Endocrinology and Metabolism

Original Articles

Diabetes, obesity and metabolism
Financial Benefits of Renal Dose-Adjusted Dipeptidyl Peptidase-4 Inhibitors for Patients with Type 2 Diabetes and Chronic Kidney Disease: Hun Jee Choe, Yeh-Hee Ko, Sun Joon Moon, Chang Ho Ahn, Kyoung Hwa Ha, Hyeongsuk Lee, Jae Hyun Bae, Hyung Joon Joo, Hyejin Lee, Jang Wook Son, Dae Jung Kim, Sin Gon Kim, Kwangsoo Kim, Young Min Cho; Endocrinol Metab. 2024;39(4):622-631. Published online August 1, 2024; DOI: https://doi.org/10.3803/EnM.2024.1965

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Abstract PDF Supplementary Material PubReader ePub: Background
Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently prescribed for patients with type 2 diabetes; however, their cost can pose a significant barrier for those with impaired kidney function. This study aimed to estimate the economic benefits of substituting non-renal dose-adjusted (NRDA) DPP4 inhibitors with renal dose-adjusted (RDA) DPP4 inhibitors in patients with both impaired kidney function and type 2 diabetes.
Methods
This retrospective cohort study was conducted from January 1, 2012 to December 31, 2018, using data obtained from common data models of five medical centers in Korea. Model 1 applied the prescription pattern of participants with preserved kidney function to those with impaired kidney function. In contrast, model 2 replaced all NRDA DPP4 inhibitors with RDA DPP4 inhibitors, adjusting the doses of RDA DPP4 inhibitors based on individual kidney function. The primary outcome was the cost difference between the two models.
Results
In total, 67,964,996 prescription records were analyzed. NRDA DPP4 inhibitors were more frequently prescribed to patients with impaired kidney function than in those with preserved kidney function (25.7%, 51.3%, 64.3%, and 71.6% in patients with estimated glomerular filtration rates [eGFRs] of ≥60, <60, <45, and <30 mL/min/1.73 m², respectively). When model 1 was applied, the cost savings per year were 7.6% for eGFR <60 mL/min/1.73 m² and 30.4% for eGFR <30 mL/min/1.73 m². According to model 2, 15.4% to 51.2% per year could be saved depending on kidney impairment severity.
Conclusion
Adjusting the doses of RDA DPP4 inhibitors based on individual kidney function could alleviate the economic burden associated with medical expenses.

Diabetes, obesity and metabolism
Risk of Pancreatic Cancer and Use of Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes: A Propensity Score-Matching Analysis: Mee Kyoung Kim, Kyungdo Han, Hyuk-Sang Kwon, Soon Jib Yoo; Endocrinol Metab. 2023;38(4):426-435. Published online July 20, 2023; DOI: https://doi.org/10.3803/EnM.2023.1737

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Background
The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors over the course of long-term treatment remain unclear, and concerns have been raised regarding the role of DPP-4 inhibitors in carcinogenesis in the pancreas. Earlier studies of pancreatic adverse events have reported conflicting results.
Methods
This study analyzed Korean National Health Insurance Service data from January 2009 to December 2012. Patients who had type 2 diabetes mellitus and took two or more oral glucose-lowering drugs (GLDs) were included. Patients prescribed DPP-4 inhibitors (n=51,482) or other GLDs (n=51,482) were matched at a 1:1 ratio using propensity score matching. The risk of pancreatic cancer was calculated using Kaplan-Meier curves and Cox proportional-hazards regression analysis.
Results
During a median follow-up period of 7.95 years, 1,051 new cases of pancreatic cancer were identified. The adjusted hazard ratio (HR) for DPP-4 inhibitor use was 0.99 (95% confidence interval [CI], 0.88 to 1.12) compared with the other GLD group. In an analysis limited to cases diagnosed with pancreatic cancer during hospitalization, the adjusted HR for the use of DPP-4 inhibitors was 1.00 (95% CI, 0.86 to 1.17) compared with patients who took other GLDs. Using the other GLD group as the reference group, no trend was observed for elevated pancreatic cancer risk with increased DPP-4 inhibitor exposure.
Conclusion
In this population-based cohort study, DPP-4 inhibitor use over the course of relatively long-term follow-up showed no significant association with an elevated risk of pancreatic cancer.

Citations

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Ji-Hyun Kim, Seung-Hwan Lee, Kyu Na Lee, Kyungdo Han, Mee Kyoung Kim
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Diabetes, obesity and metabolism
Efficacy of Gemigliptin Add-on to Dapagliflozin and Metformin in Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Study (SOLUTION): Byung Wan Lee, KyungWan Min, Eun-Gyoung Hong, Bon Jeong Ku, Jun Goo Kang, Suk Chon, Won-Young Lee, Mi Kyoung Park, Jae Hyeon Kim, Sang Yong Kim, Keeho Song, Soon Jib Yoo; Endocrinol Metab. 2023;38(3):328-337. Published online June 28, 2023; DOI: https://doi.org/10.3803/EnM.2023.1688

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Background
This study evaluated the efficacy and safety of add-on gemigliptin in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with metformin and dapagliflozin.
Methods
In this randomized, placebo-controlled, parallel-group, double-blind, phase III study, 315 patients were randomized to receive either gemigliptin 50 mg (n=159) or placebo (n=156) with metformin and dapagliflozin for 24 weeks. After the 24-week treatment, patients who received the placebo were switched to gemigliptin, and all patients were treated with gemigliptin for an additional 28 weeks.
Results
The baseline characteristics were similar between the two groups, except for body mass index. At week 24, the least squares mean difference (standard error) in hemoglobin A1c (HbA1c) changes was –0.66% (0.07) with a 95% confidence interval of –0.80% to –0.52%, demonstrating superior HbA1c reduction in the gemigliptin group. After week 24, the HbA1c level significantly decreased in the placebo group as gemigliptin was administered, whereas the efficacy of HbA1c reduction was maintained up to week 52 in the gemigliptin group. The safety profiles were similar: the incidence rates of treatment-emergent adverse events up to week 24 were 27.67% and 29.22% in the gemigliptin and placebo groups, respectively. The safety profiles after week 24 were similar to those up to week 24 in both groups, and no new safety findings, including hypoglycemia, were noted.
Conclusion
Add-on gemigliptin was well tolerated, providing comparable safety profiles and superior efficacy in glycemic control over placebo for long-term use in patients with T2DM who had poor glycemic control with metformin and dapagliflozin.

Citations

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Myung Jin Kim, Yun Kyung Cho, Sehee Kim, Jung Yoon Moon, Chang Hee Jung, Woo Je Lee
Diabetes, Obesity and Metabolism.2025; 27(9): 5019. CrossRef
Triple oral therapy with metformin, DPP‐4 inhibitor, and SGLT2 inhibitor for adults with type 2 diabetes: Consensus recommendations of a Chinese expert panel (version 2025)
Miao Yu, Tong Wang, Chun Xu, Yan Bi, Ling Gao, Guang Wang, Guangda Xiang, Yaoming Xue, Tao Yang, Deying Kang, Zhiguang Zhou, Lixin Guo, Xinhua Xiao
Diabetes, Obesity and Metabolism.2025; 27(S9): 3. CrossRef
Dipeptidyl peptidase 4 (DPP-4) inhibitors for people with chronic kidney disease and diabetes
Patrizia Natale, Suetonia C Green, David J Tunnicliffe, Giovanni Pellegrino, Tadashi Toyama, Giovanni FM Strippoli
Cochrane Database of Systematic Reviews.2025;[Epub] CrossRef
Missing imputation under estimand framework using treatment policy strategy for intercurrent events
Jaehyuk Kim, Eunjung Song, Siyoen Kil
Communications for Statistical Applications and Methods.2025; 32(6): 783. CrossRef
Dual add‐on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study
Kyung Ah Han, You‐Cheol Hwang, Shin Je Moon, Ho Chan Cho, Hye Jin Yoo, Sung Hee Choi, Suk Chon, Kyoung‐Ah Kim, Tae Nyun Kim, Jun Goo Kang, Cheol‐Young Park, Jong Chul Won, Eunjoo Cho, Jeongyun Kim, Kyong Soo Park
Diabetes, Obesity and Metabolism.2024; 26(9): 3743. CrossRef

Brief Report

Diabetes, Obesity and Metabolism
Dipeptidyl Peptidase-4 Inhibitors and COVID-19-Related Deaths among Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Observational Studies: Dimitrios Patoulias, Michael Doumas; Endocrinol Metab. 2021;36(4):904-908. Published online July 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1048

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The coronavirus disease 2019 (COVID-19) pandemic remains an unbeaten enemy. Unfortunately, no targeted treatment option is available. Patients with type 2 diabetes mellitus (T2DM) have increased odds for severe or fatal disease, as demonstrated in recent observational studies. There is an ongoing discussion regarding the impact of different antidiabetic drug classes on outcomes of interest among affected subjects. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been placed at the epicenter, since the DPP-4 enzyme seems to be implicated in the disease pathogenesis. Herein we present an updated meta-analysis of observational studies addressing the risk of COVID-19 death among patients with T2DM on prior DPP-4 inhibitor treatment. We pooled data from 10 observational studies, showing that DPP-4 inhibitors produce a non-significant decrease in the risk for COVID-19-related death. However, when administered in the inpatient setting, DPP-4 inhibitors decrease the risk for COVID-19-related death by 50%. Ongoing randomized controlled trials will shed further light.

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Association between dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists and COVID-19 infection and adverse outcomes: a cohort study
Wade Thompson, Bing Yu, Joan Porter, Jiming Fang, Laura E Ferreira-Legere, Peter C Austin, Cynthia A Jackevicius, Heather Ross, Douglas S Lee, Alanna Weisman, Michael E Farkouh, Andrea S Gershon, Clare L Atzema, Jeffrey C Kwong, Andrew Ha, Vladimír Džavík
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Original Articles

Clinical Study
Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis: Jae Hyun Bae, Eun-Gee Park, Sunhee Kim, Sin Gon Kim, Seokyung Hahn, Nam Hoon Kim; Endocrinol Metab. 2021;36(2):388-400. Published online March 31, 2021; DOI: https://doi.org/10.3803/EnM.2020.912

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Background
To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes.
Methods
We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at least one kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worsening nephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methods and calculated absolute risks and rank probabilities of each treatment for the outcomes.
Results
Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria (OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46 to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKD than placebo or DPP-4 inhibitors.
Conclusion
SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type 2 diabetes.

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Dipeptidyl peptidase 4 (DPP-4) inhibitors for people with chronic kidney disease and diabetes
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Rüdiger Landgraf, Jens Aberle, Andreas L. Birkenfeld, Baptist Gallwitz, Monika Kellerer, Harald H. Klein, Dirk Müller-Wieland, Michael A. Nauck, Tobias Wiesner, Erhard Siegel
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Significant reduction in chronic kidney disease progression with sodium‐glucose cotransporter‐2 inhibitors compared to dipeptidyl peptidase‐4 inhibitors in adults with type 2 diabetes in a UK clinical setting: An observational outcomes study based on inte
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Clinical Study Big Data Articles (National Health Insurance Service Database)
Effect of Teneligliptin versus Sulfonylurea on Major Adverse Cardiovascular Outcomes in People with Type 2 Diabetes Mellitus: A Real-World Study in Korea: Da Hea Seo, Kyoung Hwa Ha, So Hun Kim, Dae Jung Kim; Endocrinol Metab. 2021;36(1):70-80. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.777

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Background
Results regarding the cardiovascular (CV) effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconsistent. This study aimed to assess the effects of teneligliptin, a DPP-4 inhibitor, on the risk of major CV outcomes in type 2 diabetes mellitus (T2DM) patients compared to sulfonylurea.
Methods
From January 1, 2015 to December 31, 2017, we conducted a retrospective cohort study using the Korean National Health Insurance Service database. A total of 6,682 T2DM patients who were newly prescribed DPP-4 inhibitors or sulfonylurea were selected and matched in a 1:1 ratio by propensity score. The hazard ratios (HRs) for all-cause mortality, hospitalization for heart failure (HHF), all-cause mortality or HHF, myocardial infarction (MI), stroke, and hypoglycemia were assessed.
Results
During 641 days of follow-up, the use of teneligliptin was not associated with an increased risk of all-cause mortality (HR, 1.00; 95% confidence interval [CI], 0.85 to 1.19), HHF (HR, 0.99; 95% CI, 0.86 to 1.14), all-cause mortality or HHF (HR, 1.02; 95% CI, 0.90 to 1.14), MI (HR, 0.90; 95% CI, 0.68 to 1.20), and stroke (HR, 1.00; 95% CI, 0.86 to 1.17) compared to the use of sulfonylurea. However, it was associated with a significantly lower risk of hypoglycemia (HR, 0.68; 95% CI, 0.49 to 0.94) compared to sulfonylurea therapy.
Conclusion
Among T2DM patients, teneligliptin therapy was not associated with an increased risk of CV events including HHF, but was associated with a lower risk of hypoglycemia compared to sulfonylurea therapy.

Citations

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Association between age at diagnosis of type 2 diabetes and cardiovascular morbidity and mortality risks: A nationwide population-based study
Da Hea Seo, Mina Kim, Young Ju Suh, Yongin Cho, Seong Hee Ahn, Seongbin Hong, So Hun Kim
Diabetes Research and Clinical Practice.2024; 208: 111098. CrossRef
Association between Age at Diagnosis of Type 2 Diabetes and Subsequent Risk of Dementia and Its Major Subtypes
Da Hea Seo, Mina Kim, Yongin Cho, Seong Hee Ahn, Seongbin Hong, So Hun Kim
Journal of Clinical Medicine.2024; 13(15): 4386. CrossRef
Assessment of cardiovascular risk with sulfonylurea use in type 2 diabetes mellitus: A retrospective cohort study
Jari Delbaere, Ewoud Deboever, Bert Vaes, Frank Nobels, Pavlos Mamouris, Geert Goderis
Primary Care Diabetes.2024; 18(6): 599. CrossRef
Systematic review and meta-analysis of teneligliptin for treatment of type 2 diabetes
R. Pelluri, S. Kongara, V. R. Nagasubramanian, S. Mahadevan, J. Chimakurthy
Journal of Endocrinological Investigation.2023; 46(5): 855. CrossRef
Finding the most cost-effective option from commonly used Dipeptidyl peptidase-4 inhibitors in India: a systematic study
Harmanjit Singh, Ekta Arora, Seerat Narula, Mandeep Singla, Armaan Otaal, Jatin Sharma
Expert Review of Endocrinology & Metabolism.2023; 18(4): 347. CrossRef
Association Between DPP4 Inhibitor Use and the Incidence of Cirrhosis, ESRD, and Some Cancers in Patients With Diabetes
Yewon Na, Soo Wan Kim, Ie Byung Park, Soo Jung Choi, Seungyoon Nam, Jaehun Jung, Dae Ho Lee
The Journal of Clinical Endocrinology & Metabolism.2022; 107(11): 3022. CrossRef

Clinical Study
Gemigliptin Inhibits Interleukin-1β–Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway: Oak-Kee Hong, Seong-Su Lee, Soon Jib Yoo, Min-Kyung Lee, Mee-Kyoung Kim, Ki-Hyun Baek, Ki-Ho Song, Hyuk-Sang Kwon; Endocrinol Metab. 2020;35(2):384-395. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.384

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Background
Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor.
Methods
We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins.
Results
Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1β-induced EndMT.
Conclusion
We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.

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Diabetes
Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis: Jae Hyun Bae, Sunhee Kim, Eun-Gee Park, Sin Gon Kim, Seokyung Hahn, Nam Hoon Kim; Endocrinol Metab. 2019;34(1):80-92. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.80

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Background

To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes.

Methods

MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome.

Results

We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, −1.11 mL/min/1.73 m²; 95% CI, −1.78 to −0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475).

Conclusion

DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents.

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Diabetes
Retrospective Analysis of the Efficacy of Dapagliflozin in Patients with Type 2 Diabetes in a Primary Clinic in Korea: Sang Hyun Park, Young Ju Choi, Eun-Jung Rhee, Kab Bum Huh; Endocrinol Metab. 2019;34(1):70-79. Published online March 21, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.70

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Abstract PDF PubReader ePub

Background

We aimed to retrospectively analyze the efficacy of 10 mg dapagliflozin (DAPA), which is a sodium-glucose cotransporter-2 inhibitor, in Korean patients with type 2 diabetes who visited a primary diabetes clinic.

Methods

In total, 83 patients with type 2 diabetes, who received treatment with DAPA for the first time in a primary diabetes clinic between January 2015 and October 2015, were included in the study. The effect of DAPA in lowering glycosylated hemoglobin (HbA1c) levels was evaluated via chart review at 6 months follow-up. The patients were categorized into five groups according to add-on to or switched from other glucose-lowering agents: add-on to metformin (MET, n=10), add-on to MET+dipeptidyl peptidase 4 inhibitor (DPP4i, n=12), switched from sulfonylurea (SU, n=13), switched from DPP4i (n=11), and switched from thiazolidinedione (TZD, n=37). All the participants had already used MET for their regimen.

Results

Treatment with DAPA reduced HbA1c level by 1.2%±0.8%. Moreover, a significant decrease was observed in all subgroups: add-on to MET, −1.2%±0.7%; add-on to MET+DPP4i, −1.4%±0.8%; switched from SU, −1.4%±0.7%; switched from DPP4i, −0.5%±0.7%; and switched from TZD, −1.2%±0.9% (P<0.01). A significant decrease in body weight (−3.1±2.6 kg, P<0.001) was observed after DAPA administration. Estimated glomerular filtration rate and urine microalbumin were significantly decreased after 6 months of treatment with DAPA (−4.0±13.5 mL/min/1.73 m², P=0.03; −23.6±45.9 mg/L, P<0.001).

Conclusion

Treatment with DAPA, whether added to or switched from other glucose-lowering agents, significantly decreased HbA1c levels in Korean patients with type 2 diabetes who visited a single primary diabetes clinic. DAPA can be considered as an optimal second-line treatment for patients with type 2 diabetes, as supported by real-world evidence studies.

Citations

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The sodium glucose co-transporter 2 inhibitor dapagliflozin ameliorates the fluid-retaining effect of the endothelin A receptor antagonist zibotentan
Vandana Veenit, Hiddo J L Heerspink, Christine Ahlström, Peter J Greasley, Stanko Skritic, Natalie van Zuydam, Donald E Kohan, Pernille B L Hansen, Robert I Menzies
Nephrology Dialysis Transplantation.2023; 38(10): 2289. CrossRef

Review Article

Effects of Incretin-Based Therapies on Diabetic Microvascular Complications: Yu Mi Kang, Chang Hee Jung; Endocrinol Metab. 2017;32(3):316-325. Published online September 18, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.3.316

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The morbidity and mortality associated with diabetic complications impose a huge socioeconomic burden worldwide. Therefore, the ultimate goal of managing diabetes mellitus (DM) is to lower the risk of macrovascular complications and highly morbid microvascular complications such as diabetic nephropathy (DN) and diabetic retinopathy (DR). Potential benefits of incretin-based therapies such as glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on the diabetic macrovascular complications have been recently suggested, owing to their pleiotropic effects on multiple organ systems. However, studies primarily investigating the role of these therapies in diabetic microvascular complications are rare. Nevertheless, preclinical and limited clinical data suggest the potential protective effect of incretin-based agents against DN and DR via their anti-inflammatory, antioxidative, and antiapoptotic properties. Evidence also suggests that these incretin-dependent and independent beneficial effects are not necessarily associated with the glucose-lowering properties of GLP-1 RAs and DPP-4 inhibitors. Hence, in this review, we revisit the preclinical and clinical evidence of incretin-based therapy for DR and DN, the two most common, morbid complications in individuals with DM. In addition, the review discusses a few recent studies raising concerns of aggravating DR with the use of incretin-based therapies.

Citations

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Original Articles

Effects of Vildagliptin or Pioglitazone on Glycemic Variability and Oxidative Stress in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy: A 16-Week, Randomised, Open Label, Pilot Study: Nam Hoon Kim, Dong-Lim Kim, Kyeong Jin Kim, Nan Hee Kim, Kyung Mook Choi, Sei Hyun Baik, Sin Gon Kim; Endocrinol Metab. 2017;32(2):241-247. Published online June 23, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.2.241

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Background

Glycemic variability is associated with the development of diabetic complications through the activation of oxidative stress. This study aimed to evaluate the effects of a dipeptidyl peptidase 4 inhibitor, vildagliptin, or a thiazolidinedione, pioglitazone, on glycemic variability and oxidative stress in patients with type 2 diabetes.

Methods

In this open label, randomised, active-controlled, pilot trial, individuals who were inadequately controlled with metformin monotherapy were assigned to either vildagliptin (50 mg twice daily, n=17) or pioglitazone (15 mg once daily, n=14) treatment groups for 16 weeks. Glycemic variability was assessed by calculating the mean amplitude of glycemic excursions (MAGE), which was obtained from continuous glucose monitoring. Urinary 8-iso prostaglandin F₂α, serum oxidised low density lipoprotein, and high-sensitivity C-reactive protein were used as markers of oxidative stress or inflammation.

Results

Both vildagliptin and pioglitazone significantly reduced glycated hemoglobin and mean plasma glucose levels during the 16-week treatment. Vildagliptin also significantly reduced the MAGE (from 93.8±38.0 to 70.8±19.2 mg/dL, P=0.046), and mean standard deviation of 24 hours glucose (from 38±17.3 to 27.7±6.9, P=0.026); however, pioglitazone did not, although the magnitude of decline was similar in both groups. Markers of oxidative stress or inflammation including urinary 8-iso prostaglandin F₂α did not change after treatment in both groups.

Conclusion

In this 16-week treatment trial, vildagliptin, but not pioglitazone, reduced glycemic variability in individuals with type 2 diabetes who was inadequately controlled with metformin monotherapy, although a reduction of oxidative stress markers was not observed.

Citations

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Clinical Study
Effects of Dipeptidyl Peptidase-4 Inhibitors on Hyperglycemia and Blood Cyclosporine Levels in Renal Transplant Patients with Diabetes: A Pilot Study: Jaehyun Bae, Min Jung Lee, Eun Yeong Choe, Chang Hee Jung, Hye Jin Wang, Myoung Soo Kim, Yu Seun Kim, Joong-Yeol Park, Eun Seok Kang; Endocrinol Metab. 2016;31(1):161-167. Published online March 16, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.1.161

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Background

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors is increasing among renal transplant patients with diabetes. However, the glucose-lowering efficacies of various DPP-4 inhibitors and their effects on blood cyclosporine levels have not been fully investigated. We compared the glucose-lowering efficacies of DPP 4 inhibitors and evaluate their effects on the blood levels of cyclosporine in renal transplant recipients with diabetes.

Methods

Sixty-five renal allograft recipients who received treatment with DPP-4 inhibitors (vildagliptin, sitagliptin, or linagliptin) following kidney transplant were enrolled. The glucose-lowering efficacies of the DPP-4 inhibitors were compared according to the changes in the hemoglobin A1c (HbA1c) levels after 3 months of treatment. Changes in the trough levels of the cyclosporine were also assessed 2 months after treatment with each DPP-4 inhibitor.

Results

HbA1c significantly decreased in the linagliptin group in comparison with other DPP-4 inhibitors (vildagliptin –0.38%±1.03%, sitagliptin –0.53%±0.95%, and linagliptin –1.40±1.34; P=0.016). Cyclosporine trough levels were significantly increased in the sitagliptin group compared with vildagliptin group (30.62±81.70 ng/mL vs. –24.22±53.54 ng/mL, P=0.036). Cyclosporine trough levels were minimally changed in patients with linagliptin.

Conclusion

Linagliptin demonstrates superior glucose-lowering efficacy and minimal effect on cyclosporine trough levels in comparison with other DPP-4 inhibitors in kidney transplant patients with diabetes.

Citations

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