{"id":30720,"date":"2020-03-28T11:50:46","date_gmt":"2020-03-28T11:50:46","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=30720"},"modified":"2021-03-17T07:30:51","modified_gmt":"2021-03-17T07:30:51","slug":"lipid-lowering-effect-of-teneligliptin-in-comparison-to-simvastatin-in-diet-induced-hyperlipidemic-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol13no1\/lipid-lowering-effect-of-teneligliptin-in-comparison-to-simvastatin-in-diet-induced-hyperlipidemic-rats\/","title":{"rendered":"Lipid Lowering Effect of Teneligliptin in Comparison to Simvastatin in Diet Induced Hyperlipidemic Rats"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Hyperlipidemia is a metabolic disorder that involves abnormally increased levels of lipids and lipoproteins in the blood. Most dyslipidemias (80%) are related to diet and lifestyle, although familial disorders (20%) are important as well. The American Heart Association estimates a prevalence of 11.9% which is around28.5 million adults \u226520 years of age having serum total cholesterol levels \u2265240 mg\/dl, which is considered a high level necessitating treatment.1<\/sup> A study conducted by Indian Council of Medical Researchshows a high prevalence in India with approximately 79% of the 16607 study subjects manifesting abnormalities inat least one of the lipid parameters.2<\/sup><\/p>\n

Hyperlipidemia is one of the major risk factors that causearteriosclerosis, cerebral stroke, coronary heart disease, myocardial infarction and renal failure. Statins are widely used to lower cholesterol levels because of their inhibitory effects on the 3-hydroxyl-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the rate-limiting step in cholesterol biosynthesis. The most important adverse effects of statins are increased concentrations of liver enzymes, myopathy, rhabdomyolysis and increased risk of diabetes.3, 4<\/sup> In addition, reports of an increase in the potential risk of cognitive impairment with statins have been documented. 5<\/sup><\/p>\n

Teneligliptin is a dipeptidylpeptidase-4 inhibitor that inhibits the enzyme dipeptidyl peptidase-4 (DPP-4) and is a potent treatment option for type 2 diabetes (T2DM) either as monotherapy or in combination with other hypoglycemic agents. Gliptins are used for the treatment of T2DM when patients fail to show adequate glycemic control after dietary changes and exercise or with a combination of lifestyle modification and metformin \/sulfonylurea treatment.6, 7<\/sup>They have relatively lesser adverse effects, weight neutral and do not cause any significant hypoglycemia.7,8<\/sup>Dyslipidemia is an important risk factor for cardiovascular complications in type 2 diabetic patients. It is unclear whether gliptins favorably improve lipid profile in type 2 diabetic patients as there are contradicting evidences from clinical studies. 9, 10<\/sup><\/p>\n

The DPP-4 inhibitors are also currently being evaluated for their effects on obesity and other metabolic traits.11, 12<\/sup>In addition, their role in chronic liver diseases including non-alcoholic steatohepatitis is also under investigation.13, 14<\/sup><\/p>\n

In animal studies, a beneficial effect on blood lipids has been detected in type 2 diabetic animal models like Zucker fatty rats. studies indicate a potential lipid lowering effect of teneligliptinin T2DM, the efficacy of the drug as an independent anti-hyperlipidemic agent is not yet determined.Thus the aim of this study was to evaluate the lipid lowering effect of teneligliptin in high fat diet rat model as there is paucity of studies assessing the hypolipidemic action of gliptins in diet induced hyperlipidemia model. So, in this study, we compared the effect of gliptins(teneligliptin) to that of statins (simvastatin) on hyperlipidemia induced in ratsusing high fat diet.<\/p>\n

Materials and Methods<\/strong><\/p>\n

After the approval of the Institutional Animal Ethics Committee (Approval number:288\/2015\/IAEC),the study was done in the department of Pharmacology at a Medical college and research institute in Coimbatore.\u00a0 22 healthy adult Sprague Dawley male rats of weight 180 g to 250g and age more than 2 months were chosen for the study. They were housed in polypropylene cages at normal ambient temperature and 12-hour light dark cycle. The animals were administered high cholesterol diet over a period of 4 weeks to induce hyperlipidemia after which,with 2 rats as controls, 10 rats were randomly allotted to each of the groups 1 and 2 following which they were administered the drug\/vehicle during the last two weeks (5th<\/sup>,6th<\/sup>) along with normal standard chow diet.<\/p>\n

Standard group (1): 10 rats given simvastatin(10mg\/kg\/day)<\/p>\n

Treatment group (2): 10 rats given teneligliptin (20 mg\/kg\/day)<\/p>\n

Control group (3): 2 rats given vehicle (sterile water)<\/p>\n

The composition of high-lipid diet consisted of 1% (w\/w) cholesterol, 10% (w\/w) fat lard, 0.2% propylthiouracil, 5% yolk and 1% sodium tauroglycocholate.15<\/sup>The rats were allowed the high fat diet and water ad <\/em>. The drugs simvastatin at a dose of 10 mg\/kg and teneligliptin at a dose of 20 mg\/kg were dissolved in sterile water and the control animals were given the vehicle (sterile water) all of which were administeredby oral gavage.<\/p>\n

Blood samples (1.5 ml) were collected from tail vein of each rat using tail snip method under anesthesia. Blood sample collection was done at baseline, at the end of 4th<\/sup> week and 6th<\/sup> week. Lipid profiling was done to determine the levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). The LDL-C, HDL-C and (TC) estimations were done in auto-analyzer using GenX lipid parameter kits from Proton Biologicals and the (TG) was estimated in auto-analyzer using Coral clinical systems kit.<\/p>\n

At the end of the study, the two control animals and three animals from the group 1 (standard) and group 2 (treatment) were sacrificed for collection of liver and aorta specimens for histopathology examination.Tissue sections of liver and aorta were preserved in 10% neutral buffered formalin later processed and stained using H&E stain.The slides were observed under microscope for fatty degeneration in liver and sub-intimal fat deposition in aorta.<\/p>\n

Statistical Analysis<\/strong><\/p>\n

The changes in lipid parameters within the groupswere analyzed using paired t-test to detect statistically significant difference. One way ANOVAwith post-hoc<\/em>Tukey test was done to evaluate the statistically significant difference between the treatment and standard groups. The results were expressed as mean \u00b1 SD. A value of p<0.05 was considered statistically significant. The histopathological changes were analyzed descriptively.<\/p>\n

Results<\/strong><\/p>\n

All the three groups exhibited a rise in mean TG after induction which was statistically significant compared to the baseline. Following treatment with teneligliptin, the mean TG was 57.51 \u00b1 16.00 mg\/dl while that in the simvastatin group was 46.21 \u00b1 16.05 mg\/dl (Table 1) and the mean reduction of TG (28.70 \u00b1 7.61 mg\/dl) in group 2 was statistically different (p< 0.001) as that of the mean reduction in group 1(24.71 \u00b1 18.11 mg\/dl) with p = 0.021 (Table 2).However there was no statistical significance in the mean difference in TG levels between the two groups at the end of 6 weeks with p = 0.318(Table 3).<\/p>\n

Likewise, serum TC level which increased significantly due to induction with high cholesterol diet demonstrated a reduction following treatment both in standard as wellas the treatment groups (Table 2). There was no statistically significant difference (p= 0.923) between the mean TC group 2 (122.22 \u00b1 28.75 mg\/dl) compared to that of group 1(127.21\u00b1 24.86 mg\/dl) after treatment (Table 1 & 3).<\/p>\n

Tables 1:\u00a0<\/strong>Comparison of mean\u00b1 standard deviation of<\/strong> the<\/strong> body weight and lipid parameters after treatment between the three groups<\/strong><\/p>\n\n\n\n\n\n\n\n\n
Parameters<\/strong><\/td>\nGroup 1<\/strong><\/td>\nGroup 2<\/strong><\/td>\nGroup 3<\/strong><\/td>\n<\/tr>\n
Body weight (g)<\/td>\n267.62\u00b118.91<\/td>\n258.37\u00b137.20<\/td>\n324.33 \u00b1 19.66<\/td>\n<\/tr>\n
Triglycerides(mg\/dl)<\/td>\n46.21\u00b116.05<\/td>\n57.51\u00b116.00<\/td>\n77.25 \u00b1 10.08<\/td>\n<\/tr>\n
Total cholesterol(mg\/dl)<\/td>\n127.21 \u00b1 24.86<\/td>\n122.21 \u00b1 28.75<\/td>\n168.65 \u00b1 22.58<\/td>\n<\/tr>\n
LDL(mg\/dl)<\/td>\n44.96\u00a0 \u00b1 7.61<\/td>\n40.70\u00a0 \u00b1 10.62<\/td>\n62.90 \u00b1 4.49<\/td>\n<\/tr>\n
HDL(mg\/dl)<\/td>\n36.82\u00a0 \u00b1 6.61<\/td>\n33.08\u00a0 \u00b1 6.68<\/td>\n30.55 \u00b1 3.34<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

In addition, at the end of 6 weeks, serum LDL-C also revealed a parallel reduction in both groups with the mean of group 1 (44.96\u00b17.61 mg\/dl) and 2(40.70 \u00b1 10.62 mg\/dl) at the end of intervention beingstatistically significant compared to that of mean serum after induction with p=0.002 & p=0.003 for groups 1 and 2 respectively using paired t test (Table 1 & 2). A statistical significance in mean LDL-C levels could not be detected (p = 0.735) between the two groups using ANOVA (Table 3). However, a similar trend was not evident for serum HDL-C. A fall in HDL-C level could be noted in both groups with induction compared to the baseline. The mean HDL-C value after induction for group 1 (33.65 \u00b1 4.41 mg\/dl)and group 2 (32.06 \u00b1 4.27 mg\/dl) revealed a rise with the standard (36.82 \u00b1 6.61 mg\/dl) as well as the treatment drug (33.08 \u00b1 6.68 mg\/dl) but the increase produced by either of the drugs was not statistically significantwith p=0.476 & p=0.796 for groups 1 and 2 respectively (Table 1 & 2).<\/p>\n

Table 2: Comparison of lipid parameters within groups using paired t test<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
Parameter (mg\/dl)<\/strong><\/td>\nGroup<\/strong><\/td>\nPair<\/strong><\/td>\nMean Paired difference<\/strong><\/td>\nStd. Deviation<\/strong><\/td>\nStd. Error Mean<\/strong><\/td>\nP value<\/strong><\/td>\n<\/tr>\n
TG<\/td>\nGroup1<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-54.20<\/td>\n10.83<\/td>\n4.42<\/td>\n.000<\/td>\n<\/tr>\n
Group1<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

24.71<\/td>\n18.11<\/td>\n7.39<\/td>\n.021<\/td>\n<\/tr>\n
Group2<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-39.51<\/td>\n8.92<\/td>\n3.64<\/td>\n.000<\/td>\n<\/tr>\n
Group2<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

28.70<\/td>\n7.61<\/td>\n3.10<\/td>\n.000<\/td>\n<\/tr>\n
TC<\/td>\nGroup1<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-181.80<\/td>\n28.64<\/td>\n10.82<\/td>\n.000<\/td>\n<\/tr>\n
Group1<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

132.95<\/td>\n23.57<\/td>\n8.90<\/td>\n.000<\/td>\n<\/tr>\n
Group2<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-129.35<\/td>\n31.98<\/td>\n10.66<\/td>\n.000<\/td>\n<\/tr>\n
Group2<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

66.85<\/td>\n35.02<\/td>\n11.67<\/td>\n.000<\/td>\n<\/tr>\n
LDL-C<\/td>\nGroup1<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-35.03<\/td>\n8.51<\/td>\n3.47<\/td>\n.000<\/td>\n<\/tr>\n
Group1<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

21.06<\/td>\n8.82<\/td>\n3.60<\/td>\n.002<\/td>\n<\/tr>\n
Group2<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

-31.30<\/td>\n6.79<\/td>\n2.77<\/td>\n.000<\/td>\n<\/tr>\n
Group2<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

21.13<\/td>\n9.72<\/td>\n3.97<\/td>\n.003<\/td>\n<\/tr>\n
HDL-C<\/td>\nGroup1<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

11.88<\/td>\n5.49<\/td>\n2.24<\/td>\n.003<\/td>\n<\/tr>\n
Group1<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

-3.16<\/td>\n10.07<\/td>\n4.11<\/td>\n.476<\/td>\n<\/tr>\n
Group2<\/td>\nBaseline<\/p>\n

Induction<\/td>\n

14.05<\/td>\n5.21<\/td>\n2.12<\/td>\n.001<\/td>\n<\/tr>\n
Group2<\/td>\nInduction<\/p>\n

Treatment<\/td>\n

-1.01<\/td>\n9.11<\/td>\n3.72<\/td>\n.796<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Thus the net effect of teneligliptin evident was a statistically significant reduction in TC (p<0.001), TG (p<0.001) and LDL-C (p=0.003), but not the HDL-C (p=0.796) (Table 2 & Fig.1).A between group analysis using one way ANOVA revealed that there was no statistically significant difference between the groups treated with simvastatin and teneligliptin in all the four lipid parameters studied (Table 3).<\/p>\n\n\n\n
\"Fig.2<\/td>\nFigure 1: Comparison of means of <\/strong>lipid parameters (mg\/dl<\/strong>) of group 2<\/strong><\/p>\n

Click here to View Figure<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Table 3: Comparison between groups using one way <\/strong><\/p>\n\n\n\n\n\n\n\n\n
Parameters<\/strong><\/td>\nMean difference between group 1 and 2<\/strong><\/td>\nStandard error<\/strong><\/td>\nSignificance<\/strong><\/td>\n<\/tr>\n
Body weight(g)<\/td>\n9.25<\/td>\n14.67<\/td>\n.805<\/td>\n<\/tr>\n
Triglycerides(mg\/dl)<\/td>\n11.30<\/td>\n9.53<\/td>\n.318<\/td>\n<\/tr>\n
Total cholesterol(mg\/dl)<\/td>\n4.99<\/td>\n13.11<\/td>\n.923<\/td>\n<\/tr>\n
LDL(mg\/dl)<\/td>\n4.26<\/td>\n5.64<\/td>\n.735<\/td>\n<\/tr>\n
HDL(mg\/dl)<\/td>\n3.73<\/td>\n3.32<\/td>\n.516<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Compared to baseline mean body weight of group 1(273.75\u00b134.13 g) and group 2 (274.62\u00b137.20 g), there was a rise in body weight in both standard (286.62\u00b121.59 g) and treatment groups (280.87\u00b140.99 g)after induction though the increase was not statistically significant. In addition, a reduction in body weight was discernable in the study animals of both groups with treatment using standard\/drug, yet the fall in mean body weight was also not statistically significant in both groups. At the end of 6th<\/sup> week, the mean body weight of the standard group (267.62\u00b118.91 g) did not differ significantly (p=0.805) from that of the treatment group(258.37\u00b1 37.20 g)(Table 1 &\u00a03).<\/p>\n

Histopathologic examination using H&E stain revealed a normal liver section in groups 1 and 2 while mild fatty changes in the form of intracytoplasmic vacuolation with occasional areas of congestion could be detected in the control group. This indicates therapy with both simvastatin and teneligliptin had reversed the mild fatty change induced by the disease model. Sections of aorta on histopathology examination failed to reveal any significant changes in all three groups including the control group indicating that induction for a period of 4 weeks withhigh fat diet had not caused any significant atherosclerotic changes in the aorta of our study animals (Fig.2).<\/p>\n\n\n\n
\"Figure<\/td>\nFigure 2: Histopathological examination of the sections of liver under H&E staining<\/strong><\/p>\n

Click here to View Figure<\/span><\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Fig.2 shows normal liver section in groups 1 and 2 while mild fatty changes in the form of intracytoplasmicvacuolation with occasional areas of congestion in the control group. Section of aorta of group3 reveals normal histology<\/p>\n

Discussion<\/strong><\/p>\n

This study which was done in a rat model of diet induced hyperlipidemia has explicitly brought out the lipid lowering property of teneligliptin. This study has demonstrated that there is no statistical significance in the reduction in blood lipids between simvastatin and teneligliptin including serum TC, TG, LDL-C. In addition, though the change in mean serum HDL-C revealed a greater rise with simvastatin compared to teneligliptin, the rise was not statistically significant in both groups implying that the beneficial effect of teneligliptin on HDL-C levels closely paralleled that of simvastatin though had lesser magnitude to be statistically significant.<\/p>\n

Teneligliptin, classified as a class III DPP-4 inhibitor, has a unique structural feature that provides strong binding to DPP-4 enzymes compared with other gliptins and additional pleiotropic benefits6<\/sup>.The mechanism of action of teneligliptin which is used as a hypoglycemic agent in the treatment of T2DM is to amplify the levels of incretins namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide in response to meal intake, in turn resulting in augmented insulin secretion and attenuated glucagon secretion.6,7<\/sup><\/p>\n

The hypolipidemic effect of teneligliptin is probably due to increased lipid mobilization from the adipose tissue and its oxidation by sympathetic activation facilitated through GLP-1 receptor activation, thereby reducing blood lipid levels as demonstrated by Boschmann et al.16<\/sup><\/p>\n

Also, the administration of teneligliptin has been shown to reduce the body weight in six-weeks-old C57BL\/6N mice fed on a high-fat diet. The study has also established that teneligliptin increased oxygen consumption by 22% apart from proving that adipocyte hypertrophy and hepatic steatosis induced by a high-fat diet were suppressed by teneligliptin. In addition, a reduction in mean adipocyte size and hepatic TG content were demonstrable in this study.12<\/sup><\/p>\n

Another study investigating the effectiveness of teneligliptin in a mouse model of non-alcoholic steatohepatitis revealed that DPP4 inhibitors, by amplifying GLP-1 induced AMPK activation in hepatocytes inhibits hepatic lipogenesis, thus consequentially inhibiting cholesterol and TG biosynthesis. The AMPK activation also promotes fatty acid \u03b2-oxidation and reduction of free fatty acid.14<\/sup>Thus it is obvious that multiple pathophysiological mechanisms are potentially contributory to the hypolipidemic effect of teneligliptin.<\/p>\n

However two clinical studies in Japanese population have yielded conflicting results on teneligliptin\u2019s effect on lipid profile. But both these studies were done in a small sample size which could be one of the reasons in discordance in their results.9, 10<\/sup> Yet another large clinical study done in a Korean population wherein about 1732 patients on any of the six other gliptins including alogliptin, gemigliptin, sitagliptin, vildagliptin, saxagliptin and linagliptin were switched over to teneligptin, the effects of which were recorded at the end of 12 weeks.This study demonstrated that the weight decreased significantly by a mean of 0.4\u00a0kg from baseline in addition to a statistically significantdecrease in the mean BMI by 0.1\u00a0kg\/m2<\/sup>. Among the serum lipid parameters, TC and LDL-C levels decreased from baseline to week 12 (p <\u20090.05). Though a favorable trend in the change from mean baseline values were noted for TG and HDL-C they were not statistically significant.17<\/sup><\/p>\n

The greater potency and additional beneficial effects of teneligliptin could be attributed to the fact that it binds more tightly to the DPP-4 enzyme compared to other gliptins because of the \u201cJ-shaped\u201d structure formed by five rings.18 <\/sup>Thus the long-duration and strong binding property of teneligliptin could potentially yield greater clinically meaningful metabolic benefits.<\/p>\n

Conclusion<\/strong><\/p>\n

This study has delineated the hypolipidemic activity of teneligliptin which will be of potential clinical value in the therapeutic use of teneligliptinin type 2 diabetic patients especially in the face of increased concomitance in the occurrence of T2DM and hyperlipidemia.<\/p>\n

Conflicts of Interest<\/strong><\/p>\n

No conflicts of interest.<\/p>\n

Funding Source<\/strong><\/p>\n

The study was funded by an Institutional intramural grant, \u201cthe PRIME grant\u201d for academic projects by faculty investigators.<\/p>\n

References<\/strong><\/p>\n

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