Efficacy and Safety of Teneligliptin as Add on
Therapy in Indian Type 2 Diabetes Mellitus
T2DM Patients Having Dyslipidemia
Parmar Vinendra M* and Goswami Sunita S
Department of pharmacology, Gujarat Technological University, India
Submission: April 10, 2020; Published: August 12, 2020
*Corresponding author: Parmar Vinendra M, Ph. D scholar, Department of pharmacology, L. M. College of pharmacy, Gujarat Technological University, Ahmedabad, Gujarat, India
How to cite this article: Parmar V M, Goswami S S. Efficacy and Safety of Teneligliptin as Add on Therapy in Indian Type 2 Diabetes Mellitus
T2DM Patients Having Dyslipidemia. Curre Res Diabetes & Obes J 2020; 13(4): 555869. DOI: 10.19080/CRDOJ.2020.13.555869
Objectives:The purpose of this study was to investigate the efficacy and safety of teneligliptin, a completely unique and highly selective DPP-4 inhibitor in type 2 diabetes mellitus (T2DM) patients having dyslipidemia who are inadequately controlled by relevant conventional therapy in India.
Methods: Study protocol was approved by Institutional Ethics Committee. Diabetic patients having dyslipidemia (male/female) were randomized to receive treatments in two groups, namely conventional therapy [treatment (A)] and add on teneligliptin 20 mg with conventional therapy [treatment (B)] for 24 weeks. Predesigned case report form (CRF) was used to collect information from the prescribing physicians regarding the efficacy and safety of teneligliptin. Efficacy variables included change in serum glycaemic, lipid, and cytokines (IL-6, TNF- α and adiponectin) levels from baseline to week 24. Treatment-emergent adverse events (TEAEs) were also assessed.
Results: A complete of 120 T2DM patient having dyslipidemia were analysed using graph pad prism. Teneligliptin, as add on therapy to conventional therapy significantly reduced serum lipid profile (TC, TG, and LDL) as well as glycaemic parameters (HbA1c, FBG, and PPBG) along with significant rise in serum adiponectin levels as compared to conventional therapy
Conclusion: Add- on therapy with teneligliptin was found superior over convetional therapy in term of significantly reduced glycemic as well as lipid profile. Further, it was found safe and well tolerated in T2DM patients having dyslipidemia.
Keywords: Teneligliptin; DDP-4 inhibitor; Metformin; Total Cholesterol; Glycated haemoglobin; Adiponectin; Type 2 diabetes mellitus; Dyslipidemia
Abbreviations: NCD: Non-Communicable Disease; IDF: International Diabetes Federation; T2DM: Type 2 Diabetes Mellitus; DPP-4: Dipeptidyl Peptidase-4; GLP-1: Glucagon-like Peptide-1; HbA1c: Glycated Haemoglobin; IEC: Institutional Ethics Committee; DCGI: Drugs Controller General of India; BMI: Body Mass Index; FBG: Fasting Plasma Glucose; PPBG: Post Prandial Blood Glucose; AE: Adverse Event; SAP: Sample Analysis Plan; SD: Standard Deviation
Diabetes mellitus (DM) is found to be related to alterations in lipid metabolism in term of high total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) and low high density lipoprotein (HDL), that ends up in dyslipidemia and worsens the prognosis of diabetic patients having atherosclerosis and Cardiovascular disorder(CVD) . The International Diabetes Federation (IDF) estimates the whole number of diabetic subjects is to rise to 69.9 million by the year 2025 . The population of diabetes is rapidly growing because of the expansion of population, urbanisation, ageing, and increasing prevalence of obesity and morbidity .
Dyslipidemia, a long-time established risk factor for CVD has effect on 50% of diabetes patients as compared to non-diabetic population . In DM patient’s insulin deficiency or resistance activates intracellular hormone-sensitive lipase which increases the discharge of non-esterified fatty acids (NEFA) from triglycerides that’s stored in centrally distributed adipose tissue. High circulating levels of NEFA also increase hepatic triglyceride production [5,6]. Lower levels of adiponectin are considered as an independent risk factor for developing Type 2 DM, dyslipidemia, and cardiovascular diseases .
A recent statement from one amongst the meta analysis report
for the standards of medical care in Diabetes by the American
Diabetes Association (ADA) has recommended that initially
treatment with metformin as monotherapy after inadequate life
style modification, followed by sulfonylurea, thiazolidinedione,
Dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter
2 inhibitors (SGLT2-i), glucagon like peptide 1 (GLP 1)
receptor agonist, or insulin alone or in combination . However,
it’s still difficult to search out an antidiabetic agent with long-term
glucose control, minimal hypoglycaemia, no weight gain with
affordable price. The optimum treatment with antidiabetic drugs
to get fair glycaemic control should go hand-in-hand with lipidlowering
drugs [9,4]. In diabetic patients having dyslipidemia, in
keeping with current guideline, statins are preferred as they are
well tolerated, efficacious and don’t adversely affect glycaemic
DPP-4 inhibitors are considered as a cornerstone within the
management of T2DM due to their robust efficacy and favourable
tolerability profile . Our previous study has demonstrated
teneligliptin as add on therapy showing better glycemic control
as compared to conventional therapy in Indian patients having
T2DM . As there is no future study conducted on add on
therapy of teneligliptin in diabetic dyslipidemic patients, our
study was designed to evaluate efficacy, safety, and tolerability
treatment which can led to improvement in the effectiveness of
standard therapy in diabetic patients having dyslipidemia in India.
Currently only few reports are available on the role of inflammatory
biomarkers in type 2 diabetes and folks with impaired lipid
metabolism in Indian population. During this manuscript, we
have also tried to incorporate the role of inflammatory regulators
(IL 6, TNF ά and adiponectin) with respect to add on teneligliptin
therapy in type 2 diabetic patients having dyslipidemia in Indian
The protocol of clinical study, informed consent form and
relevant essential documents were approved by Institutional Ethics
Committee (IEC); Safety, Health and welfare Ethics committee,
registered under Drug Controller General of India (DCGI). The
study was conducted according to the Ethical principles of
Declaration of Helsinki; Good Clinical Practices guidelines issued
by the Central Drugs Standard Control Organization (CDSCO),
Indian Councils of Medical Research (ICMR).
A prospective, randomized, open label, study to assess
the efficacy and safety of teneligliptin as an add-on therapy to
conventional treatment in T2DM patients having dyslipidemia.
This study was conducted at Jivraj Mehta Hospital and Bakeri
Medical Research Centre, Ahmedabad.
Study protocol was clearly defined for the patients and
informed consent was obtained from all patients before to
participation. The study included male and female patients with
T2DM having dyslipidemia, aged >18 years, HbA1c levels of >7.0%,
and body mass index (BMI) of 20.0–35.0 kg/m2 (both inclusive).
Patients were excluded if they had serious disease such as
kidney, liver, and cerebral stroke, history of severe heart disease
or arrhythmias, taking DPP-4 inhibitor other than teneligliptin,
taking statin other than atorvastatin and on insulin therapy,
pregnant, and history of alcohol and tobacco use.
Eligible patients were randomized in 1:1 ratio to receive
either metformin/glimepiride and atorvastatin (treatment A) or
metformin/glimepiride, atorvastatin, and add on teneligliptin
(Treatment B). Treatment for both the groups remained stable
and it included: teneligliptin 20 mg/day, metformin 500 mg/day,
glimepiride 2 mg/day and atorvastatin 20 mg/day for 24 weeks.
Patient’s demographics data, physical and clinical examination,
laboratory assessments were documented in predesigned case
report form (CRF).
Lipid profile including serum Total cholesterol (TC),
Triglyceride (TG), Low density lipoprotein (LDL), High density
lipoprotein (HDL) and Glycemic parameters including serum
glycated haemoglobin (HbA1c), fasting blood glucose (FBG) and
post prandial blood glucose (PPBG) levels and Inflammatory
cytokine levels IL6, TNF-α, and adiponectine levels were measured
at baseline and at the end of 24 weeks in both the treatment
Serum cholesterol was estimated by cholesterol oxidase
method from ROCHE on COBAS INTEGRA 400 WITH Exteranal
quality control (EQAS) from BIO-RAD laboratories (USA) internal
quality control from ROCHE diagnostic. Serum LDL and HDL were
tested by direct non-immunological method on COBAS INTEGRA
400PLUS. Serum Triglyceride was tested by lipase glycerol
method. Values of serum lipids were entered into the computer
and computer analysis of the data was obtained
From each subject, serum were collected and stored at -80ºC
until further analysis. Serum IL-6 and TNF-α levels were measured
using the enzyme-linked immunosorbent assay (ELISA) according
to the manufacturer’s instructions (KRISHGEN Biosytems,
Mumbai). The assay sensitivity ranges of KRISHGEN Biosytems
kits were 3.12-200 pg/ml for IL-6 and 6.8-500 pg/ml for TNF-α
in serum samples. The ELISA kits were validated with inter- and
intra-assay precision. For adiponectin level was measured using the enzyme-linked immunosorbent assay (ELISA) according to the
manufacturer’s instructions (KINESIS Dx). The assay sensitivity
ranges of KINESIS Dx kit was 2-34 μg /ml adiponectine in serum
samples. The ELISA kit was validated with inter- and intraassay
precision. The (IL-6, TNF- α, and adiponectin) cytokines
absorbance measured at 450nm.
The primary efficacy end point was the change in glycemic
and lipid parameter from baseline to 24 weeks. Secondary efficacy
endpoints include change in inflammatory (IL-6, TNF- α, and
adiponectin) cytokine levels from baseline to 24 weeks. During
the clinical study period, we monitored possible adverse events
(AEs), laboratory values, vital sign and physical examination
results. Safety aspects were measured by recording AEs including
symptomatic assessment by Naranjo causality scale for adverse
events . The incidence of AE in terms of number per patient
was calculated based on the number of events, the number of
patients and the total observation period.
The primary end point, difference in mean HbA1c from
baseline to 24 week was assumed 0.5% and also the standard
deviation (SD) of 0.9% for each treatment group. Based on a
power of 80% and a type I error rate of alpha= 0.05 (2-tailed),
a sample size of at least 60 patients per group was required to
detect a clinically significant difference between both the groups
. Categorical data was presented as absolute number/
percentage of patients while quantitative data was presented as
mean ± standard deviation (SD). Within group comparison was
performed using paired t-test based on the distribution of data.
Unpaired t-test was used to analyse the quantitative data for
between group comparisons. Missing data was handled using Last
observation carried forward (LOCF) method. P value of less than
0.05 was considered as statistical significant difference. Data were
calculated using Graph Pad prism version 5.0.
A flow chart is presented showing the disposition of
participants throughout the study (Figure 1). Out of 159 screened
patients, 132 eligible patients were randomized during this
clinical study. Treatment A included 61 patients and treatment
B included 63 patients. As per sample analysis plan (SAP),
sixty patients in each group were analysed to detect a clinically
significant difference between both the groups. Both the groups
had similar demographic and clinical characteristic parameters at
baseline (Table 1).
HbA1c level was found comparable in both the treatment
groups at the baseline. However, there was gradual reduction in
HbA1c over the period of 24 weeks in both the treatment groups.
Between groups comparison showed significant reduction
(p<0.05) in HbA1c in treatment B as compared to treatment A
Blood glucose levels (FBG and PPBG) were found comparable
in both the treatment groups at the baseline. However, there
were significant reduction in FBG and PPBG levels over a period
of 24 weeks in both the treatment groups. However, reduction in
glycaemic parameters (HbA1c, FBG and PPBG) was statistically
significant in treatment B as compared to treatment A after 24
weeks (Table 2). Reduction in mean change of HbA1c was 0.96 ±
0.46 and 1.20 ±0.45 in in treatment A & B respectively. Reduction
in mean changes in FBG and PPBG levels were 23.56 ± 8.40 and
28.89 ± 9.17 in treatment A as compared to 32.62±11.45 and
36.62± 9.92in treatment B respectively.
Lipid parameters were found comparable in both the
treatment groups at the baseline. However, there were gradual
reduction in Total cholesterol (TC), Triglyceride (TG), atherogenic
index (TC/HDL ratio) and Low density lipoprotein (LDL) over
the period of 24 weeks in both the treatment groups (paired
student t-test). The improvement in lipid profile was significant in
treatment B as compared to treatment A at the end of 24 weeks.
Mean changes of these parameters have been shown in table 2.
There was significant decrease in serum TC levels after 24
weeks from baseline in both treatment groups. The treatment
A reduced the serum concentration of TC from 218.08± 20.15
mg/dL to 176.78 ±13.22 mg/dL and in the treatment B 219.00
±14.18 mg/dL to 166.90 ±19.56 mg/dL. Further, between groups
comparison showed significant reduction in TC in treatment B as
compared to treatment A (Figure 3).
Reduction in mean change of TG level was 30.75±11.56 mg/
dL and 39.48 ±15.25 mg/dL in treatment A & B. The mean change
in TG levels significantly increased in treatment B as compared to
treatment A at the end of 24 week. Between groups comparison
showed significant reduction in TG in treatment B as compared to
treatment A (Figure 4).
At the end of 24 weeks, add on teneligliptin group (treatment
B) showed tendency to reduce in serum LDL levels. Reduction
in mean change of LDL in treatment B was 34.06% as compared
to 28.24 mg/dL in treatment A. The mean change in LDL levels
significantly increased in treatment B as compared to treatment
A at the end of 24 week. Between groups comparison showed
significant reduction in LDL in treatment B as compared to
Serum Adiponectin levels: At the end of 24 weeks, add on
teneligliptin group (treatment B) showed tendency to increase
adiponectin level. Mean change of adiponectin in treatment B was
4.776±1.68 μg/ml as compared to 0.629±0.87 μg/ml in treatment
A. The mean change in adiponectin levels significantly improved
in treatment B as compared to treatment A at the end of 24 week.
Between groups comparison showed better improvement in HDL
in treatment B as compared to treatment A (Figure 5).
In addition to above, reduction in inflammatory cytokine
levels (IL 6 and TNF-α &) was also observed in treatment B as
compared to treatment A at the end of 24 weeks but was not found
statistically significant (Table 2).
The most common AEs experienced in both the treatment
groups were hypoglycaemia, constipation, abdominal pain,
acidity, weakness and headache. The incidence of AE was 35%
in treatment A and 21.66% in treatment B group (Table 3).
Revealing better tolerability and safety of teneligliptin under the
add on therapy.
Diabetes is progressive disease which include both
microvascular and macrovascular complications . The
relation between DM and lipid profile has been established during
the past decades . Both lipid profile and diabetes are shown to
be the important predictors for metabolic disturbances including
dyslipidaemia, hypertension, and cardiovascular diseases .
Diabetic dyslipidemia accounts for around 80 percent diabetic
deaths due to cardiovascular complications . Diabetes is
typically managed employing a stepwise approach involving diet
and lifestyle modification followed by addition of oral as well as
IV antidiabetic drugs . Although international and native
guideline recommended lifestyle management as the mainstay of
treatment for T2DM, with metformin as the preferred initial oral
antihyperglycemic agent in most of the patients, but there is need
for extra additional approach synergistic .
In the present study, a trial has been made to evaluate
the efficacy and safety of newly developed DPP-4 inhibitor,
teneligliptin 20 mg in T2DM patients having dyslipidemia who
are not adequately controlled by ongoing conventional therapy.
The potential effect of teneligliptin in the management of
hyperlipidemia and obesity has been established in preclinical
studies [20,21]. Dipeptidyl peptidase 4 inhibitors which inhibit
the endogenous glucagon like peptide 1 (GLP) metabolism and
thereby increases GLP-1 level in the physiological range .
They act by regulating insulin and glucagon secretion . Rise in
new beta-cells and inhibition of their apoptosis is seen with DPP-
4 which might be potentially improve the disease pathogenesis
. Teneligliptin suppresses proinflammatory activation of
macrophages and adipocytes . Therefore, it is a possible
target for cardio protective effect.
Present work clearly demonstrated that teneligliptin addition
to glimepiride/ metformin stable dose significantly reduced
HbA1c level as compared to conventional therapy at 24 weeks
from the baseline. Further, we also observed significant reduction
in blood glucose levels (FBG and PPBG) in both the treatment
groups. Results of the present study are found consistent with
the previous clinical reports from japan, where efficacy of
teneligliptin as add on treatment decreased HbA1c, FBG and PPBG
levels at 12 weeks and the same study was expanded to 52 weeks
. Our study suggested that, the addition of teneligliptin 20 mg
to conventional therapy (metformin/glimepiride) significantly
improved the efficacy of conventional therapy. Our study results
support the previous clinical study wherein, combination of
teneligliptin with that of insulin reduced HbA1c level and showed
synergistic effect . HbA1c levels in blood are one of key marker
to know glycemic control . In our study, tenligliptin as add on
treatment significantly decreased HbA1c in patients with T2DM
which might be possibly due to its synergistic action.
DM is often related to with alterations in lipid metabolism and
abnormalities in serum lipid profile. Dyslipidemia is common in
T2DM patients with poorly controlled glycemia . We observed
significant decrease in HbA1c and lipid profile at the end of 24
weeks in teneligliptin treated patients. Addition of teneligliptin
showed significant reduction in TC at the end of 24 weeks. These
findings are supported by one in all the meta-analysis report
where in lipid lowering effect of DPP-4 inhibitors revealed a
decrease in TC .
Beneficial effects of metformin on lipids could be because of
inhibition of fatty acids released from adipose tissues, its direct
effect on VLDL-C metabolism and/or secondary to enhance
insulin sensitivity . Elevated TG levels have been recognized
as a risk factor for progression of CVD . In this study, addition
of teneliglptin reduced TG levels by 20.02% at the end of 24 week.
Reduction in TG rich lipoprotein may include enhanced expression
of the LDL receptors, increased expression of lipoprotein lipase,
and reduced expression of apo C-III and very low-density
lipoproteins . Thus, teneligliptin might act through either of
these mechanism to reduce this.
Besides, add on therapy of teneligliptin showed reduction in
LDL-C levels (34.06 %) in treatment B. Meta-analysis report by
Wulffle et al., showed efficacy of metformin in reducing TC, TG
and LDL-C in their study with a minimum of 6 weeks of treatment
in T2DM patients . So, we conclude that add on therapy of
teneligliptin together with metformin might give better reduction
in serum LDL levels. Further, mean atherogenic index (TC/HDL
ratio) was found comparable from baseline to week 24 for both
the treatment groups. The mean atherogenic index decreased
(30.03%) in treatment B when put next with the treatment A
(28.24%) from baseline data. There is a report of significant
decrease in TC, TG and LDL-C with increase in levels of HDL-C
after 3 months of treatment with metformin in T2DM patients
. Pravin Kumar and Gokul reported a decrease of 16%, 12%
and 10% of TC, TG and LDL-C respectively and a 15% increase
of HDL-C; and achieving the lipid control goals with metformin
- glimepiride combination therapy of 26 weeks in T2DM in their
Thus, our results were also parallel with the findings of various
reports. Therefore, it will be suggested that teneligliptin addition
with conventional antidiabetic therapy can be useful in controlling
diabetes with dyslipidemia. Thus our results shown promising
data of teneligliptin in T2DM patients with dyslipidemia.
Increased in adipose tissue mass occurs by the expansion of
pre-existing adipocytes or by generating new small adipocytes.
Chronic overfeeding leads to adipocyte hypertrophy and is related
to decrease adiponectin levels and increased IL-6, and TNF-α production. In addition, the abnormal functioning of adipocytes
like lipodystrophy and inability to store triglycerides and fatty
acids may lead to ectopic fat storage in liver, skeletal muscle etc.,
thus causing dyslipidemia and insulin resistance. This condition
can also play an crucial role in the development of a chronic
low-grade pro-inflammatory state related to adipose tissue
dysfunction and diabetes .
Tumor necrosis factor-α and IL-6 are important mediators of
inflammation and will provide a possible link between visceral
fat and systemic inflammation. They are both known to promote
lipolysis and therefore the secretion of free fatty acids, which
contribute to a rise in hepatic glucose output and IR, impair
adipocyte differentiation, and promote inflammation .
Experimental studies and cross-sectional analysis have shown that
circulating IL-6 is related to hyperglycemia and insulin resistance.
It’s also been shown that circulating IL-6 increases with the degree
of insulin resistance . The protective effects of adiponectin
in the prevention of progression of insulin resistance and in
cardiovascular events, and its potent influence in components
of the metabolic syndrome, have made it a highly promising
therapeutic target . These markers though well understood
in terms of their regulation in diabetes population are still lacking
acceptance as clinical markers because of the variation of levels
among various ethnic groups . Currently limited information
is available on inflammatory cytokines in type 2 diabetes and
people with impaired glucose and lipid metabolism in Indian
population. Our study has demonstrated significantly raised
adiponectine levels in treatment B as compared to treatment A.
Also, an improvement in adiponectin level found associated with
reduction(p>0.005) of inflammatory cytokines (IL-6 & TNF-α)
which was clearly demonstrated in our study.
Clinical symptomatic assessment was done for AEs like
hypoglycemia and constipation, which were considered as
definite; abdominal pain, and acidity were considered as probable;
weakness and headache considered as possible and doubtful
respectively by Naranjo AE assessment scale. It is also to be noted
that, the incidence of hypoglycemic symptoms was similar 3.33%
in both the groups. For selection of antihyperglycemic agents
for add on therapy it include, individual patient characteristic,
glucose-lowering efficacy, risk of hypoglycemia, body weight
gain, and cardiovascular benefits associated with the drugs are
preferentially considered .
In summary, results of our study showed that, add on therapy
of teneligliptin with standard therapy of anti-diabetic class of
drug significantly improved lipid levels by increasing level of
good cholesterol as compared to the conventional therapy, this
was possibly due to synergistic action of teneligliptin. Hence,
during this scenario, the present study supports the initiation of
treatment of T2DM with dyslipidemia using teneligliptin, which
is affordable and effective in decreasing the glycaemic as well
as lipid levels together with lifestyle modifications. Further add
on therapy should be initiated if treatment is not satisfactory
because optimum glycaemic level is must for the reduction of
elevated lipid levels and thereby preventing atherosclerosis and
In our study teneligliptin, as add on therapy was found
well tolerated and effective in T2DM with dyslipidemic patient
population. Tenligliptin add on treatment with atorvastatin was
found better alongwith conventional-therapy in reducing glycemic
and lipid parameters as well as improvement in adiponectin levels
in diabetic patients with dyslipidemia.
The authors acknowledge the guidance of Dr.Parag Shah,
Dr. Krishna Shah, Dr. Alka Makad, Dr. Chirag Vaghela, Dr. Premal
Thakor and Dr. Shubha Desai without their support this work
would not have been possible. We also thankful to Krishna shah
for providing scientific evaluation and assessment of cytokines.
We are also thankful to staff of research department Jivraj Mehta
Hospital and Bakeri medical research centre, Ahmedabad for
extending required help and research facility for the present study.
(2014) Draft Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. Silver Spring, MD: US Food and Drug Administration.