option for patients with type 2 diabetes who refuse insulin, particularly in newly diagnosed individuals. While less effective in long-standing diabetes, it can serve as a transitional approach to improve glycemic control and promote future treatment adherence.
Clinical trial number
Not applicable.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12902-026-02390-z.
Keywords: Glycemic control, Combination therapy, Diabetes mellitus, Newly diagnosed diabetes, Dipeptidyl-peptidase IV inhibitors, Sodium-glucose transporter 2 inhibitors
Introduction
Recently, new drugs that control blood sugar through various mechanisms have been developed [1]. Despite the significant burden of diabetes, current treatments have limitations, making combination therapy increasingly important for effective management [2, 3]. The concept of combination therapy involving two or more drugs targeting various pathophysiological processes has emerged, considering that intensive glycemic control is crucial for reducing complications [4–6]. In addition, recently updated American Diabetes Association (ADA) guideline suggests that initiating early combination therapy in adults with type 2 diabetes mellitus (DM) can be advantageous for achieving personalized treatment goals more rapidly [7].
Consequently, while there is active research on the effects of multiple drug combinations in early DM treatment, clinical data on the quadruple combination of metformin, sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP4) inhibitors, and sulfonylureas (SU) are limited [4]. There have been studies where SGLT2 inhibitors or DPP4 inhibitors were added on when glucose control was inadequate with metformin plus DPP4 inhibitor or SGLT2 inhibitor, or where both were added simultaneously to metformin [8–10]. However, these studies are primarily limited to combinations of three or fewer drugs, with research on quadruple therapy being very scarce. One study reported that adding teneligliptin to patients inadequately controlled on metformin, SU, and an SGLT2 inhibitor reduced glycated hemoglobin (HbA1c) by 0.75% compared to the placebo group [11]. However, this study only evaluated teneligliptin as a single agent and was conducted in a controlled clinical trial setting, not reflecting real-world data.
In cases of newly diagnosed DM with high blood glucose levels or when patients do not meet treatment targets during follow-up, current guidelines recommend insulin or other injection therapies [7]. However, many patients in real-world settings refuse insulin therapy [12]. There is limited evidence supporting the use of quadruple therapy at initial diagnosis, particularly in patients with high HbA1c levels (≥ 8%) for whom insulin therapy is recommended but declined. This study aims to address this gap by exploring the safety and efficacy of quadruple therapy as an alternative in this specific patient population. Therefore, this study aims to evaluate the effectiveness and safety of a quadruple combination therapy (metformin, DPP4 inhibitors, SGLT2 inhibitors, and SU) in patients with high HbA1c at initial diagnosis or those not achieving treatment goals. Additionally, the study seeks to provide empirical evidence on the efficacy of quadruple therapy as a viable alternative for patients refusing insulin treatment. Specifically, this study aims to address the clinical question of whether initiating quadruple therapy at diagnosis offers superior glycemic control compared to a delayed approach, which begins quadruple therapy only after other treatments have failed.
Methods
Study design and participants
This study targeted diabetic patients who received quadruple treatment regimen (including a DPP4 inhibitor, SGLT2 inhibitor, SU, and metformin) at Uijeongbu St. Mary’s Hospital from January 1, 2023 to December 31, 2023. The electronic medical records (EMR) of the hospital were searched using prescription codes for diabetes medications to identify patients who were prescribed a quadruple therapy regimen retrospectively. A total of 490 patients were initially identified. These patients were who was first diagnosed with hyperglycemia or, due to the suboptimal glycemic control, the attending physician recommended insulin therapy, but the patient refused. 70 patients were excluded due to lack of follow-up data, making it impossible to determine the treatment effect as their 3-month HbA1c data were unavailable. 8 patients who were using a five-drug regimen, including TZD or insulin, were also excluded. Thus, a total of 412 patients were included in the final analysis.
The study population was divided into two groups. Group A: Initial treatment group (N = 31), consisting of patients who began DM treatment during the study period. Group B: Subsequent treatment group (N = 381), consisting of patients who had been on diabetes treatment prior to the study period and were subsequently prescribed the quadruple regimen. For inclusion in the study, patients in the initial treatment group (Group A) were required to have newly diagnosed diabetes with an HbA1c ≥ 8%, indicating the need for intensive glycemic control where insulin therapy is often recommended. In the subsequent treatment group (Group B), patients were included if they had not achieved optimal glycemic control (HbA1c < 7%) despite prior diabetes treatment and were advised by their physician to initiate insulin therapy. Patients in Group A were either first-time visitors to the hospital (newly diagnosed at Uijeongbu St. Mary’s Hospital) or confirmed to have no prior diabetes medication prescriptions within our institution based on a 12-month review of their electronic medical records (EMRs). Subsequent treatment was further divided into 5 groups depending on which drug was added or how it was changed from the previous regimen: adding SGLT2 inhibitor (N = 130), adding DPP4 inhibitor (N = 180), adding SU (N = 25), switching from insulin or other injection treatment(N = 34), and switching from TZD (N = 12). All individuals in both Group A and Group B were prescribed quadruple therapy (metformin, DPP4 inhibitors, SGLT2 inhibitors, and SU) for at least three months. The follow-up period for HbA1c assessment began uniformly at the time of initiating quadruple therapy for both groups. A detailed flow chart illustrating the patient disposition process, including inclusion and exclusion criteria and group categorization, has been provided (Fig. 1).
Fig. 1.
Flow chart of patient disposition. This flow chart illustrates the patient disposition process. A total of 490 patients who received quadruple therapy (metformin, dipeptidyl peptidase-4 [DPP4] inhibitor, sodium-glucose cotransporter-2 [SGLT2] inhibitor, and sulfonylurea [SU]) were identified using prescription codes. After exclusions due to loss to follow-up (N = 70) and the use of five-drug regimens, including thiazolidinedione [TZD] or insulin (N = 8), 412 patients were included in the final analysis
Data collection
Age, sex, height and weight were brought from the medical records. The duration of DM was defined as the period from when the patients first started diabetes medication at Uijeongbu St. Mary’s Hospital to the initiation of the quadruple therapy. If there was no record of the first prescription, DM duration was determined based on the medical record.
Baseline laboratory data, including insulin and C-peptide levels, were collected from tests conducted within 2 months before or after the initiation of treatment. HbA1c levels at 3- and 6-months post-quadruple treatment were recorded. The occurrence of side effects and any changes in the treatment regimen at the last follow-up were also documented. The side effects were obtained from medical records.
Primary outcome and secondary outcome
The primary outcomes of this study were change in HbA1c at 3- and 6-months post-treatment, and proportion of patients achieving HbA1c < 7.0% and HbA1c < 6.5% at 3- and 6-months post-treatment.
The secondary outcome was identification of factors affecting the achievement of HbA1c < 7.0% and HbA1c < 6.5%. Evaluation of regimen changes and occurrence of side effects at the last follow-up were also included in the secondary outcome.
Statistical analysis
Statistical analyses were conducted to compare baseline characteristics, glycemic control, and HbA1c reduction between the groups. Continuous variables were tested for normality using the Shapiro-Wilk test. Variables following a normal distribution were presented as mean ± standard deviation (SD). Non-normally distributed variables were presented as median (interquartile range, IQR). Categorical variables were presented as number and percentage [N(%)]. Baseline characteristics were compared between Group A and Group B using the t-test for normally distributed continuous variables and the Mann-Whitney U test for non-normally distributed continuous variables. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate. Changes in HbA1c at 3- and 6-months post-treatment were analyzed using paired t-tests for normally distributed variables and Wilcoxon signed-rank tests for non-normally distributed variables. Analysis of variance (ANOVA) was used to compare continuous variables across multiple groups, followed by multiple comparisons test to evaluate differences among the subsequent treatment groups.
Factors associated with achieving HbA1c < 7.0% and HbA1c < 6.5% at 3 and 6 months were identified using binary logistic regression analysis. In the univariate analysis, each potential factor was individually tested for its association with the outcome. Variables that were statistically significant in the univariate analysis (P < 0.05) or were clinically relevant were included in the multivariable logistic regression model to adjust for potential confounders. The results of the logistic regression analysis were reported as odds ratios (ORs) with 95% confidence intervals (CIs).
All statistical analyses were conducted using statistical software like SPSS (version 24; IBM Corp., Armonk, NY, USA) or R (version 4.1.1; R Project for Statistical Computing, Vienna, Austria). Graphs were created using Prism (version 8.02; GraphPad Software Inc., La Jolla, CA, USA).
Ethics
This study’s data were approved by the Catholic University Data Review Committee, with all information anonymized. Given the retrospective cohort study design, there was no risk of physical or mental harm to patients. Consequently, the review board waived the requirement for informed consent. This study complied with the principles of the Declaration of Helsinki and received approval from the Institutional Review Board of Uijeongbu St. Mary’s Hospital (UC24RISI0077).
Results
Baseline characteristics
The mean age of total study population was 59.5 ± 11.5 years, the female sex occupied about 40% of study population, and mean BMI was 26.1 ± 7.2 kg/m2. Group A (initial treatment group) significantly younger than Group B (Subsequent treatment group) (P < 0.001). The sex distribution was similar between the groups (P = 0.465). Both groups had similar BMI values (P = 0.797). Diabetes duration differed significantly (P < 0.001).
Regarding treatment regimens, the use of SGLT2 inhibitors was similar between groups (P = 0.860). There was a borderline difference in the use of DPP4 inhibitors (P = 0.048). The use of SU showed a statistical difference (P < 0.001), with glimepiride used exclusively in Group A (100.0%) and by 58.5% in Group B, while gliclazide was not used in Group A and was used by 41.5% in Group B.
Group A had higher glucose (285.1 ± 125 mg/dL) and HbA1c levels (11.3 ± 1.7%) than Group B (174.6 ± 64.4 mg/dL and 8.7 ± 1.1%, respectively) (P < 0.001). Insulin and C-peptide levels were also higher in Group A (P = 0.003 and P = 0.034, respectively). Group A had better renal function but higher ALT levels (P = 0.040), with no significant difference in AST (P = 0.096). Group A also had higher cholesterol and LDL-C levels (P < 0.001 for both), while HDL-C levels were similar (P = 0.493). Detailed numbers are descripted in Table 1.
Table 1.
Baseline characteristics
| Total (N = 412) | Group A Initial treatment (N = 31) |
Groub B Subsequent treatment (N = 381) |
P | |
|---|---|---|---|---|
| Age, year | 59.5 ± 11.5 | 49.2 ± 14.2 | 60.4 ± 10.8 | < 0.001 |
| Female sex | 165 (40.0%) | 10 (32.3%) | 155 (40.7%) | 0.465 |
| Height, cm | 163.8 ± 10.2 | 166.3 ± 8.6 | 163.7 ± 10.3 | 0.276 |
| Weight, kg | 70.0 ± 14.0 | 75.0 ± 17.7 | 69.6 ± 13.6 | 0.141 |
| BMI, kg/m2 | 26.1 ± 7.2 | 26.5 ± 6.3 | 26.0 ± 7.3 | 0.797 |
| DM duration, year | 7.0 ± 6.5 | 0.0 ± 0.0 | 7.5 ± 6.4 | < 0.001 |
| Regimen | ||||
| Sglt2 | 0.860 | |||
| Empagliflozin | 199 (48.3%) | 14 (45.2%) | 185 (48.6%) | |
| Dapagliflozin | 213 (51.7%) | 17 (54.8%) | 196 (51.4%) | |
| DPP4i | 0.048 | |||
| Linagliptin | 81 (19.7%) | 9 (29.0%) | 72 (18.9%) | |
| Teneligliptin | 90 (21.8%) | 11 (35.5%) | 79 (20.7%) | |
| Gemigliptin | 141 (34.2%) | 5 (16.1%) | 136 (35.7%) | |
| Evogliptin | 100 (24.3%) | 6 (19.4%) | 94 (24.7%) | |
| SU | < 0.001 | |||
| Glimepiride | 254 (61.7%) | 31 (100.0%) | 223 (58.5%) | |
| Gliclazide | 158 (38.3%) | 0 (0.0%) | 158 (41.5%) | |
| Laboratory data | ||||
| Glucose, mg/dl | 182.9 ± 76.2 | 285.1 ± 125.1 | 174.6 ± 64.4 | < 0.001 |
| HbA1c, % | 8.9 ± 1.4 | 11.3 ± 1.7 | 8.7 ± 1.1 | < 0.001 |
| Insulin | 13.1 ± 13.8 | 23.4 ± 17.3 | 11.6 ± 18.2 | 0.003 |
| C-peptide | 3.2 ± 2.0 | 3.9 ± 1.8 | 3.0 ± 2.0 | 0.034 |
| 3.5 (2.8–4.7) | 2.6 (1.8–3.8) | 0.009 | ||
| HOMA-IR | 0.2 ± 0.3 | 0.3 ± 0.3 | 0.2 ± 0.7 | 0.075 |
| 0.2 (0.1–0.3) | 0.1 (0.0-0.1) | < 0.001 | ||
| HOMA- β | 77.3 ± 228.5 | 258.4 ± 598.7 | 52.6 ± 92.6 | 0.131 |
| 35.2 (22.9–88.6) | 26.4 (16.7–60.3) | 0.164 | ||
| BUN, mg/dL | 17.1 ± 5.8 | 14.5 ± 4.3 | 17.3 ± 5.9 | 0.018 |
| Creatinine, mg/dL | 0.9 ± 0.3 | 0.8 ± 0.2 | 0.9 ± 0.3 | 0.017 |
| GFR, mL/min/1.73m2 | 86.2 ± 21.6 | 101.8 ± 15.1 | 85.0 ± 21.5 | < 0.001 |
| Sodium, mEq/L | 138.9 ± 2.5 | 135.9 ± 3.0 | 139.2 ± 2.2 | < 0.001 |
| Potassium, mEq/L | 4.7 ± 0.5 | 4.5 ± 0.5 | 4.7 ± 0.5 | 0.030 |
| AST, U/L | 24.3 ± 13.9 | 32.4 ± 26.4 | 23.6 ± 12.0 | 0.096 |
| ALT, U/L | 25.6 ± 17.5 | 40.1 ± 37.9 | 24.3 ± 13.8 | 0.040 |
| Total cholesterol, mg/dL | 159.9 ± 45.4 | 224.9 ± 44.6 | 153.0 ± 39.7 | < 0.001 |
| Triglyceride, mg/dL | 181.3 ± 132.9 | 259.4 ± 211.1 | 173.3 ± 119.9 | 0.051 |
| HDL-C, mg/dL | 48.7 ± 12.4 | 50.3 ± 15.4 | 48.5 ± 12.1 | 0.493 |
| LDL-C, mg/dL | 92.0 ± 40.1 | 147.2 ± 40.2 | 85.9 ± 35.1 | < 0.001 |
BMI, body mass index; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-β, homeostatic model assessment of β-cell function; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, γ-glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol
Comparative Analysis of HbA1c Reduction and Glycemic Target Achievement in Groups A (initial treatment) and B (subsequent treatment) (Fig. 2).
Fig. 2.
(A) HbA1c changes during the study period by initial or subsequent treatment group. (B) HbA1c changes from the baseline. (C) HbA1c < 7% or < 6.5% achieve rate at 3 months or 6 months from the treatment begin. Although the baseline HbA1c was higher in initial treatment group, it showed a greater reduction in HbA1c at both 3 and 6 months compared to subsequent treatment group. In results, the initial treatment group showed a significant reduction in HbA1c from baseline compared to subsequent treatment group. The initial treatment group achieved significantly higher rates of HbA1c < 7% and HbA1c < 6.5% at both 3 and 6 months compared to the subsequent treatment group (P < 0.001 for all comparisons)
For the total population, the baseline HbA1c was 8.9 ± 1.4%. At 3 months, the mean HbA1c was 7.7 ± 1.2% (decreased by -12.0 ± 15.5%), and at 6 months, it was 7.8 ± 1.2% (decreased by -10.6 ± 16.4%). Regarding glycemic targets, 23.5% of the total population achieved HbA1c < 7% and 8.7% achieved HbA1c < 6.5% at 3 months. At 6 months, 21.6% achieved HbA1c < 7% and 8.7% achieved HbA1c < 6.5%.
Group A showed a greater reduction in HbA1c at both 3 and 6 months compared to Group B. Group A showed a significant reduction in HbA1c from baseline compared to Group B (-38.1 ± 11.9% vs. -9.9 ± 13.7%) (P < 0.001). So, at 3 months, HbA1c levels were significantly lower in Group A (6.8 ± 0.9%) compared to Group B (7.8 ± 1.1%) (P < 0.001). This trends persist until 6 months (Fig. 2A). Group A showed a significant reduction in HbA1c from baseline (-38.1 ± 11.9%) compared to Group B (-9.9 ± 13.7%) (P < 0.001). At 6 months, these trends persist. (HbA1c level: 7.0 ± 1.5% in Group A and 7.9 ± 1.2% in Group B P < 0.001) (Fig. 2B).
At 3 months, 51.6% of Group A achieved HbA1c < 7% compared to 21.3% in Group B, and 38.7% of Group A achieved HbA1c < 6.5% compared to 6.3% in Group B. At 6 months, 54.5% of Group A reached HbA1c < 7% compared to 18.9% in Group B with 36.4% of Group A achieving HbA1c < 6.5% compared to 6.4% in Group B (all P < 0.001) (Fig. 2C). Detailed information is in the supplementary Table 1.
The sub-group analysis of group B according to their subsequent treatments
The median age varied significantly among the groups (P < 0.001), with the highest median age in the TZD group (68.5 years) and the lowest in the Insulin group (55.5 years). The sex distribution was similar across the groups (P = 0.145). There was a significant variation in diabetes duration among the groups (P = 0.008), with the longest duration in the TZD group (13.0 years) and the shortest in the SU group (1.0 year). The baseline HbA1c levels were comparable across the groups (P = 0.848).
HbA1c reduction at 3 months was notable in all groups except the TZD group (P = 0.185). The proportion of patients achieving HbA1c < 7% at 3 months varied significantly (P = 0.039), highest in the Insulin group (41.2%) and lowest in the TZD group (8.3%). Achieving HbA1c < 6.5% at 3 months also varied significantly (P = 0.003), with the highest in the Insulin group (20.6%) and lowest in the DPP4 inhibitor group (2.8%).
At 6 months, HbA1c reduction varied significantly (P = 0.038), greatest in the adding SGLT2 group (-11.2%) and smallest in the TZD group (-1.1%). The proportion achieving HbA1c < 7% at 6 months varied (P = 0.050), highest in the Insulin group (33.3%) and lowest in the adding SU group (6.2%). Achieving HbA1c < 6.5% at 6 months was highest in the Insulin group (16.7%) and lowest in the adding SU and TZD groups (0.0%) (P = 0.190). Detailed information is in the supplementary Tables 2 and P-values from multiple comparisons test are in the Fig. 3.
Fig. 3.
The sub-group analysis of Group B according to their subsequent treatment. (A) HbA1c changes from the baseline according to sub-groups. (B) Achieving rate to HbA1c < 7% or 6.5% according to sub-groups. HbA1c reduction at 3 months was notable in all groups except the TZD group (P = 0.185). The proportion of patients achieving HbA1c < 7% at 3 months varied significantly (P = 0.039), highest in the Insulin group (41.2%) and lowest in the TZD group (8.3%). Achieving HbA1c < 6.5% at 3 months also varied significantly (P = 0.003), with the highest in the Insulin group (20.6%) and lowest in the DPP4 inhibitor group (2.8%)
Furthermore, we performed a subgroup analysis stratified by diabetes duration (< 10 years vs. ≥10 years) to evaluate differential responses to specific treatment modifications. In patients with diabetes duration < 10 years, the addition of sulfonylurea (SU) or switching from insulin showed relatively greater glycemic efficacy, with higher proportions of patients achieving HbA1c < 6.5% or < 7.0% at both 3 and 6 months. In contrast, no such benefit was observed in patients with longer diabetes duration (≥ 10 years). These findings are detailed in Supplementary Table 3.
Regimen changes rate and side effects
Table 2 presents the data on regimen changes and the occurrence of side effects at the time of the last follow-up for Group A (initial treatment) and Group B (subsequent treatment). The median follow-up duration was 6.0 months (IQR 5.0-9.5 months) for Group A and 7.0 months (IQR 4.0–9.0 months) for Group B.
Table 2.
Changes in the quadruple regimen and occurrence of side effects at the time of the last follow-up
| Group A (initial treatment) | Group B (Subsequent treatment) | |||||||
|---|---|---|---|---|---|---|---|---|
| Regimen change (N = 14) |
Continue the regimen (N = 6) |
Dose reduction (N = 11) |
P | Regimen change (N = 95) |
Continue the regimen (N = 242) |
Dose reduction (N = 44) |
P | |
| Change reason | 0.175 | 0.291 | ||||||
| Improved glycemic control | 13 (92.9%) | 0 (0.0%) | 7 (63.6%) | 39 (41.1%) | 0 (0.0%) | 20 (45.5%) | ||
| Uncontrolled glycemic control | 1 (7.1%) | 0 (0.0%) | 3 (27.3%) | 34 (35.8%) | 0 (0.0%) | 14 (31.8%) | ||
| Others | 0 (0.0%) | 0 (0.0%) | 1 (9.1%) | 7 (7.4%) | 0 (0.0%) | 6 (13.6%) | ||
| Adverse effect | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 15 (15.8%) | 1 (0.4%) | 4 (9.1%) | ||
| UGI | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 8 (8.4%) | 1 (0.4%) | 2 (4.5%) | ||
| Weight loss | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 4 (4.2%) | 0 (0.0%) | 0 (0.0%) | ||
| hypoglycemia | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (2.1%) | 0 (0.0%) | 1 (2.3%) | ||
| General weakness | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.1%) | 0 (0.0%) | 0 (0.0%) | ||
| GI trouble | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.1%) | 0 (0.0%) | 1 (2.3%) | ||
Median follow-up duration: Group A; 6.0 (5.0-9.5) months, and Group B: 7.0 (4.0–9.0) months
UGI, urogenital infection; GI, gastrointestinal
Group A had 14 (45.2%) patients undergo regimen changes, 6 (19.4%) continued with the same regimen, and 11 (35.5%) had a dose reduction. No adverse effects were reported in Group A. Group B had 95 (24.9%) regimen changes, 242 (63.5%) continued with the same regimen, and 44 (11.6%) had dose reductions, with adverse effects reported in 15.8% of the regimen change group, 0.4% of the continue group, and 9.1% of the dose reduction group. Specific adverse effects included urogenital infections, weight loss, hypoglycemia, general weakness, and gastrointestinal trouble.
Factors associated with achieving HbA1c < 7.0% at 3 months and 6 months post-treatment
Table 3 presents the univariate and multivariable analyses of factors associated with achieving HbA1c levels below 7.0% at 3- and 6-months post-treatment. At 3 months, in the univariate analysis, individuals aged ≥ 65 years had lower odds of achieving HbA1c < 7.0% compared to those aged 40–65 years (OR 0.39, 95% CI: 0.22–0.68, P = 0.001). Female patients were less likely to achieve the target compared to males (OR 0.60, 95% CI: 0.37–0.97, P = 0.037). Patients with diabetes duration ≥ 10 years were less likely to achieve the target compared to those with < 10 years of diabetes duration (OR 0.42, 95% CI: 0.25–0.73, P = 0.002). Conversely, patients with baseline HbA1c ≥ 10 had higher odds of achieving the target compared to those with baseline HbA1c < 10 (OR 1.97, 95% CI: 1.13–3.45, P = 0.017). Those in the subsequent treatment group had significantly lower odds compared to the initial treatment group (OR 0.20, 95% CI: 0.12–0.53, P < 0.001).
Table 3.
Univariate and multivariable analysis of factors associated with achieving HbA1c < 7.0% at 3- and 6-months post-treatment
| Variables | For HbA1c < 7.0 at 3 months from treatment | For HbA1c < 7.0 at 6 months from treatment | ||||||
|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariable | Univariate | Multivariable | |||||
| OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | |
| Age | ||||||||
| Age < 40 years | 1.15 (0.42–3.15) | 0.780 | 0.44 (0.66–2.88) | 0.388 | 0.99 (0.20–4.97) | 0.993 | 0.30 (0.02–4.62) | 0.389 |
| Age ≥ 65 years | 0.39(0.22–0.68) | 0.001 | 0.27 (0.09–0.84) | 0.023 | 1.09 (0.60-2.00) | 0.775 | 0.43 (0.10–1.83) | 0.254 |
| Female to male | 0.60 (0.37–0.97) | 0.037 | 0.52 (0.18–1.52) | 0.231 | 1.03 (0.58–1.83) | 0.913 | 1.82 (0.53–6.26) | 0.339 |
| BMI ≥ 23 | 0.63 (0.34–1.15) | 0.134 | 0.65 (0.23–1.86) | 0.422 | 1.62 (0.70–3.77) | 0.262 | 1.37 (0.32–5.82) | 0.674 |
| DM duration ≥ 10 years | 0.42 (0.25–0.73) | 0.002 | 0.32 (0.09–1.19) | 0.089 | 0.57 (0.30–1.08) | 0.084 | 1.00 (0.24–4.18) | 0.997 |
| HbA1c (ordinary) | 0.92 (0.77–1.09) | 0.324 | 0.75 (0.52–1.09) | 0.131 | 1.10 (0.90–1.35) | 0.344 | 0.75 (0.43–1.30) | 0.306 |
| HbA1c ≥ 10 | 1.97 (1.13–3.45) | 0.017 | 1.09 (0.30–4.05) | 0.894 | 1.80 (0.90–3.56) | 0.095 | 0.91 (0.15–5.58) | 0.916 |
| Subsequent treatment to initial treatment | 0.2 (0.12–0.53) | < 0.001 | 0.37 (0.07–1.86) | 0.225 | 0.19 (0.08–0.47) | < 0.001 | 0.11 (0.10–1.14) | 0.064 |
| Regimen | ||||||||
| glimepiride to gliclazide | 1.35 (0.84–2.19) | 0.215 | 0.90 (0.50–1.61) | 0.723 | ||||
| Empagliflozin to dapagliflozin | 0.81 (0.51–1.28) | 0.371 | 1.03 (0.59–1.81) | 0.920 | ||||
| DPP4 inhibitor | ||||||||
| Linagliptin | 1 (reference) | 1 (reference) | 1 (reference) | |||||
| Teneligliptin | 0.98 (0.49–1.95) | 0.956 | 1.28 (0.56–2.93) | 0.561 | ||||
| Gemigliptin | 0.81 (0.43–1.52) | 0.505 | 0.94 (0.44-2.00) | 0.862 | ||||
| Evogliptin | 0.81(0.41–1.60) | 0.538 | 0.59 (0.24–1.45) | 0.248 | ||||
| C-peptide | 1.10 (0.94–1.28) | 0.253 | 0.82 (0.54–1.24) | 0.339 | 1.01(0.84–1.22) | 0.911 | 0.80 (0.52–1.21) | 0.287 |
| HOMA-IR | 4.56 (1.01–20.48) | 0.048 | 10.0(0.29–351.0) | 0.204 | 2.97 (0.72–12.31) | 0.134 | 0.45 (0.03–8.05) | 0.586 |
| HOMA-beta | 1.00 (1.00–1.00) | 0.066 | 1.00 (0.99-1.00) | 0.591 | 1.00 (0.99–1.01) | 0.147 | 1.02 (1.00-1.03) | 0.065 |
Multivariable analysis includes variables such as age, sex, BMI, DM duration, C-peptide, HOMA-IR, HOMA-beta, initial/subsequent treatment, and baseline HbA1c (excluding baseline HbA1c for HbA1c ≥ 10%)
Reference groups for comparisons: For age, the reference group is patients aged 40–65 years. For sex, the reference group is female patients. For BMI, the reference group is patients with BMI < 23. For diabetes duration, the reference group is < 10 years. For HbA1c ≥ 10, the reference group is patients with HbA1c < 10. Within the sulfonylurea (SU) group, glimepiride serves as the reference for comparisons with gliclazide; for SGLT2 inhibitors, empagliflozin is the reference for dapagliflozin; for DPP4 inhibitors, linagliptin is the reference for teneligliptin, gemigliptin, and evogliptin. Odds ratios for HbA1c, C-peptide, HOMA-IR, and HOMA-beta represent the effect per unit increase in these continuous variables
HbA1c, glycated hemoglobin; Dpp4 inhibitor, dipeptidyl peptidase inhibitor; HOMA-IR, homeostatic model assessment of insulin resistance; HOMA-β, homeostatic model assessment of β-cell function
In the multivariable analysis at 3 months, age ≥ 65 years remained significant, with individuals having lower odds of achieving HbA1c < 7.0% compared to those aged 40–65 years (OR 0.27, 95% CI: 0.09–0.84, P = 0.023). Other variables, including sex, BMI ≥ 23, diabetes duration ≥ 10 years, and baseline HbA1c ≥ 10, were not significantly associated.
At 6 months, the univariate analysis showed that individuals in the subsequent treatment group had significantly lower odds of achieving HbA1c < 7.0% compared to the initial treatment group (OR 0.19, 95% CI: 0.08–0.47, P < 0.001). None of the other variables, including age < 40 years, age ≥ 65 years, sex, BMI ≥ 23, diabetes duration ≥ 10 years, or baseline HbA1c ≥ 10, were significant. Multivariable analysis at 6 months confirmed no significant associations for these variables, with subsequent treatment group showing a trend toward lower odds (OR 0.11, 95% CI: 0.10–1.14, P = 0.064).
To minimize baseline heterogeneity, we conducted an additional logistic regression analysis restricted to Group B (patients already on triple therapy requiring intensification). As shown in Supplementary Table 4, younger age (40–65 years as reference) and lower baseline HbA1c were independently associated with achieving the target of HbA1c < 7.0% at 3 months post-treatment. Specifically, age ≥ 65 years (OR 0.21, 95% CI 0.08–0.57, P = 0.002) and higher baseline HbA1c (OR 0.57 per 1% increase, 95% CI 0.38–0.86, P = 0.007) were significantly associated with lower odds of achieving glycemic targets. No significant predictors were identified at 6 months.
Discussion
Our study demonstrates that a quadruple therapy regimen (metformin, DPP4 inhibitors, SGLT2 inhibitors, and SU) is effective for glycemic control, especially in newly diagnosed patients (Group A), where early initiation led to significantly greater HbA1c reductions compared to those with longer disease duration (Group B). These findings emphasize the importance of early treatment intensification for optimal outcomes. Our findings highlight the importance of personalized treatment approaches based on patient characteristics. For newly diagnosed patients who refuse insulin, initiating treatment with a quadruple therapy regimen can achieve significant glycemic control with minimal side effects. For patients already on treatment, especially those transitioning from insulin, oral quadruple therapy can enhance compliance and control.
In our study, during the 6 months, the quadruple gained about 1% reduction in HbA1c level and a 10% reduction from the baseline HbA1c level. In a randomized controlled study, adding teneligliptin to a triple therapy (metformin, SU, SGLT2 inhibitor) reduce HbA1c by 0.9% [11]. However, this study targeted only one drug and did not include first-time DM treatment patients. Ildiko Lingvay et al. compared insulin-based therapy with triple oral therapy (metformin, pioglitazone, glyburide) in newly diagnosed type 2 DM patients [13]. Initially, all patients received insulin and metformin for three months, then were randomly assigned to continue with either insulin and metformin or switch to triple oral therapy [14]. After three years, 83% of the insulin group and 72% of the oral group completed the study, with HbA1c levels of 6.1 ± 0.6% and 6.0 ± 0.8%, respectively, showing no significant difference. While the authors highlight the effectiveness of insulin therapy, the study also shows that triple oral therapy is equally effective in controlling blood sugar. Recent studies involving SGLT2 inhibitors showed that adding empagliflozin to a failed triple oral treatment had similar blood sugar control to adding basal insulin (-1.5% vs.-1.0%) and a benefited weight loss compared to insulin treatment [15]. In a Korean retrospective study, adding a fourth drug to failed triple therapy reduced HbA1c by 1.1% [16]. However, Most studies focus on adding a fourth medication to patients inadequately controlled on triple therapy. To our knowledge, there is a lack of evidence on the use of quadruple therapy as an initial treatment for newly diagnosed type 2 DM. Our study indicates that initial quadruple therapy is more effective in reducing HbA1c levels compared to subsequent regimens. Patients in the initial treatment group achieved greater HbA1c reductions at 3 and 6 months, with a higher proportion reaching target HbA1c levels of < 7.0% and < 6.5%. Early intensive glycemic control with quadruple therapy can benefit newly diagnosed DM patients who refuse insulin therapy. Researches has shown that early and sustained intensive glycemic control significantly reduced the risk of vascular complications and mortality in type 2 DM patients, supporting the efficacy of early quadruple therapy in achieving better outcomes [17–20].
In contrast, Group B showed less pronounced reductions, highlighting the challenges of managing long-standing diabetes with potentially exhausted β-cell function. Our sub-group analysis revealed that switching from insulin to oral quadruple therapy significantly improved HbA1c control, suggesting better compliance and glycemic outcomes for patients struggling with insulin injections. Given the high incidence of insulin refusal among type 2 diabetes patients, quadruple therapy is a viable alternative. Turchin et al. reported that 42.7% of patients declined insulin therapy, leading to suboptimal glycemic control and prolonged time to reach target HbA1c levels [12]. Participants were more likely to accept insulin therapy recommendations if they had diabetes complications (OR 1.32) or a higher HbA1c (OR 1.10), and less likely if they were older (OR 0.81) or were taking more non-insulin diabetes medications (OR 0.78). Implementing quadruple therapy can bridge this gap, effectively managing blood sugar in patients resistant to insulin. However, as the number of medications increases, future insulin therapy refusal may rise, potentially affecting long-term outcomes. Comprehensive patient education is crucial to ensure patients understand the importance of flexible treatment plans and are prepared to transition to insulin therapy if necessary.
Logistic regression analysis identified several factors influencing treatment success. Older age and longer diabetes duration were associated with lower likelihoods of achieving target HbA1c levels. This aligns with existing literature that suggests older patients and those with prolonged diabetes may have reduced β-cell function and increased insulin resistance, necessitating more aggressive or insulin treatment [20–24]. In contrast, for younger patients with a shorter duration of diabetes, intensive oral therapy can rapidly reverse glucotoxicity and preserve remaining β-cell function, leading to a more robust glycemic response. This is particularly important for preventing future complications in young-onset diabetes [25–27]. Furthermore, subgroup analysis by diabetes duration and treatment type (Supplementary Table 3) showed that adding sulfonylurea (SU) or switching from insulin appeared to be more effective in patients with a shorter duration of diabetes. These findings suggest that treatment strategies, including quadruple therapy, may benefit from being tailored according to diabetes duration and prior treatment history.
The side effects were minimal, with no adverse events in Group A. While urogenital infections were the most common side effect in Group B, the combination of SGLT2 and DPP4 inhibitors may mitigate this risk. Despite the urogenital infections are the most frequently reported adverse events associated with SGLT2 inhibitor therapy, recent evidence suggests that DPP4 inhibitors may mitigate this risk [28, 29], Indeed, the relative risk of genital infection with SGLT2 inhibitor/DPP4 inhibitor was lower that with SGLT2 inhibitor alone (RR = 0.42) [30]. Although the exact mechanisms how DPP4 inhibitor might reduce the risk of SGLT2 inhibitor associated genital infections remain uncertain, it could be a rationale for using the combination therapy to reduce the side effects of each medication [29, 30]. Although SGLT2 inhibitors carry a risk of euglycemic diabetic ketoacidosis (DKA), no cases were observed in our cohort [31]. This may be attributed to the outpatient-based setting and the absence of acute hyperglycemic symptoms in the initial treatment group. Nonetheless, careful patient selection remains essential when using SGLT2 inhibitors without insulin.
Our study has several limitations that should be acknowledged. Firstly, as a retrospective study, it is prone to selection bias and cannot establish causality. Treatment strategies were determined by the attending physicians, which may have introduced selection bias in group assignment, particularly for patients with advanced diabetes in Group B. While we clearly defined inclusion criteria and adjusted for confounders, unmeasured factors may still have influenced outcomes. Diabetes duration was based on available medical records, which may have underestimated the true duration, particularly in patients previously treated at other institutions. Secondly, the small sample size in the initial treatment group (31 patients), as well as the overall study population, limits the robustness and generalizability of our findings. Thirdly, we were unable to use an insulin treatment group as a control, which would have provided a more robust comparison. Moreover, while we identified factors such as age and diabetes duration as influencing HbA1c levels at the 3-month mark, these factors did not show a significant impact at 6 months. This discrepancy might be due to regimen changes or physician biases introduced during the course of treatment. Although our study reported a low incidence of hypoglycemia, this may reflect proactive dose adjustments by physicians to mitigate this risk. Furthermore, as this was a retrospective study conducted at a single tertiary institution, the findings may be subject to selection bias and have limited generalizability to other clinical settings or broader populations. Additionally, our study did not assess the impact of quadruple therapy on diabetic retinopathy, an important complication that warrants further investigation. Prospective studies are needed to provide clearer evidence regarding the long-term safety of quadruple therapy, including its effects on diabetic retinopathy and other microvascular complications. Therefore, future studies should prioritize well-designed, prospective trials with larger cohorts and insulin-treated controls to validate these findings. Long-term research is needed to evaluate the impact of quadruple therapy on microvascular complications, cost-effectiveness relative to insulin, and the interplay between β-cell function and treatment response. Additionally, the financial burden of quadruple therapy varies by regional insurance systems, and further economic analyses will be essential for clinical decision-making.
The primary goal of our study was not to demonstrate the superiority of quadruple therapy over insulin, but to evaluate its real-world effectiveness and safety in patients who refuse insulin. Our findings indicate that for newly diagnosed patients, intensive oral therapy can serve as a safe and effective ‘bridge’ to improve glycemic control when insulin is declined. However, in advanced cases with reduced β-cell reserve, early insulin initiation remains essential. In summary, quadruple therapy is a pragmatic and safe option for achieving glycemic targets, particularly when initiated early or as a transitional approach from insulin. Personalized treatment plans that consider disease duration and patient-specific factors will be essential for maximizing the benefits of this therapeutic approach.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Acknowledgements
During the course of preparing this work, the authors used Chat GPT for the purpose of English editing, including grammar and style checks. Following the use of this tool/service, the authors formally reviewed the content for its accuracy and edited it as necessary. The authors take full responsibility for all the content of this publication.
Author contributions
Han-Sang Baek contributed to data extraction, analysis, and manuscript writing. All authors reviewed, approved, and agreed to the submission of the manuscript.
Funding
None.
Data availability
The datasets generated and/or analysed during the current study are not publicly available due to personal data protection legislation but are available from the first author or corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study’s data were approved by the Catholic University Data Review Committee, with all information anonymized. Given the retrospective cohort study design, there was no risk of physical or mental harm to patients. Consequently, the review board waived the requirement for informed consent. This study complied with the principles of the Declaration of Helsinki and received approval from the Institutional Review Board of Uijeongbu St. Mary’s Hospital (UC24RISI0077).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analysed during the current study are not publicly available due to personal data protection legislation but are available from the first author or corresponding author on reasonable request.