|Year : 2021 | Volume
| Issue : 2 | Page : 146-150
Renoprotective effects of teneligliptin: An observational study
Prabhat Agrawal1, Ashish Gautam1, Apoorva Jain1, Nikhil Pursnani1, Manjula S2, Krishna Kumar M2
1 Post Graduate Department of Medicine, S N Medical College, Agra, Uttar Pradesh, India
2 Department of Medical Services, Micro Labs Limited, Bengaluru, Karnataka, India
|Date of Submission||30-May-2020|
|Date of Decision||23-Jul-2020|
|Date of Acceptance||30-Jul-2020|
|Date of Web Publication||31-Mar-2021|
Dr. Nikhil Pursnani
Post Graduate Department of Medicine, S N Medical College, Central Library, Moti Katra, Mantola, Agra 282003, Uttar Pradesh.
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study was to validate the potential of teneligliptin in managing type 2 diabetes mellitus (T2DM) with renal impairment and to evaluate its effect on renal parameters in Indian subjects. Patients and Methods: The prospective observational study included 86 subjects aged >40 years with suboptimal control of T2DM (HbA1c >7.5). The demographic details of the selected subjects were recorded. The patients were continued on existing oral hypoglycemic agents (OHAs) and antihypertensives. The following clinical and anthropometric parameters were measured at baseline, 4 months, 8 months, and 12 months during the treatment using 20 mg of teneligliptin per day: HbA1c, eGFRs, UACR, FBG, and PPBG levels. Comparisons of anthropometric and laboratory parameters were carried out using analysis of variance (ANOVA) and t test for normal data, Kruskal–Wallis for nonnormal data, and chi-square test for counts data. Results: The mean age of the subjects was 54.28 ± 6.8 years and the male-to-female ratio noted was 1:0.65. The mean values of FBG (mg/dL ± SD) at 4, 8, and 12 months were found to be statistically significant (P < 0.001, 117.12 ± 30.51, 109.69 ± 43.66, and 113.16 ± 56.93, respectively). t test carried out for PPBG indicated that the levels at respective intervals were significantly reduced as opposed to baseline (P < 0.05). The difference in HbA1c (%) across baseline, 4, 8, and 12 months was found to be statistically significant (P < 0.001) and the mean levels noted were 8.09 ± 2.26, 7.57 ± 1.84, 6.95 ± 1.80, and 6.46 ± 1.81, respectively. The difference in UACR across different intervals was found to be statistically significant (P < 0.001) and the corresponding mean UACRs (mg/g ± SD) noted were 417.21 ± 182.87, 291.82 ± 98.30, 296.84 ± 109.48 and 284.18 ± 103.26. Conclusion: Teneligliptin monotherapy is well tolerated with a persistent reduction in HbA1C and significant improvement in renal function.
Keywords: Chronic kidney disease, diabetes, proteinuria, renoprotection, T2DM, teneligliptin
|How to cite this article:|
Agrawal P, Gautam A, Jain A, Pursnani N, Manjula, KrishnaK. Renoprotective effects of teneligliptin: An observational study. J Diabetol 2021;12:146-50
| Introduction|| |
India being the diabetes capital of the world is witnessing an alarming increase in the disease prevalence. As per the estimates of International Diabetes Federation, 82 million people are suffering from diabetes in India and it is projected to reach 151 million by 2045. According to the findings from the Global Burden of Disease Study 2016, diabetes and chronic kidney disease linked to hyperglycemia pose formidable burden in the country, warranting urgent program and policies for reducing the associated risk factors. In 2016, the disease accounted for 3.1% of all death in the country and the disability-adjusted life years due to diabetes and hyperglycemia was around 27.5 million.
Teneligliptin, a recently developed oral dipeptidyl peptidase 4 (DPP-4) inhibitor, has been reported to show a reduction in HbA1c of 0.8%–0.9% within 3 months of treatment. Moreover, the safety and tolerability of the drug are found to be comparable to that of other DPP-4 inhibitors. The unique ‘J-shaped’ structure of teneligliptin, formed by five consecutive rings, assists in conferring potent and long-lasting glucose-lowering effects. A randomized, phase III study conducted across 24 centers in India has concluded that once-daily teneligliptin treatment is well tolerated by Indian diabetic patients and it assists in achieving clinically meaningful reductions in HbA1c. A 2017 systematic review by Awadhesh Kumar Singh has reported that evidence from short-term studies and two 52 weeks extension studies validate the safety and tolerability of teneligliptin as monotherapy or add-on therapy to other agents for managing diabetes.
There is a significant association between development of proteinuria in diabetics and elevated risks for renal and cardiac diseases. Although several studies have validated the role of teneligliptin in managing hyperglycemia, there is insufficient clinical evidence regarding the renoprotective effect of teneligliptin in T2DM patients, especially from Indian settings. A 2016 study by Sharma et al. has reported the safety of teneligliptin in diabetic patients with mild to severe renal impairment, without dose adjustments. This study was intended to corroborate the potential of teneligliptin in managing T2DM patients with inadequate disease control and to study its effect on renal parameters.
| Patients and Methods|| |
The prospective observational study included subjects aged >40 years with suboptimal control of T2DM (glycated hemoglobin (HbA1c) >7.5%), despite following a good exercise, dietary plan and oral hypoglycemic agents (OHAs) to manage blood glucose levels. The study was approved by the institutional ethics committee and informed consent was obtained from all the participants. The inclusion criteria considered were subjects aged between 40 and 70 years and patients with glycated hemoglobin (HbA1c) >7.5%. The study excluded pregnant/lactating women and subjects who had T1DM, known hypersensitivity to any components of the formulation. No change in (OHA) was done within 8 weeks before screening. The patients also did not receive insulin within 12 weeks of screening, or were treated with systemic corticosteroids. The demographic details of the study subjects such as age, gender, body mass index (BMI), smoking habit, duration of diabetes, and associated comorbidities were recorded. The participants received 20 mg of teneligliptin per day for 12 months. The following clinical and anthropometric parameters were measured at baseline, 4 months, 8 months and 12 months during the treatment: HbA1c, estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), fasting blood glucose (FBG) and postprandial blood glucose (PPBG) levels. FBG and PPBG levels were measured using hexokinase method, and glycated hemoglobin (HbA1c) levels using turbidimetric inhibition immunoassay (TINIA) with a reference range of 4.2%–21% (Cobas c 111 by Roche Diagnostics India Pvt. Ltd). The outcome measures considered were, eGFR, UACR, FBS, PPBS and HbA1c over time from baseline.
Results were presented as descriptive statistics in the form of mean/ proportion and percentage, and possible associations were derived using suitable parametric and nonparametric tests of significance. Comparisons of anthropometric and laboratory parameters were carried out using analysis of variance (ANOVA) and t test for normal data, Kruskal–Wallis for nonnormal data, and chi-square test for counts data. All the statistical analyses were performed using R (version 3.6.1) software. P < 0.05 is considered statistically significant for all the analyses. Results are presented as tables, charts, and figures as applicable.
| Results|| |
The study included 86 patients with inadequately controlled T2DM, as per the HbA1c status. The demographic characteristics of the study participants including age, gender, BMI profile, and smoking habits are given in [Table 1]. The mean age of the subjects was 54.28 ± 6.8 years and the male-to-female ratio noted was 1:0.65. The respective number of patients belonging to the age group of 41–50 years, 51–60 years, 61–70 years were 23 (26.7%), 42 (48.8%), and 21 (24.4%). Among the total study subjects, 23 (26.7%) had the habit of smoking and 63 (73.3%) were nonsmokers. Mean duration of diabetes in the patients was found to be 13.42 ± 1.33 years. Hypertension was the most common comorbidity noted among the subjects (43%), followed by dyslipidemia (39%), cardiovascular disorders (29%), hypothyroidism (9%), chronic renal disease (18%), and other diseases (16%). Distribution of patients based on the additional comorbid diseases is depicted in [Figure 1]. The distribution of patients receiving OHA was: metformin alone: 11, metformin plus sulfonylurea: 52, sulfonyl urea alone: 4, sulfonylurea plus metformin plus pioglitazone: 12, metformin plus pioglitazone: 7. The pre-existing antihypertensive regimen were calcium channel blocker (CCB) alone: 20, CCB plus thiazide diuretics: 10, CCB plus angiotensin receptor blocker (ARB): 7, ARB plus thiazide diuretics:9, CCB plus beta blockers:12, combination of CCB, and thiazide diuretics and ARB: 28.
The FBG and PPBG measurements were performed at baseline, 4 months, 8 months, and 12 months [Figure 2]. The mean baseline values noted for FBG and PPBG (mg/dL ± SD) were 169.83 ± 42.60 and 258.17 ± 65.54, respectively. The mean values of FBG (mg/dL ± SD) at 4 months, 8 months, and 12 months were 117.12 ± 30.51, 109.69 ± 43.66, and 113.16 ± 56.93, respectively. FBG levels at different timelines were found to be statistically significant (P < 0.001). t test analyses revealed that the levels at 4 months, 8 months, and 12 months were significantly reduced when compared to the baseline (P < 0.05).
|Figure 2: Graphical representation of FBG and PPBG distribution at different time intervals|
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The mean values for PPBG (mg/dL ± SD) at 4 months, 8 months and 12 months were 171.22 ± 57.31, 178.89 ± 41.81and 184.55 ± 51.44, respectively [Figure 2]. PPBG levels at different time intervals were found to be significantly different (P < 0.001). t test carried out for PPBG indicated that the levels at 4 months, 8 months, and 12 months were significantly reduced as opposed to baseline (P < 0.05). However, the measurements across the different time intervals (4 months, 8 months, and 12 months) did not differ significantly (P > 0.05) for both FBG and PPBG.
The mean HbA1Cs (% ± SD) noted at baseline, 4 months, 8 months and 12 months were 8.09 ± 2.26, 7.57 ± 1.84, 6.95 ± 1.80 and 6.46 ± 1.81, respectively. The difference in HbA1c across different time intervals was found to be statistically significant (P < 0.001). Further t test analyses revealed that decrease in HbA1C from baseline to 4 months was not statistically significant, whereas decrease at 8 months and 12 months from baseline and 4 months was statistically significant (P < 0.05) [Figure 3]. The difference between HbA1C values at 8 months and 12 months was not statistically significant. These findings indicate that the teneligliptin administration contributed to a significant reduction in HbA1C by the end of 6 months and its persistence in the following months.
|Figure 3: Distribution of HbA1C, eGFR, and UACR at different time intervals|
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Regarding renal parameters, the difference in eGFR across different time intervals was not statistically significant (P 0.958), indicating that administration of teneligliptin did not have any impact on eGFR. Mean eGFR (mL/min/1.73 m2) values noted at baseline, 4 months, 8 months and 12 months were 85.22 ± 25.03, 84.61 ± 24.37, 85.68 ± 24.71, and 86.65 ± 24.98, respectively [Figure 3]. The difference in UACR across different time intervals was found to be statistically significant (P < 0.001). The corresponding mean UACRs (mg/g ± SD) noted at baseline, 4 months, 8 months, and 12 months were 417.21 ± 182.87, 291.82 ± 98.30, 296.84 ± 109.48, and 284.18 ± 103.26 [Figure 3]. Further t test analyses indicated that decrease in UACR levels from baseline to 4 months, 8 months, and 12 months was statistically significant (P < 0.05). Administration of teneligliptin resulted in a significant decrease in UACR from baseline to 4 months. However, there was no significant difference in values across 4 months, 8 months, and 12 months.
| Discussion|| |
This study findings corroborate the potential of teneligliptin monotherapy in reducing HbA1c levels (mean % change 0.8) and its persistence thereafter. The study also noted its renoprotective effects by reducing proteinuria, without affecting the GFR. A study published in the International Journal of Research in Medical Sciences (2018) has reported that 12 weeks teneligliptin add-on treatment to oral antidiabetic drugs or insulin in Indian subjects with uncontrolled diabetes has resulted in significant reduction of HbA1c, FPG, and PPG after 12-week treatment. The study has also noted a reduction in microalbuminuria in nonsignificant proportion of patients.
A comparative study by Tintu Chacko has reported that teneligliptin has more therapeutic advantages than sitagliptin and vildagliptin in T2DM patients. The study has highlighted the improved safety of tenligliptin in renal impaired patients due to dual mode of elimination (renal and hepatic)
It is imperative to adopt customized glycemic control strategies in India, as the vascular abnormalities accompanying diabetes has been identified as a major etiological factor for kidney disease. The START-India study (2015) has found that the prevalence of CKD in T2DM patients is >40% and one out of five hypertensive subjects are suffering from renal disease. The management of hyperglycemia in diabetic patients with renal impairment is highly challenging because of the complexity of the treatment and the need of formulating the ideal therapeutic strategy by considering the inherent associated risks. The declining GFR in CKD patients limits the use of certain therapeutic agents for optimal glycemic control, as the reduced urinary excretion in such patients may prolong the exposure of the drugs that are eliminated via renal route. Moreover, there is no sufficient literature-based evidence to corroborate the benefits of stringent glycemic control in this subset of patients.
The emerging evidence validates the pleotropic benefits of DPP-4 inhibitors including cardiovascular and renal protection. This study has noted that the administration of teneligliptin did not have any impact on eGFR. The study has also noted statistically significant (P < 0.05) persistent decrease in UACR levels from baseline to 4 months, 8 months, and 12 months. In concurrence with the present findings, a review by Abubaker et al. has concluded that the teneligliptin holds immense potential in managing T2DM in patients with renal impairment, as the treatment helps in improving the renal parameters such as glycated albumin, urinary albumin, and eGFR. A retrospective analysis of Asian Indian subjects with early CKD has also noted that the teneligliptin therapy contributed to sustained improvement in glycemic control and the treatment was well tolerated. Furthermore, all the patients who had proteinuria at baseline did not report the condition at 24 weeks (40.5%, P = 0.001). The ATEND-CKD study has evaluated efficacy and safety of teneligliptin in Indian patients with T2DM and chronic kidney disease. In line with this study results, the researchers have noted a statistically significant reduction in HbA1c (0.9%), serum creatinine (4%) and BUN (9%). The interim analysis involving 11,677 subjects has found that the two-year teneligliptin treatment helped in achieving significant improvement in glycemic control in all subsets of patients including patients having mild to severe renal impairment and those on dialysis. Another added advantage of teneligliptin treatment is that it does not require any does adjustment based on the eGFR levels in renal impaired patients, unless other anti-diabetic agents. However, it has not been elucidated whether the mechanism by which teneligliptin decreases the UACR is independent of its glucose‐lowering effect. Further comparative studies are necessary to explore the direct effects of the drug in conferring renoprotection.
Limited studies are available, especially from India, evaluating the effects of teneligliptin on renal parameters. The present findings hold immense relevance, as the study has shown that it may serve as an effective agent for managing hyperglycemia and proteinuria in diabetes patients in Indian settings. However, the study has certain limitations including smaller sample size, single-center based, and nonrandomized study design. Hence the observations of the study cannot be generalized. Another major limitation is not evaluating other co-variables influencing the renal function.
| Conclusion|| |
Teneligliptin monotherapy has contributed to a significant and persistent reduction in HbA1C. In addition, the treatment is well tolerated with significant improvement in renal function. The study warrants prospective cohort studies involving larger sample size to explore the long-term safety of the drug on renal impaired subjects.
Financial support and sponsorship
Conflicts of interest
Dr. Manjula S and Dr. Krishna Kumar M are employees of Micro Labs Ltd, India Makers of Tenepride (Teneligliptin).
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[Figure 1], [Figure 2], [Figure 3]