Factors Correlated to the Renoprotective Effect of Sitagliptin in Patients with Type 2 Diabetes Mellitus: Retrospective Observational Study

Background Sitagliptin functions similarly to GLP-1RAs by incretin and insulin secretion and has a renoprotective effect. Diabetic kidney disease (DKD) is a kidney complication that increases the mortality rate in type 2 diabetes mellitus (T2DM) patients. The important parameters that predict appropriate sitagliptin treatment are known as factors. This study aimed to assess factors that correlated with the renoprotective effect of sitagliptin in patients with T2DM. Methods This retrospective study collected data from a tertiary hospital in Thailand. All T2DM patients who were treated with sitagliptin and had complete data were recruited to analyze the outcome. The primary outcome was a correlation between demographics, laboratory data, and kidney outcome. The secondary outcome was the different laboratory results between pre- and posttreatment of patients treated with sitagliptin. Results The number of patients who were treated for T2DM with sitagliptin was 191. Only 102 patients had complete laboratory parameters. Results showed a positive correlation between baseline FBS, HbA1c, and Scr change (p value = 0.042 and 0.005) at 6 months and baseline age, TG, and Scr change (p value = 0.010 and 0.022) at 18 months; while a negative correlation was observed between baseline FBS, HbA1c, and eGFR change (p value = 0.017 and 0.007) at 6 months and baseline age and eGFR change (p value = 0.010) and between HDL-cholesterol and Scr change at 18 months (p value = 0.044). The eGFR stage 1 subgroup showed a positive correlation between baseline HbA1c and Scr change (p value <0.001) and baseline DM duration and eGFR change (p value = 0.004). Moreover, sitagliptin showed statistically significant FBS, HbA1c, LDL-cholesterol, and TC reduction. Furthermore, HDL-cholesterol showed statistically significant elevation. Conclusion FBS, HbA1c, and age were factors that correlated with the renoprotective effect of sitagliptin. The eGFR ≥90.00 ml/min/1.73 m2 patients group showed a duration of DM in which factors correlated with renoprotective effect. Moreover, sitagliptin also can improve glucose levels and lipid profile.


Introduction
Type 2 diabetes mellitus (T2DM) is one of the noncommunicable diseases (NCDs) that cause insulin resistance.Most of the patients are adults [1].T2DM patients who cannot have blood glucose level control for a long time lead to many complications, especially chronic kidney disease (diabetic kidney disease (DKD)).DKD is one of the microvascular complications that can be found after a diabetes duration of 10 years in type 1 diabetes [2].On the other hand, T2DM is still unclear.Te time to development of DKD depends on risk factors such as type of diabetes, age at diagnosis, glucose level, blood pressure level, lipid level, alcohol use, and obesity [3,4].Tis phenomenon was diagnosed by albuminuria and/or reduced estimated glomerular fltration rate (eGFR) in patients with the absence of signs or symptoms of other causes of kidney damage.Generally, eGFR is reported with serum creatinine in the routine laboratory.In addition, it can be calculated from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation by using serum creatinine in the formula.So, DKD also can be indicated via serum creatinine change.20-40% of adults with chronic kidney disease were reported to have diabetic kidney disease.Moreover, this complication is a high risk to mortality rate.Te previous study demonstrated that incidence rates per 1000 personyears in DKD patients reported 6.9 for end-stage renal disease (ESRD) and 50.3 for mortality [5].Terefore, T2DM patients should be screened for kidney function at least annually to assess kidney function [2].American Diabetes Association recommended sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) for T2DM with chronic kidney disease (CKD) or high risk of chronic kidney disease treatment [2,6].
Sitagliptin is one of the antihyperglycemic agents in the dipeptidyl peptidase 4 inhibitors (DPP4is) class.Tis agent acts to inhibit the degradation of the incretin hormones similar to GLP-1RAs [7].On the other hand, this class is rarely mentioned for T2DM patients with high-risk DKD or renal impairment treatment.DPP4is class consists of vildagliptin, linagliptin, alogliptin, and saxagliptin, including sitagliptin.Te linagliptin study reported risk reduction and slowed kidney function progression [8], whereas no clinically signifcant changes in renal function were reported [9][10][11].In addition, T2DM patients who were treated with saxagliptin showed good tolerance also in moderate and severe kidney disease [12,13].For vildagliptin, the previous study demonstrated safety in moderate and severe CKD with T2DM patients [14,15].In addition, some studies showed an increase in blood urea nitrogen (BUN) slightly, but it was not statistically signifcant [16].Furthermore, alogliptin was administered in patients with moderately and severely impaired renal function or ESRD.Te study reported a change in eGFR according to the baseline kidney function and incidences of initiation of dialysis were not diferent between the alogliptin and placebo groups [17].Almost all these agents' studies showed a renoprotective efect.For sitagliptin, the previous study demonstrated that sitagliptin afects eGFR reduction in each eGFR stage group [18].Te study by Chan et al. reported a decrease in serum creatinine for patients with moderate renal insufciency [19].However, the sitagliptin studies about kidney outcomes in humans are fewer when compared to the other agents in this class.
As mentioned above, the mechanism of action and the previous study of sitagliptin showed the renoprotective efect.Moreover, DKD is an important complication that increases the mortality rate in T2DM patients.Tis complication is the absence of signs or symptoms until it develops into ESRD or proceeds to the renal failure stage.Some patients need dialysis or transplantation.Nowadays, there is no report of factors for identifying T2DM patients who should receive sitagliptin approximately to slow DKD progression and renal failure.Terefore, this study aimed to investigate the factors correlated with the renoprotective efect of sitagliptin in patients with T2DM.Tese factors are benefcial to planning sitagliptin prescriptions.

Patient
Population.Tis study's design is a retrospective observational study.All data were screened from a tertiary hospital in Tailand.Te inclusion criteria were patients who were older than 18 years, were diagnosed with type 2 diabetes mellitus (T2DM), and were prescribed sitagliptin as one of the T2DM treatment regimens.Tey were excluded if they were treated with SGLT2is, GLP-1RAs, and other DPP4is.In addition, they also were excluded if laboratory data were not complete, i.e., there was no kidney laboratory result (eGFR and Scr) before treatment and there was a kidney laboratory result from only one visit.
For patients who were recruited in this retrospective study, we collected information and laboratory data such as age, body weight, height, comorbid diseases, concurrent medication, diabetes mellitus duration, eGFR, Scr, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood sugar (FBS), hemoglobin A1c (Hb A1c ), low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglyceride (TG), and total cholesterol.Tis information was recorded at the frst visit when patients were prescribed sitagliptin as baseline parameters.In addition, these parameters were collected at the 6-month, 12-month, and 18-month visits.

Outcome Measurement.
Te primary outcome was the correlation between kidney laboratory results, i.e., serum creatinine (Scr) and estimated glomerular fltration rate (eGFR) change and other variables, such as age, body mass index (BMI), diabetes mellitus duration, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood sugar (FBS), hemoglobin A1c (Hb A1c ), total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, aspartate transaminase (AST), and alanine transferase (ALT) of the T2DM patients treated with sitagliptin.Te correlation shows the factors that afect kidney complications in people with diabetes mellitus.Secondary outcomes were diferent in Scr, eGFR, BMI, FBS, Hb A1c , total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol between pre-and posttreatment of T2DM patients treated with sitagliptin.
Renoprotection was defned as a phenomenon that interrupts or reverses renal function loss.It was indicated via renal parameters, i.e., eGFR, Scr, or albumin level in urine [20,21].

Statistical Analysis.
Baseline characteristics on demographic data of all patients were reported as numbers and percentages.Baseline laboratory data were reported as median and 95% confdence interval (95% CI).Linear regression was used to investigate the association between the factors and kidney function parameters.Te correlation between serum creatinine (Scr) and estimated glomerular fltration rate (eGFR) change and expected relevant variables was performed using Spearman correlation analysis.Comparison of Scr, eGFR, BMI, FBS, HbA1c, total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol between pre-and posttreatment of sitagliptin was performed

Baseline Characteristics. Te baseline characteristics are
shown in Table 1.Te number of patients who were treated for type 2 diabetes mellitus (T2DM) from January 2021 to November 2023 with sitagliptin was 191.102 patients had complete laboratory parameters.So, these patients were analyzed in this study (Figure 1).Te number of males and females was similar.Te majority of these patients were younger than 60 years old (44.12%).Markedly, patients had body mass index (BMI) higher than 25.00 kg/m 2 (60.78%) and the most common comorbidity diseases of patients were hypertension and dyslipidemia.Te number of patients with each disease was equal (56.86%).Concomitant medications especially diabetes medications showed biguanides (87.25%), sulfonylureas (41.18%), insulin (18.63%), and thiazolidinediones (9.80%).For renin-angiotensin system (RAS) inhibitors, medications were 47.06%, i.e., angiotensin receptor blockers (ARBs) (30.39%) and angiotensin-converting enzyme inhibitors (ACEis) (16.67%).Furthermore, T2DM duration, i.e., less than 10, 11-20, 21-30, and more than 30 years was 52.94, 31.37,11.76, and 3.92%, respectively.Te number of patients' smoking status in each group was almost the same.Te CVD risk score that was calculated from the atherosclerotic cardiovascular disease (ASCVD) risk estimator plus calculator [22] showed the number of patients over half in less than 10% group.For median baseline kidney parameters, patients reported that the estimated glomerular fltration rate (eGFR) was 90.80 ml/min/1.73m 2 and serum creatinine (Scr) was 0.84 mg/dL.Most patients showed baseline eGFR in eGFR stage 1 (≥90.00)which was classifed from chronic kidney disease classifcation of Kidney Disease Improving Global Outcomes (KDIGOs) 2024 [23] (49.02%).

Efect on Kidney and Cardiometabolic Parameter.
Prior to the sitagliptin treatment, this study showed that the mean of serum creatinine (Scr) was 0.86 mg/dL.Focusing on the baseline eGFR subgroup, the result of this study demonstrated a positive correlation between baseline Hb A1c and Scr change in T2DM patients in eGFR stage 1.It indicated that high baseline Hb A1c correlates with Scr elevation highly (p value <0.001) (Figure 4(a)).Regression analysis indicated that 0.05% of Hb A1c elevation afected 1 mg/dL of Scr increasing.Moreover, the result also showed a positive correlation between baseline DM duration and eGFR change.It means high baseline DM duration correlates with eGFR reduction highly (p value � 0.004) (Figure 4(b)).

Discussion
Te result of this study reported no statistically signifcant diference in eGFR and Scr between pre-and postsitagliptin treatment.It indicated that sitagliptin can slow the progress of chronic kidney disease or diabetic kidney disease (DKD) complications.Markedly, sitagliptin was the renoprotective antihyperglycemic agent.For albuminuria, we tried our best   6 Advances in Pharmacological and Pharmaceutical Sciences Advances in Pharmacological and Pharmaceutical Sciences to ensure albuminuria.Since the limitation of the retrospective study, a parameter that indicated albuminuria may not be clear.However, this study indicated that sitagliptin afected proteinuria elevation posttreatment at 18 months.Te previous study reported that sitagliptin reduced albuminuria via blood glucose control [25][26][27][28].Moreover, preliminary data reported that albuminuria change was lower than the placebo group [29].We suggest collecting albumin levels in urine for prospective study in future.Te previous study reported no change in eGFR rate in patients not on hemodialysis [30].Moreover, ten-year sitagliptin treatment also reported no change in eGFR [31].DPP4 enzyme showed the highest expression levels in mammals' kidneys [32].Consequently, the kidney is an important target organ for sitagliptin.Incretin has been known for kidney function regulation [33,34], whereas T2DM patients showed incretin dynamics alteration, i.e., vascular tonus, diuretic, and natriuretic properties in kidney and DPP4 upregulation in glomeruli for T2DM patients.In addition, DPP4 also involved extracellular matrix proteins during DKD development and vascular endothelial growth factor (VEGF) regulation which have key roles in the pathophysiology of DKD [35].Terefore incretin hormone (GLP-1) in the kidney may have a half-life reduction.[32,36,37].
Te aforementioned result of this study is the renoprotective efect of sitagliptin as a result of DPP4 inhibition.Since the DKD stage was classifed by eGFR alteration and albuminuria [38], therefore, diferent DKD stages have diferent efects on DPP4 inhibitors.Interestingly, this study indicated that T2DM patients with high baseline FBS or Hb A1c correlated with eGFR reduction slowly at 6 months of sitagliptin therapy.Moreover, sitagliptin can reduce FBS and Hb A1C levels.Similarly, the previous study demonstrated that sitagliptin can initially reduce Hb A1c levels in 24 weeks.T2DM patients with higher baseline Hb A1c lead to greater reductions in Hb A1c compared with the lower baseline Hb A1c group [39].Sitagliptin also decreases FBS levels, and there is no signifcant diference when compared to pioglitazone [40].Since the agent inhibits the DPP4 enzyme that cleavages GLP-1 and glucosedependent insulinotropic polypeptide (GIP), this mechanism increases insulin and reduces glucagon.It leads to improved T2DM [41,42].Efect of sitagliptin on high Hb A1c level reduction in high baseline Hb A1c patient afect slow DKD progression in these patients.High blood glucose for a long time can induce oxidative stress and proinfammatory cytokines release which is the cause of DKD [43][44][45].In addition, sitagliptin was reported to prevent proapoptotic and infammatory states afecting renal function improvement in diabetic rat kidneys [46].On the other hand, these factors afected Scr elevation highly.Creatinine is a metabolite of creatine and creatine phosphate which is a protein in skeletal muscle [47].Muscle mass and dietary meat intake have been shown to infuence Scr levels [5,48,49].High FBS and Hb A1c levels afect muscle mass change.However, GFR is the gold standard of CKD diagnosis [50].GFR is estimated by creatinine clearance (Clcr) that is measured by Scr and creatinine excretion in a 24-h urine sample.Generally, eGFR equations consist of many parameters, i.e., age and gender, including Scr [51].Terefore, GFR is the best parameter for kidney function assessment in health and disease [52].Consequently, we focus on eGFR change for the renoprotective efect.By focusing on subgroups via baseline eGFR, the result of this study showed a positive correlation between baseline DM duration and eGFR reduction in the eGFR stage 1 group; eGFR ≥90.00 ml/min/1.73m 2 .T2DM patients who were afected by DM for a long time at baseline correlated with eGFR reduction highly at 12 months.A previous study demonstrated that the average duration of T2DM was 5-10 years, which is related with the severity of nephropathy [53].Notably in this study, the majority of DM duration in the eGFR stage 1 group was less than 10 years.Tis phenomenon indicated that sitagliptin can slow the progress of DKD via DM control and infamed process control,   Advances in Pharmacological and Pharmaceutical Sciences especially in T2DM patients who had uncontrol DM and were in older age.However, in patients with baseline eGFR of ≥90.00 ml/min/1.73m 2 who had T2DM for a long time, sitagliptin monotherapy was not recommended.Tese patients should receive treatment combined with other antihyperglycemic agents such as SGLT2is or GLP-1RAs to slow DKD progression.Moreover, the current study reported that high baseline age patients correlated with eGFR reduction slowly at 18 months.It is known that the elderly population has declined in eGFR [23,54].Tis phenomenon is possible because besides sitagliptin having benefts for glucose level control, the agent can control metabolic parameters.Results of this study showed that sitagliptin decreases LDLcholesterol and total cholesterol levels with at least 6 months of treatment.At 12 months, HDL-cholesterol showed elevation.Previous studies in rabbits showed that sitagliptin decreased LDL-cholesterol and total cholesterol including reversing the decrease in HDL-cholesterol levels [55].Furthermore, the human study reported that sitagliptin improves total cholesterol, HDL-cholesterol, LDLcholesterol, and TG levels [56], while the present study showed no signifcant decrease in the TG level.However, the efect of other DPP4is agents on metabolic parameters change is diferent [57,58].Tis result was indicated by the impact of incretin on lipid metabolic enzymes.It afects lipogenesis and lipolysis [59].Moreover, a previous study reported that sitagliptin decreased lipid peroxidation.It may improve renal impairment [28].Te capacity of sitagliptin on glucose and lipid control afects to improve of DM and dyslipidemia which is a comorbidity disease of almost all patients in this study and a risk factor for DKD development [60].Generally, older patients are at high risk for these diseases [61].Terefore it can be concluded that high baseline age patients should receive sitagliptin to slow DKD progression.In addition, sitagliptin treatment demonstrated no statistically signifcance diference in BMI.Te previous study reported a weight-neutral efect [62].Since BMI is a parameter that is calculated via weight and height [63], so weight change can afect BMI.
To the best of our knowledge, the current study demonstrated that baseline FBS, Hb A1c , and age were factors that correlated with the renoprotective efect of sitagliptin.Terefore, T2DM patients with high baseline FBS, HbA1c, and older age should receive sitagliptin to slow DKD progression.For patients with T2DM and a baseline eGFR ≥90.00 ml/min/1.73m2, who have had diabetes for a prolonged period, it is recommended to consider treatment with sitagliptin combined with SGLT2is or GLP-1RAs to achieve enhanced renoprotective benefts.Unfortunately, the limitation of this retrospective study is the number of patients who have complete data including pre-and postsitagliptin treatment and parameter collection that indicated albuminuria.It also cannot indicate the cutof level of age and DM duration as a high group, including urine albumin level, which may be a factor for this study.Further studies should collect data from a higher number of samples for more clarity.

Conclusion
Te result of this study indicates that sitagliptin is a renoprotective antihyperglycemic agent.FBS, HbA1c, and age were factors that correlated with the renoprotective efect of sitagliptin.Moreover, the duration of DM was a factor that correlated with the renoprotective efect of sitagliptin for T2DM patients with eGFR ≥90.00 ml/min/1.73m 2 .Sitagliptin also can improve glucose levels and lipid profle, i.e., FBS, Hb A1c , LDL-cholesterol, HDL-cholesterol, and total cholesterol.Based on the results of this study, baseline FBS, Hb A1c , age, and DM duration should be considered for sitagliptin treatment to slow DKD progression.

Figure 1 :Figure 2 :
Figure 1: Flow diagram of the patient recruitment process.

Figure 4 :
Figure 4: Correlation between baseline hemoglobin A1c (Hb A1c ) (a) and diference in serum creatinine (Scr) of each patient who has eGFR stage 1 treated with sitagliptin for 6 months and baseline diabetes mellitus (DM) duration and diference in estimated glomerular fltration rate (eGFR) (b) of each patient who has eGFR stage 1 treated with sitagliptin for 12 months.
stage 1: p value � 0.453, 0.718, and 0.116; eGFR stage 2: p value � 0.170, 0.475, and 0.313 respectively) (Figure2(a)).Te efect on the eGFR parameter is shown in Figure2(b).Tis study compared the diference between pre-and posttreatment at 6, 12, and 18 months in all patients, eGFR stage 1, and eGFR stage 2 groups.Mean eGFR pre-and posttreatment for all patients were 82.69, 83.13, 82.88, and 82.63 ml/min/1.73m2;eGFRstage 1: 99.31, 99.63, 99.97, and 101.86; and eGFR stage 2: 77.19, 77.09, 77.07, and 76.78, respectively.Tis study showed no statistically signifcant diference (all patients: p value � 0.178, 0.872, and 0.276; eGFR stage 1: p value � 0.176, 0.614, and 0.508; and eGFR stage 2: p value � 0.153, 0.713, 0.251, respectively) between pre-and posttreatment in all groups.Te efects on proteinuria posttreatment at 6, 12, and 18 months in all patients showed 4, 6, and 8 patients; in eGFR stage 1 group, there were 1, 1, and 5 patients; and in eGFR stage 2 group, there were 3, 4, and 3 patients, respectively.Tis study showed a statistically signifcant diference in the number of proteinuria patients between posttreatment at 6 and 18 months in all patients and 6 and 18 months and 12 and 18 months in the eGFR stage 1 group (all patients: p value � 0.019 and eGFR stage 1: p value � 0.005 and 0.018, respectively).3.3.Factors Correlated to the Renoprotective Efect.Te result of this study demonstrated no statistically signifcant difference for eGFR and Scr between pre-and postsitagliptin treatment in all patients, eGFR stage 1, and eGFR stage 2 groups.Almost all patients reported normal eGFR and Scr levels at baseline.It means sitagliptin can slow the progress of chronic kidney disease or diabetic kidney disease (DKD) complications.Terefore sitagliptin has a renoprotective efect.

Table 1 :
Continued.Each patient could have more than one disease.HDL, high-density lipoprotein; LDL, low-density lipoprotein. *