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Original Article
Drug/Regimen Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors
Sangmo Hong1*orcid, Chang Hee Jung2*orcid, Song Han3, Cheol-Young Park4orcidcorresp_icon
Diabetes & Metabolism Journal 2022;46(1):63-70.
DOI: https://doi.org/10.4093/dmj.2020.0253
Published online: April 19, 2021
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1Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Seoul, Korea

2Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

3Life Sciences, LG Chem Ltd., Seoul, Korea

4Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

corresp_icon Corresponding author: Cheol-Young Park orcid Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongro-gu, Seoul 03181, Korea E-mail: cydoctor@chol.com
*Sangmo Hong and Chang Hee Jung contributed equally to this study as first authors.
• Received: October 23, 2020   • Accepted: January 26, 2021

Copyright © 2021 Korean Diabetes Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Background
    It is not known which type 2 diabetes mellitus (T2DM) patients would most benefit from dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. We aimed to investigate the predictors of response to DPP-4 inhibitors considering degree of DPP-4 inhibition.
  • Methods
    This study is a post hoc analysis of a 24-week, randomized, double-blind, phase III trial that compared the efficacy and safety of a DPP-4 inhibitor (gemigliptin vs. sitagliptin) in patients with T2DM. Subjects were classified into tertiles of T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35% by DPP-4 inhibition. We analyzed the change from baseline in glycosylated hemoglobin (HbA1c) according to DPP-4 inhibition with multiple linear regression adjusting for age, ethnicity, body mass index, baseline HbA1c, and DPP-4 activity at baseline.
  • Results
    The mean age was greater in the high tertile group compared with the low tertile group (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3±9.5, P<0.001) of DPP-4 inhibition. Although HbA1c at baseline was not different among tertiles of DPP-4 inhibition (P=0.398), HbA1c after 24-week treatment was lower in the higher tertile compares to the lower tertile (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). In multiple regression analysis, DPP-4 enzyme inhibition rate was not a significant determent for HbA1c reduction due to age. In subgroup analysis by tertile of DPP-4 inhibition, age was the only significant predictor and only in the highest tertile (R2=0.281, B=–0.014, P=0.024).
  • Conclusion
    This study showed that HbA1c reduction by DPP-4 inhibitor was associated with increasing age, and this association was linked with higher DPP-4 inhibition.
• The predictors of clinical response to DPP-4 inhibitors were age, ethnicity, and HbA1c at baseline.
• Older patients with DPP-4 inhibitor associated with higher degree of DPP-4 inhibition.
• The association between age and HbA1c reduction was dependent on higher degree of DPP-4 inhibition.
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used as a therapeutic option for patient with type 2 diabetes mellitus (T2DM) [1]. They improve glycemic control in patients with T2DM by increasing circulating levels of incretins, endogenous gut-derived peptide hormones that enhance insulin secretion and suppress glucagon release in a dose-dependent manner [2]. Despite the widespread use of DPP-4 inhibitors; however, it has not yet been established which patients would benefit most from the treatment. Although previous studies have suggested predictors of better clinical response to DPP-4 inhibitors [3-6], the results were somewhat inconsistent.
It has been demonstrated that currently available DPP-4 inhibitors might differ in potency of DPP-4 inhibition [7]. For example, once-daily treatment with sitagliptin provided significantly greater DPP-4 inhibition than saxagliptin or vildagliptin administered once daily and was similar to that of vildagliptin administered twice daily [8]. Furthermore, a meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results demonstrated that weighted average inhibition of DPP-4, a summary of the time course of DPP-4 inhibition over the dosing interval, was a useful biomarker related to glycosylated hemoglobin (HbA1c) response after chronic therapy with DPP-4 inhibitor [9]. However, few studies have suggested the predictors of better clinical response to DPP-4 inhibitors based on degree of DPP-4 inhibition.
Gemigliptin (LC15-0444) is a potent, highly selective, and long acting DPP-4 inhibitor. Various studies have demonstrated the efficacy and safety of gemigliptin for treatment of T2DM [10,11]. In addition, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycemic variability as measured by continuous glucose monitoring as an initial combination with metformin in patients with T2DM [12]. In this study, we aimed to investigate the predictors of better clinical response to DPP-4 inhibitors according to degree of DPP-4 inhibition.
Study population
This study is a post-hoc analysis of a multinational, randomized, active-controlled, parallel group, double-blind, phase 3 clinical trial in which the efficacy and safety of a DPP-4 inhibitor, gemigliptin versus sitagliptin added to metformin, were investigated in patients with T2DM (https://clinicaltrials.gov/ct2/show/NCT01602003). The detailed protocol of the study has been previously described [13]. Briefly, after screening (n=604), patients with T2DM (18 to 75 years of age) who were being treated with metformin monotherapy for at least 12 weeks with at least 4 weeks of 1,000 mg/day or higher dose of metformin before screening were randomized to one of the three treatment groups (sitagliptin 100 mg daily [n=142], gemigliptin 25 mg twice a day [n=141], or gemigliptin 50 mg daily [n=142]) at a 1:1:1 ratio. Each group was treated with the assigned treatment regimen for 24 weeks. We analyzed 323 patients who completed the treatment regimen and underwent measurement of DPP-4 activity at baseline and after 24 weeks. Approval was obtained from the Institutional Review Board of Kangbuk Samsung Hospital for the study protocol (KBSMC 2021-02-036). Informed consent was waived by the board.
Endpoint assessment
The primary endpoint of this post-hoc analysis was the change in HbA1c from baseline according to the degree of DPP-4 inhibition after treatment with DPP-4 inhibitors for 24 weeks.
Laboratory measurements
All blood samples for efficacy assessment were analyzed at the Seoul Clinical Laboratory, except for HbA1c and glucose collected during the first visit in Indian sites, which were analyzed at Super Religare Laboratories Ltd., Mumbai, India. Measurement techniques included the hexokinase method for glucose and enzymatic colorimetric assays (7600 Clinical Analyzer, Hitachi, Tokyo, Japan) for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Immunoradiometric assays were used for insulin (INS-IRMA, BiosourceKit, Biosource, Nivelles, Belgium) and C-peptide (IRMA, Immunotech Kit, Immunotech, Prague, Czech Republic) measurements. HbA1c was measured using turbidimetric inhibition immunoassays (TINIA, A1C-2 [tina-quant hemoglobin A1c Gen2], Roche Diagnostics, Mannheim, Germany). Homeostasis model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-β) at baseline were calculated as previously described [14]. Fasting plasma samples were stored at –80°C for measurement of DPP-4 activity using a continuous fluorometric assay with the substrate Gly-Pro-AMC (Bachem, Bubendorf, Switzerland) [15]. The degree of DPP-4 inhibition was calculated as 100×(1–W24/W0), where W0 was the enzyme activity measured before administration, and W24 was the activity measured after administration at week 24.
Statistical analysis
This post hoc analysis was based on the full analysis set population consisting of all patients at our institute who received the investigational drug at least once and showed signs of efficacy after randomization. Continuous variables were expressed as mean±standard deviation, whereas categorical variables were expressed as proportion (%). The tertile groups according to degree of DPP-4 inhibition were as follows: T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35%. Demographic and biochemical characteristics of the study population according to degree of DPP-4 inhibition were compared using two-sample t-test or Wilcoxon’s rank sum test for continuous variables and the chi-square test for categorical variables. The difference in change of HbA1c from baseline to week 24 according to degree of DPP-4 inhibition was compared using Kruskal-Wallis test, while the change of HbA1c from baseline to week 24 within each tertile group by degree of DPP-4 inhibition was analyzed using Wilcoxon signed rank test. The association between degree of DPP-4 inhibition and HbA1c reduction was investigated by multiple linear regression, with HbA1c reduction as the dependent variable. This analysis was adjusted for age, ethnicity (Korean vs. Indian), body mass index, HbA1c at baseline, and DPP-4 activity at baseline. All statistical analyses were carried out with SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA).
Demographics and baseline characteristics according to degree of DPP-4 inhibition
As previously described [13], 425 (296 from Korea and 129 from India) of 604 screened patients with T2DM were enrolled in the double-blind treatment period: 142 received sitagliptin 100 mg daily, 141 received gemigliptin 25 mg twice a day, and 142 received gemigliptin 50 mg daily. Among the 425 eligible patients, 323 had data for HbA1c level and DPP-4 activity at baseline and 24 weeks. Table 1 shows the baseline clinical and biochemical characteristics according to degree of DPP-4 inhibition. The average age of the study subjects was 52.9±9.7 years, and the average body mass index was 25.8±3.5 kg/m2. The mean HbA1c at baseline was 8.01%±0.8%, and mean fasting plasma glucose (FPG) value was 144.7±30.6 mg/dL. Sex (P=0.161), ethnicity (P=0.170), body mass index (P=0.676), waist circumference (P=0.618), HbA1c (P=0.398), FPG (P= 0.152), lipid profile (total cholesterol [P=0.996], HDL-C [P= 0.067], LDL-C [P=0.572], and triglyceride [P=0.375]), HOMA-IR (P=0.558), and HOMA-β (P=0.880) at baseline were similar across degrees of DPP-4 inhibition. However, the higher was the tertile by degree of DPP-4 inhibition, the higher was mean age (T1: 49.8±8.3 vs. T2: 53.1±10.5 vs. T3: 55.3± 9.5, P<0.001). And the higher tertile by degree of DPP-4 inhibition showed higher baseline DPP-4 activity (T1: 21.70±5.58 vs. T2: 21.99±4.37 vs. T3: 23.47±4.32, P=0.013)
HbA1c reduction according to degree of DPP-4 inhibition
Table 2 shows HbA1c at baseline and at week 24 after DPP-4 inhibitor treatment. The mean HbA1c at baseline was not different among the tertile groups by degree of DPP-4 inhibition (P=0.398) (Table 2). Overall, there was significant HbA1c reduction of –0.88%±0.76% after 24-week treatment (P<0.001) and in each tertile group by degree of DPP-4 inhibition (all P<0.001). The HbA1c at week 24 was significantly lower with increasing degree of DPP-4 inhibition (T1: 7.30%±0.88% vs. T2: 7.12%±0.78% vs. T3: 7.00%±0.78%, P=0.021). And the decrease of HbA1c from baseline to week 24 was higher with increasing degree of DPP-4 inhibition (T1: –9.60%±9.34% vs. T2: –10.29%±8.50% vs. T3: –12.12%±8.11%, P=0.062; P=0.037, between T1 and T3).
Independent association of degree of DPP-4 inhibition with HbA1c reduction
Table 3 shows the association of degree of DPP-4 inhibition with HbA1c reduction by multiple linear regression, with HbA1c reduction serving as the dependent variable.
In model 3 (R2=0.240) in which age, ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline, and degree of DPP-4 inhibition were adjusted, age (B=–0.013, P=0.001), ethnicity (Korean vs. Indian, B=0.169, P=0.047), and HbA1c at baseline (B=–0.470, P<0.001) were significant determinants for HbA1c reduction. In model 6 in which age was not adjusted, degree of DPP-4 inhibition (R2=0.240, B=–0.005, P<0.031) was a significant determinant for HbA1c reduction and ethnicity (Korean vs. Indian, B=0.213, P=0.013), as was HbA1c at baseline (B=–0.463, P<0.001).
Predictors of better clinical response to DPP-4 inhibitors by degree of DPP-4 inhibition
We conducted subgroup analysis by tertile group according to degree of DPP-4 inhibition (T1 <65.26%, T2=65.26%–76.35%, and T3 ≥76.35%), with HbA1c reduction serving as the dependent variable (Table 4). In subgroup analysis, baseline HbA1c was a significant predictor of better clinical response to DPP-4 inhibitors in all subgroups, and age was a significant predictor of better clinical response to DPP-4 inhibitors in the highest tertile (B=–0.014, P=0.024), marginal in the middle tertile (B=–0.012, P=0.057), and not significant in the lowest tertile (B=–0.014, P=0.161) (Table 4).
This present study investigates the predictors of better clinical response (HbA1c reduction) to DPP-4 inhibitors with consideration of pharmacokinetic response (degree of DPP-4 inhibition). The predictors of clinical response to DPP-4 inhibitors were age, ethnicity, and HbA1c at baseline in this study. In the consideration of pharmacokinetic response, the highest degree of DPP-4 inhibition was associated with higher age and with greater HbA1c reduction, but it was dependent on patient age.
Some studies have investigated the HbA1c response to DPP-4 inhibitors in patients with T2DM, but the results were heterogeneous. A meta-analysis by Kim et al. [16] reported that DPP-4 inhibitors exhibit better glucose-lowering efficacy in Asians than in other ethnic groups, and body mass index was significantly correlated with HbA1c reduction in response to DPP-4 inhibitors in patients with T2DM, especially in an Asian population. The Predicting Response to Incretin Based Agents in Type 2 Diabetes (PRIBA) study comprised mostly of Caucasians showed that markers of higher insulin resistance were associated with reduction in response to DPP-4 inhibitors [5]. This suggests that Asian populations have a higher risk of developing diabetes due to genetic defects affecting insulin secretory function and β-cell mass compared to the Caucasian population developing diabetes due to insulin resistance [17]. Like the above study, Korean of this study showed lower insulin resistance (HOMA-IR: 3.15±1.59 vs. 5.33±6.66, P<0.001) and lower β-cell function (HOMA-β: 42.54%±22.28% vs. 67.85%±45.15%, P<0.001) (Supplementary Table 1) comparing with Indian of this study. And ethnicity (Korean vs. Indian) was statistically significantly associated with HbA1c reduction but not degree of DPP-4 inhibition in our study. These showed that there was significantly different in HbA1c reduction in response to DPP-4 inhibitors between ethnicity, but this difference was not relying on the degree of DPP-4 inhibition. Body mass index was not statistically significantly associated with HbA1c reduction or degree of DPP-4 inhibition in our study despite the Asian population. In other meta-analysis with 98 randomized clinical trials (RCTs) with 100 arms, Esposito et al. [6] observed that baseline HbA1c level explained most of the variance in HbA1c reduction in response to DPP-4 inhibitors (34% of the variance between studies), but mean baseline age, duration of treatment, and previous diabetes drugs did not provide predictive power (less than 1%) to the DPP-4 inhibitor treatment response. However, in another meta-analysis with 63 RCTs, Monami et al. [3] reported the results of meta-analysis with 63 RCTs that DPP-4 inhibitors are more effective in older patients with mild to moderate fasting hyperglycemia, compatible with our study. Compared to previous study, the strengths of our study include inclusion of degree of DPP-4 inhibition in the analysis as a predictor of clinical response to DPP-4 inhibitors. Age is an independent predictor of clinical response to DPP-4 inhibitor based on degree of DPP-4 inhibition.
Age is one of the most important risk factors for T2DM, and there is evidence of differences in pathophysiology of T2DM in older compared with younger patients. It has been hypothesized that impaired insulin secretion, rather than insulin resistance, is responsible for most diabetes in elderly populations compared with younger populations. It has been repeatedly reported that the capacity of pancreatic β-cells to provide adequate insulin for metabolic demand is decreased with increasing age [18-21]. This age-related loss of β-cell secretory capability has been attributed to several factors, including attenuation of the enteroinsular axis, incretin potentiate insulin secretion. Faerch et al. [22] have suggested that a reduction in GLP-1 response to oral glucose could predispose one to T2DM. Other longitudinal study showed that a low tertile of GLP-1 response to the oral glucose tolerance test was associated with a steeper increase in fasting glucose level than higher tertiles during 7 years of follow-up [23]. A recent longitudinal study showed that fasting GIP and GLP-1 and glucose-stimulated GLP-1 decreased significantly over a mean period of 5.9 years and suggested that reduction in incretin hormone responses with aging may predispose one to the glucose intolerance and T2DM [24]. A major mechanism of action of DPP-4 inhibitors is potentiation of β-cell insulin secretion and inhibition of glucagon secretion by elevating endogenous GLP-1 in a glucosedependent mode of action [25]. In our study, we divided study population into younger (<53 years old) and older (≥53 years old) group with median age (Supplementary Table 2), there were significant different in HOMA-IR between younger group (4.328±15.354) and older group (3.281± 15.354, P<0.001) but HOMA-β (%) at baseline were not different between younger group (53.13±42.47) and older group (46.94±23.15, P=0.10). Although there was significant difference in HbA1c difference from baseline between younger and older groups (–0.76±0.79 vs. –1.00±0.72, P<0.001), there was no proof that the insulin secretory function was more improved by DPP-4 inhibitors therapy in the older group compared to younger group. HOMAβ (%) change from baseline to week 24 were not different between younger and older groups (18.06±53.48 vs. 30.53± 123.35, P=0.25). And these were also similar in highest tertile of DPP-4 inhibition rate group (21.28±40.02 vs. 41.87± 123.35, P=0.45) (Supplementary Table 3). Therefore, there was possibility for other mechanism for HbA1c reduction by DPP-4 inhibitors in older patients with high DPP-4 inhibition rate, further study needed.
There are some limitations to this study. First, due to the nature of post hoc analysis, the sample size could be inadequate to find other less significant predictors of clinical response to DPP-4 inhibitors. Second, the relatively short-term follow-up of the study (24 weeks) could hinder evaluation of predictors of clinical response to DPP-4 inhibitors. However, previous randomized studies showed great HbA1c reduction within the first 8 to 12 weeks of such treatment [26,27]. Third, we described as the elder patients were more beneficial in the treatment with DPP-4 inhibitors. However, the average age of T3 was 55.3 years old and not very advanced age and we did not suggest a cut off of any age which was more beneficial in the treatment with DPP-4 inhibitors. Therefore ‘elder’ patients should not restrict to ‘elderly’ patients.
In conclusion, our study showed that age, ethnicity, and HbA1c at baseline were predictors of clinical response to DPP4 inhibitors. In elder but not younger patients with diabetes, DPP-4 enzyme inhibition rate was associated with HbA1c reduction. Therefore, a DPP-4 inhibitor might be adequate treatment in elder patient with diabetes.
Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2020.0253
Supplementary Table 1.
Baseline clinical and biochemical characteristics according to ethnicity
dmj-2020-0253-suppl1.pdf
Supplementary Table 2.
Baseline clinical and biochemical characteristics according to age group
dmj-2020-0253-suppl2.pdf
Supplementary Table 3.
Change of HOMA-β from baseline to week 24 according to degree of DPP-4 inhibition and age groups
dmj-2020-0253-suppl3.pdf

CONFLICTS OF INTEREST

Sangmo Hong, Chang Hee Jung, and Cheol-Young Park had no potential conflict of interest relevant to this article. Song Han was hired by LG Chem Ltd., Seoul.

AUTHOR CONTRIBUTIONS

Conception or design: S.H., C.H.L., C.Y.P.

Acquisition, analysis, or interpretation of data: S.H, C.H.L., S.H., C.Y.P.

Drafting the work or revising: S.H., C.H.L.

Final approval of the manuscript: S.H., C.Y.P.

FUNDING

None

Acknowledgements
The authors thank the staff who conducted the original study, the patients for their participation and the industry sponsor (Life Sciences, LG Chem Ltd., Seoul, Korea) for coordination and funding of the original study.
dmj-2020-0253f1.jpg
Table 1.
Baseline clinical and biochemical characteristics according to degree of DPP-4 inhibition
Characteristic DPP-4 enzyme inhibition rate
Total T1 (<65.26%) T2 (65.26%–76.35%) T3 (≥76.35%) P value
No. of patients 323 96 112 115
Age, yr 52.9±9.7 49.8±8.3 53.1±10.5 55.3±9.5 <0.0001
Male sex, % 53.9 58.3 57.1 44.0 0.1611
Ethnicity (Indian/Korean), % 29.7/70.3 32.3/67.7 23.2/76.8 33.9/66.1 0.1702
The proportion of each DPP-4 inhibitor (sitagliptin/gemigliptin), % 31.6/68.4 57.3/42.7 25.0/75.0 16.5/83.5 <0.0001
Body mass index, kg/m2 25.8±3.5 25.9±3.2 26.0±3.6 25.6±3.6 0.6759
Waist circumference, cm 89.45±9.1 90.2±9.0 89.2±8.6 89.1±9.7 0.6176
HbA1c at baseline, % 8.01±0.8 8.1±0.8 8.0±0.8 8.0±0.8 0.3978
FPG at baseline, mg/dL 144.7±30.6 145.8±29.7 148.2±35.0 140.4±26.2 0.1515
Total cholesterol at baseline, mg/dL 166.9±38.8 168.2±43.9 166.0±36.5 166.6±36.6 0.9962
HDL-C at baseline, mg/dL 43.9±12.0 41.7±12.1 45.0±12.5 44.6±11.4 0.0681
LDL-C at baseline, mg/dL 91.9±31.4 93.4±31.2 92.3±31.3 90.3±31.9 0.5721
TG at baseline, mg/dL 161.6±122.2 173.0±143.6 155.2±135.4 158.1±83.7 0.3746
HOMA-IR at baseline 3.73±4.2 3.7±2.1 4.1±6.7 3.4±1.7 0.5581
HOMA-β at baseline 49.9±33.7 51.0±36.9 50.4±38.2 48.3±25.5 0.8798
Baseline DPP-4 activity 22.43±4.71 21.70±5.58 21.99±4.37 23.47±4.32 0.0130

Values are presented as mean±standard deviation.

DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function.

Table 2.
Change of HbA1c from baseline to week 24 according to degree of DPP-4 inhibition
Variable DPP-4 enzyme inhibition rate
P value
Total T1 (<65.26%) T2 (65.26%–76.35%) T3 (≥76.35%)
HbA1c at baseline, % 8.01±0.80 8.10±0.84 7.97±0.79 7.98±0.77 0.3978
HbA1c at week 24 7.13±0.82 7.30±0.88 7.12±0.78 7.00±0.78 0.0212
P value <0.001 <0.001 <0.001 <0.001
HbA1c change from baseline to week 24, % –10.74±8.67 –9.60±9.34 –10.29±8.50 –12.12±8.11 0.0620 (0.037a)

Values are presented as mean±standard deviation.

HbA1c, glycosylated hemoglobin; DPP-4, dipeptidyl peptidase-4.

a P value by t-test between T1 and T3.

Table 3.
The relationship between degree of DPP-4 inhibition and degree of HbA1c reduction from baseline to week 24
Variable R2 B SE P value
Model 1
 Age 0.0245 –0.0100 0.0045 0.0279
 Enthinicity (Indian/Korean), % 0.0509 0.0953 0.5937
 Body mass index 0.0004 0.0125 0.9751
 Degree of DPP-4 inhibition –0.0024 0.0024 0.3210
Model 2
 Age 0.2615 –0.0125 0.0040 0.0019
 Enthinicity (Indian/Korean), % 0.1827 0.0840 0.0304
 Body mass index 0.0011 0.0109 0.9173
 HbA1c at baseline –0.4758 0.0472 <0.0001
 Degree of DPP-4 inhibition –0.0039 0.0021 0.0678
Model 3
 Age 0.2403 –0.0129 0.0040 0.0013
 Enthinicity (Indian/Korean), % 0.1688 0.0848 0.0474
 Body mass index 0.0015 0.0848 0.8902
 HbA1c at baseline –0.4701 0.0109 <0.0001
 DPP-4 activity at baseline –0.0094 0.0474 0.2324
 Degree of DPP-4 inhibition –0.0033 0.0021 0.1195
Model 4 0.0096
 Enthinicity (Indian/Korean), % 0.0842 0.0946 0.3742
 Body mass index 0.0047 0.0124 0.7035
 Degree of DPP-4 inhibition –0.0033 0.0024 0.1650
Model 5 0.2386
 Enthinicity (Indian/Korean), % 0.2214 0.0842 0.0090
 Body mass index 0.0065 0.0109 0.5528
 HbA1c at baseline –0.4669 0.0477 <0.0001
 Degree of DPP-4 inhibition –0.0050 0.0021 0.0186
Model 6 0.2403
 Enthinicity (Indian/Korean), % 0.2128 0.0850 0.0128
 Body mass index 0.0069 0.0109 0.5281
 HbA1c at baseline –0.4626 0.0480 <0.0001
 DPP-4 activity at baseline –0.0066 0.0080 0.4041
 Degree of DPP-4 inhibition –0.0047 0.0021 0.0305

Model 1: age, ethnicity, body mass index; Model 2: age, ethnicity, body mass index, HbA1c at baseline; Model 3: age, ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline; Model 4: ethnicity, body mass index; Model 5: ethnicity, body mass index, HbA1c at baseline; Model 6: ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline.

DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; SE, standard error.

Table 4.
The association between age and clinical response to DPP-4 inhibitors by tertile of DPP-4 enzyme inhibition rate
DPP-4 enzyme inhibition rate Model 1
Model 2
Model 3
B SE P value B SE P value B SE P value
<65.26%
 Age –0.0167 0.0108 0.1269 –0.0137 0.0097 0.1623 –0.0138 0.0097 0.1612
 HbA1c at baseline - - - –0.4400 0.0884 <0.0001 –0.4422 0.0891 <0.0001
65.26%–76.35%
 Age –0.0039 0.0070 0.5786 –0.0098 0.0062 0.1169 –0.0123 0.0064 0.0568
 HbA1c at baseline - - - –0.4959 0.0814 <0.0001 –0.4903 0.0811 <0.0001
≥76.35%
 Age –0.0117 0.0072 0.1065 –0.0137 0.0063 0.0321 –0.0144 0.0063 0.0244
 HbA1c at baseline - - - –0.4754 0.0808 <0.0001 –0.4628 0.0811 <0.0001

Model 1: age, ethnicity, body mass index; Model 2: age, ethnicity, body mass index, HbA1c at baseline; Model 3: age, ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline.

DPP-4, dipeptidyl peptidase-4; SE, ; HbA1c, glycosylated hemoglobin.

  • 1. Ko SH, Han K, Lee YH, Noh J, Park CY, Kim DJ, et al. Past and current status of adult type 2 diabetes mellitus management in Korea: a National Health Insurance Service database analysis. Diabetes Metab J 2018;42:93-100.ArticlePubMedPMCPDF
  • 2. Roder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med 2016;48:e219.ArticlePubMedPMCPDF
  • 3. Monami M, Cremasco F, Lamanna C, Marchionni N, Mannucci E. Predictors of response to dipeptidyl peptidase-4 inhibitors: evidence from randomized clinical trials. Diabetes Metab Res Rev 2011;27:362-72.ArticlePubMed
  • 4. Bihan H, Ng WL, Magliano DJ, Shaw JE. Predictors of efficacy of GLP-1 agonists and DPP-4 inhibitors: a systematic review. Diabetes Res Clin Pract 2016;121:27-34.ArticlePubMed
  • 5. Dennis JM, Shields BM, Hill AV, Knight BA, McDonald TJ, Rodgers LR, et al. Precision medicine in type 2 diabetes: clinical markers of insulin resistance are associated with altered short- and long-term glycemic response to DPP-4 inhibitor therapy. Diabetes Care 2018;41:705-12.ArticlePubMedPDF
  • 6. Esposito K, Chiodini P, Maiorino MI, Capuano A, Cozzolino D, Petrizzo M, et al. A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ Open 2015;5:e005892.ArticlePubMedPMC
  • 7. Deacon CF. Physiology and pharmacology of DPP-4 in glucose homeostasis and the treatment of type 2 diabetes. Front Endocrinol (Lausanne) 2019;10:80.ArticlePubMedPMC
  • 8. Tatosian DA, Guo Y, Schaeffer AK, Gaibu N, Popa S, Stoch A, et al. Dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes treated with saxagliptin, sitagliptin, or vildagliptin. Diabetes Ther 2013;4:431-42.ArticlePubMedPMCPDF
  • 9. Gibbs JP, Fredrickson J, Barbee T, Correa I, Smith B, Lin SL, et al. Quantitative model of the relationship between dipeptidyl peptidase-4 (DPP-4) inhibition and response: meta-analysis of alogliptin, saxagliptin, sitagliptin, and vildagliptin efficacy results. J Clin Pharmacol 2012;52:1494-505.ArticlePubMed
  • 10. Yang SJ, Min KW, Gupta SK, Park JY, Shivane VK, Pitale SU, et al. A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes. Diabetes Obes Metab 2013;15:410-6.ArticlePubMed
  • 11. Kim SH, Yoo JH, Lee WJ, Park CY. Gemigliptin: an update of its clinical use in the management of type 2 diabetes mellitus. Diabetes Metab J 2016;40:339-53.ArticlePubMedPMCPDF
  • 12. Park SE, Lee BW, Kim JH, Lee WJ, Cho JH, Jung CH, et al. Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study). Diabetes Obes Metab 2017;19:892-6.ArticlePubMedPDF
  • 13. Rhee EJ, Lee WY, Min KW, Shivane VK, Sosale AR, Jang HC, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Obes Metab 2013;15:523-30.ArticlePubMed
  • 14. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004;27:1487-95.ArticlePubMedPDF
  • 15. Zhu L, Tamvakopoulos C, Xie D, Dragovic J, Shen X, Fenyk-Melody JE, et al. The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 2003;278:22418-23.PubMed
  • 16. Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia 2013;56:696-708.ArticlePubMedPDF
  • 17. Rhee EJ. Diabetes in Asians. Endocrinol Metab (Seoul) 2015;30:263-9.ArticlePubMedPMC
  • 18. Chang AM, Smith MJ, Galecki AT, Bloem CJ, Halter JB. Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance. J Clin Endocrinol Metab 2006;91:3303-9.PubMed
  • 19. Cobelli C, Toffolo GM, Dalla Man C, Campioni M, Denti P, Caumo A, et al. Assessment of beta-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests. Am J Physiol Endocrinol Metab 2007;293:E1-15.PubMed
  • 20. Szoke E, Shrayyef MZ, Messing S, Woerle HJ, van Haeften TW, Meyer C, et al. Effect of aging on glucose homeostasis: accelerated deterioration of beta-cell function in individuals with impaired glucose tolerance. Diabetes Care 2008;31:539-43.PubMed
  • 21. Cai X, Xia L, Pan Y, He D, Zhu H, Wei T, et al. Differential role of insulin resistance and β-cell function in the development of prediabetes and diabetes in middle-aged and elderly Chinese population. Diabetol Metab Syndr 2019;11:24.ArticlePubMedPMCPDF
  • 22. Faerch K, Torekov SS, Vistisen D, Johansen NB, Witte DR, Jonsson A, et al. GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: the ADDITION-PRO Study. Diabetes 2015;64:2513-25.ArticlePubMedPDF
  • 23. Koopman ADM, Rutters F, Rauh SP, Nijpels G, Holst JJ, Beulens JW, et al. Incretin responses to oral glucose and mixed meal tests and changes in fasting glucose levels during 7 years of follow-up: the Hoorn Meal Study. PLoS One 2018;13:e0191114.ArticlePubMedPMC
  • 24. Pham H, Marathe CS, Phillips LK, Trahair LG, Hatzinikolas S, Huynh L, et al. Longitudinal changes in fasting and glucosestimulated GLP-1 and GIP in healthy older subjects. J Clin Endocrinol Metab 2019;104:6201-6.ArticlePubMedPDF
  • 25. Gallwitz B. Clinical use of DPP-4 inhibitors. Front Endocrinol (Lausanne) 2019;10:389.ArticlePubMedPMC
  • 26. Hong S, Park CY, Han KA, Chung CH, Ku BJ, Jang HC, et al. Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24- week multicentre, randomized, double-blind, placebo-controlled phase III trial. Diabetes Obes Metab 2016;18:528-32.PubMedPMC
  • 27. Hong SM, Park CY, Hwang DM, Han KA, Lee CB, Chung CH, et al. Efficacy and safety of adding evogliptin versus sitagliptin for metformin-treated patients with type 2 diabetes: a 24-week randomized, controlled trial with open label extension. Diabetes Obes Metab 2017;19:654-63.ArticlePubMedPMCPDF

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        Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors
        Diabetes Metab J. 2022;46(1):63-70.   Published online April 19, 2021
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      Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors
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      Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors
      Characteristic DPP-4 enzyme inhibition rate
      Total T1 (<65.26%) T2 (65.26%–76.35%) T3 (≥76.35%) P value
      No. of patients 323 96 112 115
      Age, yr 52.9±9.7 49.8±8.3 53.1±10.5 55.3±9.5 <0.0001
      Male sex, % 53.9 58.3 57.1 44.0 0.1611
      Ethnicity (Indian/Korean), % 29.7/70.3 32.3/67.7 23.2/76.8 33.9/66.1 0.1702
      The proportion of each DPP-4 inhibitor (sitagliptin/gemigliptin), % 31.6/68.4 57.3/42.7 25.0/75.0 16.5/83.5 <0.0001
      Body mass index, kg/m2 25.8±3.5 25.9±3.2 26.0±3.6 25.6±3.6 0.6759
      Waist circumference, cm 89.45±9.1 90.2±9.0 89.2±8.6 89.1±9.7 0.6176
      HbA1c at baseline, % 8.01±0.8 8.1±0.8 8.0±0.8 8.0±0.8 0.3978
      FPG at baseline, mg/dL 144.7±30.6 145.8±29.7 148.2±35.0 140.4±26.2 0.1515
      Total cholesterol at baseline, mg/dL 166.9±38.8 168.2±43.9 166.0±36.5 166.6±36.6 0.9962
      HDL-C at baseline, mg/dL 43.9±12.0 41.7±12.1 45.0±12.5 44.6±11.4 0.0681
      LDL-C at baseline, mg/dL 91.9±31.4 93.4±31.2 92.3±31.3 90.3±31.9 0.5721
      TG at baseline, mg/dL 161.6±122.2 173.0±143.6 155.2±135.4 158.1±83.7 0.3746
      HOMA-IR at baseline 3.73±4.2 3.7±2.1 4.1±6.7 3.4±1.7 0.5581
      HOMA-β at baseline 49.9±33.7 51.0±36.9 50.4±38.2 48.3±25.5 0.8798
      Baseline DPP-4 activity 22.43±4.71 21.70±5.58 21.99±4.37 23.47±4.32 0.0130
      Variable DPP-4 enzyme inhibition rate
      P value
      Total T1 (<65.26%) T2 (65.26%–76.35%) T3 (≥76.35%)
      HbA1c at baseline, % 8.01±0.80 8.10±0.84 7.97±0.79 7.98±0.77 0.3978
      HbA1c at week 24 7.13±0.82 7.30±0.88 7.12±0.78 7.00±0.78 0.0212
      P value <0.001 <0.001 <0.001 <0.001
      HbA1c change from baseline to week 24, % –10.74±8.67 –9.60±9.34 –10.29±8.50 –12.12±8.11 0.0620 (0.037a)
      Variable R2 B SE P value
      Model 1
       Age 0.0245 –0.0100 0.0045 0.0279
       Enthinicity (Indian/Korean), % 0.0509 0.0953 0.5937
       Body mass index 0.0004 0.0125 0.9751
       Degree of DPP-4 inhibition –0.0024 0.0024 0.3210
      Model 2
       Age 0.2615 –0.0125 0.0040 0.0019
       Enthinicity (Indian/Korean), % 0.1827 0.0840 0.0304
       Body mass index 0.0011 0.0109 0.9173
       HbA1c at baseline –0.4758 0.0472 <0.0001
       Degree of DPP-4 inhibition –0.0039 0.0021 0.0678
      Model 3
       Age 0.2403 –0.0129 0.0040 0.0013
       Enthinicity (Indian/Korean), % 0.1688 0.0848 0.0474
       Body mass index 0.0015 0.0848 0.8902
       HbA1c at baseline –0.4701 0.0109 <0.0001
       DPP-4 activity at baseline –0.0094 0.0474 0.2324
       Degree of DPP-4 inhibition –0.0033 0.0021 0.1195
      Model 4 0.0096
       Enthinicity (Indian/Korean), % 0.0842 0.0946 0.3742
       Body mass index 0.0047 0.0124 0.7035
       Degree of DPP-4 inhibition –0.0033 0.0024 0.1650
      Model 5 0.2386
       Enthinicity (Indian/Korean), % 0.2214 0.0842 0.0090
       Body mass index 0.0065 0.0109 0.5528
       HbA1c at baseline –0.4669 0.0477 <0.0001
       Degree of DPP-4 inhibition –0.0050 0.0021 0.0186
      Model 6 0.2403
       Enthinicity (Indian/Korean), % 0.2128 0.0850 0.0128
       Body mass index 0.0069 0.0109 0.5281
       HbA1c at baseline –0.4626 0.0480 <0.0001
       DPP-4 activity at baseline –0.0066 0.0080 0.4041
       Degree of DPP-4 inhibition –0.0047 0.0021 0.0305
      DPP-4 enzyme inhibition rate Model 1
      Model 2
      Model 3
      B SE P value B SE P value B SE P value
      <65.26%
       Age –0.0167 0.0108 0.1269 –0.0137 0.0097 0.1623 –0.0138 0.0097 0.1612
       HbA1c at baseline - - - –0.4400 0.0884 <0.0001 –0.4422 0.0891 <0.0001
      65.26%–76.35%
       Age –0.0039 0.0070 0.5786 –0.0098 0.0062 0.1169 –0.0123 0.0064 0.0568
       HbA1c at baseline - - - –0.4959 0.0814 <0.0001 –0.4903 0.0811 <0.0001
      ≥76.35%
       Age –0.0117 0.0072 0.1065 –0.0137 0.0063 0.0321 –0.0144 0.0063 0.0244
       HbA1c at baseline - - - –0.4754 0.0808 <0.0001 –0.4628 0.0811 <0.0001
      Table 1. Baseline clinical and biochemical characteristics according to degree of DPP-4 inhibition

      Values are presented as mean±standard deviation.

      DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-β, homeostasis model assessment of β-cell function.

      Table 2. Change of HbA1c from baseline to week 24 according to degree of DPP-4 inhibition

      Values are presented as mean±standard deviation.

      HbA1c, glycosylated hemoglobin; DPP-4, dipeptidyl peptidase-4.

      P value by t-test between T1 and T3.

      Table 3. The relationship between degree of DPP-4 inhibition and degree of HbA1c reduction from baseline to week 24

      Model 1: age, ethnicity, body mass index; Model 2: age, ethnicity, body mass index, HbA1c at baseline; Model 3: age, ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline; Model 4: ethnicity, body mass index; Model 5: ethnicity, body mass index, HbA1c at baseline; Model 6: ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline.

      DPP-4, dipeptidyl peptidase-4; HbA1c, glycosylated hemoglobin; SE, standard error.

      Table 4. The association between age and clinical response to DPP-4 inhibitors by tertile of DPP-4 enzyme inhibition rate

      Model 1: age, ethnicity, body mass index; Model 2: age, ethnicity, body mass index, HbA1c at baseline; Model 3: age, ethnicity, body mass index, HbA1c at baseline, DPP-4 activity at baseline.

      DPP-4, dipeptidyl peptidase-4; SE, ; HbA1c, glycosylated hemoglobin.

      Hong S, Jung CH, Han S, Park CY. Increasing Age Associated with Higher Dipeptidyl Peptidase-4 Inhibition Rate Is a Predictive Factor for Efficacy of Dipeptidyl Peptidase-4 Inhibitors. Diabetes Metab J. 2022;46(1):63-70.
      Received: Oct 23, 2020; Accepted: Jan 26, 2021
      DOI: https://doi.org/10.4093/dmj.2020.0253.

      Diabetes Metab J : Diabetes & Metabolism Journal
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