Even Short-Term Telmisartan Treatment Ameliorated Insulin Resistance But Had No Influence on Serum Adiponectin and Tumor Necrosis Factor-Alpha Levels in Hypertensive Patients with Metabolic Syndrome

Abstract

Background:

We investigated the effect of short-term telmisartan usage in addition to lifestyle changes such as diet and exercise on insulin resistance, lipid metabolism, and serum adiponectin and tumor necrosis factor-alpha (TNF-α) levels in hypertensive patients with metabolic syndrome (MetS).

Methods:

A total of 36 hypertensive patients with MetS were randomized to telmisartan and control groups in an open-labeled prospective study.

Results:

There were significant decreases in anthropometric variables of patients according to baseline measurements in both groups at the end of the study. Serum insulin level and insulin resistance assessed by homeostasis model assessment-insulin resistance were decreased significantly in the telmisartan group (P = 0.040 and P = 0.034, respectively) compared with the controls, while there was no statistically significant change in the lipid profiles of the two groups. Serum adiponectin level was increased by 19.1% ± 41.7% in the telmisartan group, but intergroup analysis revealed no significant change. There was also no significant change in serum TNF-α level in either group.

Conclusion:

It has been observed that even short-term telmisartan treatment had favorable effects on insulin resistance and glucose metabolism compared with lifestyle changes alone. The fundamental effect of telmisartan treatment on insulin resistance renders it a good therapeutic option for hypertensive patients with MetS.

Introduction

Metabolic syndrome (MetS) describes the presence of a disease cluster, including glucose intolerance, insulin resistance, hypertension, visceral obesity, atherogenic dyslipidemia, and prothrombotic and pro-inflammatory state.^1,2 The prevalence of MetS is increasing and varies among different populations. Insulin resistance has been suggested as an underlying pathogenic factor in MetS, and hypertension is an important and frequently seen component of MetS.^3,4 Since MetS is associated with an increased risk of coronary heart disease, an aggressive therapeutic approach directed against all the MetS individual components is recommended. Thus, it is logical to select drugs that act on the pathophysiology of the MetS and have favorable effects on all its components.

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and thereby increases insulin sensitivity.⁵ One of the genes that regulates by the PPAR-γ-bound mechanisms is adiponectin. Adiponectin is secreted by adipose cells and serves to link obesity with insulin resistance. It has been shown that adiponectin could downregulate inflammatory responses and may promote beta cell survival.^6

–9 The effects of adiponectin and tumor necrosis factor-alpha (TNF-α) on insulin resistance and inflammatory state are opposite, and it has been shown that usage of PPAR-γ agonists increases the serum adiponectin levels and inhibits secretion of TNF-α by macrophages and adipocytes.¹⁰

It has been shown that telmisartan, an antihypertensive angiotensin II (Ang II) type 1 receptor blocker, was capable of activating PPAR-γ, to provide beneficial effects for glucose and lipid metabolism, and has provided a novel approach to addressing the multifactorial components of MetS.^11,12 In addition, unlike thiazolidinediones, telmisartan-induced PPAR-γ activation is not associated with weight gain.¹³

In this study, we aimed to investigate the effect of 80 mg/day telmisartan usage for 8 weeks in addition to lifestyle changes such as diet and exercise on body fat ratio, arterial blood pressure (BP), insulin resistance, glucose and lipid metabolism, and serum adiponectin and TNF-α levels in drug-naive hypertensive patients with MetS.

Subjects and Methods

This study was planned as a prospective open-labeled randomized trial. Patients were recruited from an endocrinology outpatient clinic of a tertiary referral center. A total of 36 uncomplicated essential hypertensive patients with MetS were enrolled into the study. Informed consent was obtained from all participants, and the study was performed in accordance with the Declaration of Helsinki and with the approval of the local ethics committee.

Subjects

Inclusion criteria were as follows: age between 18 and 70 years, presence of MetS with a diagnosis of hypertension, which was made according to the Eight Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High BP (The JNC 8 Report).¹⁴ MetS was diagnosed if three or more of the criteria listed below were present according to the National Cholesterol Education Program Adult III Treatment Panel (NCEP-ATP III) criteria: fasting plasma glucose (FG) ≥110 mg/dL; fasting triglycerides (TG) ≥150 mg/dL; high density lipoprotein cholesterol (HDL-C) <40 mg/dL (men) or <50 mg/dL (women); and waist circumference >102 cm (men) or >88 cm (women).¹⁵

Presence of identifiable causes of hypertension such as sleep apnea, renovascular and endocrine disease, usage of any medications for hypertension before the beginning of the study, usage of any drugs that interact with carbohydrate or lipid metabolism, presence of type 2 diabetes mellitus or cardiovascular, renal, gastrointestinal, hepatic, rheumatological, neoplastic, infectious, and other endocrine diseases (except dyslipidemia), and substance abuse such as alcohol and tobacco were the exclusion criteria.

Study design

At randomization, standard diet and lifestyle modification, including physical exercise, were administered to all patients according to the JNC 8 Report. Patients were encouraged to lose weight and implement diet modifications that reduced intakes of energy, saturated and trans fatty acids, cholesterol, and sodium (<6 g/day sodium chloride). Total energy intake was calculated as 25–30 kcal/kg for ideal weight of a patient and was composed of 45%–65% carbohydrate, 20%–35% fat, and 10%–15% protein. Saturated fat and dietary cholesterol intakes were limited to <7% of total calories and <200 mg/day, respectively. A physical activity program was planned as 40–60 min of walking at least 3 days per week.

For the clinical trial, patients were randomized to receive lifestyle changes only (control group, n [male/female] = 18 [4/14]) or 80 mg/day telmisartan in addition to lifestyle changes (telmisartan group, n [male/female] = 18 [3/15]) for 8 weeks. At the beginning of the study, a complete physical examination and electrocardiographic investigation were performed by the same physician. Body weight, height, and waist circumference were measured and recorded. Body mass index (BMI) was computed as weight in kilograms divided by height in meters squared. Fat percentage was measured on a daily-calibrated scale and recorded (Tanita, Body Fat Monitor; Tanita Corporation, Tokyo, Japan). BP measurements were obtained from each patient's right arm in the seated position using a standard mercury sphygmomanometer after 10 min of rest in the morning. Three successive BP readings were obtained at 5-min intervals and averaged.

Subsequently, after a 10-hr fasting period, an intravenous catheter was inserted into an antecubital vein in the morning, and blood samples were taken for biochemical parameters and determination of serum adiponectin and TNF-α levels. Serum glucose and insulin levels were measured thrice at 5-min intervals for the calculation of insulin sensitivity using the homeostasis model assessment-insulin resistance (HOMA-IR) index {formula: [(fasting glucose (mg/dL)/18) × fasting insulin (mU/mL)]/22.5}. Blood was collected into tubes with ethylendiaminetetraacetic acid (EDTA) as the anticoagulating substance for plasma preparation and serum separator tubes with clot activator. Samples were centrifuged at 2500 g for 15 min to separate plasma and serum. Specimens that would be used for the detection of serum adiponectin and TNF-α levels were stored at −80°C until analysis. All procedures were repeated at the end of the study. The primary outcome of the study was amelioration in insulin resistance, measured by the change in the HOMA-IR, from baseline to the end of the treatment period of the telmisartan group. The secondary outcome measures were the change in serum adiponectin and TNF-α levels from baseline to the end of the treatment period of the telmisartan group.

Measurements

Baseline laboratory parameters, including serum glucose, total cholesterol (T-C), TG, and HDL-C, were measured using autoanalyzer (Aeroset System Abbott; Abbott Laboratories, Diagnostic Division, IL), and insulin levels were measured by Roche Elecsys 2010 electrochemiluminescent immunoassay analyzer using the manufacturer's method (Roche, IN). Low density lipoprotein cholesterol (LDL-C) was calculated by Friedewald formula as T-C – (HDL-C+TG/5) in case of measured TG level below 400 mg/dL. Serum levels of adiponectin (Linco Research, MO) (sensitivity = 0.78 ng/mL, intra-assay variation = 3.3%, interassay variation = 5.6%) and ultrasensitive TNF-α (BioSource, CA) (sensitivity = 0.7 pg/mL, intra-assay variation = 4.5%, interassay variation = 9%) were measured using a commercial sandwich ELISA kit according to the manufacturer's instruction.

Statistical analyses

Chi-squared test was used for clinical data variables. Comparisons between groups were performed using Student's t-test for normally distributed variables and Mann–Whitney test for non-normal variables. Paired t-test and Wilcoxon signed-rank test were used for within-group comparisons. Analysis of covariance (ANCOVA) was performed for multivariate analysis. Correlation analysis was performed using Pearson's coefficient test. The data were analyzed using SPSS for Windows, Version 11.5 and shown as mean ± standard deviation. A P value of less than 0.05 was considered statistically significant.

Results

Anthropometric, clinical, and biochemical parameters of the patients at baseline and after 8 weeks intervention are summarized in Table 1. Mean ages of patients were 44.5 ± 9.8 (range: 30–57) years in the control group and 44.8 ± 6.7 (range: 34–61) years in the telmisartan group. There were no significant differences between the two groups regarding age, gender, anthropometric measurements, BP, lipid fractions, and HOMA-IR. Telmisartan was well tolerated and used regularly by the patients. No serious adverse effect was seen during the study period. All patients completed the study. Percentage changes in clinical, biochemical, and serum cytokine levels after 8 weeks are summarized in Table 2.

Table 1.

Clinical and Biochemical Parameters of Patients at Baseline and After 8-Week Intervention

	Control group (n = 18)			Telmisartan group (n = 18)
	Baseline	Eighth week	P	Baseline	Eighth week	P
BMI (kg/m²)	37.5 ± 6.7	36.1 ± 6.9	0.002	37.7 ± 5.3	37.0 ± 5.7	0.008
Fat percentage (%)	41.4 ± 7.1	39.9 ± 8.0	0.022	44.0 ± 6.9	42.9 ± 7.2	0.009
Waist C (cm)	104.6 ± 10.1	101.4 ± 12.0	0.013	104.6 ± 5.7	102.3 ± 11.0	0.023
SBP (mmHg)	155.2 ± 12.4	145.5 ± 17.3	0.033	162.2 ± 12.6	130.5 ± 12.4	0.0001
DBP (mmHg)	95.0 ± 5.9	90.0 ± 8.4	NS	98.8 ± 8.3	88.3 ± 6.8	0.0001
FG (mg/dL)	93.6 ± 12.6	95.4 ± 12.6	NS	109.8 ± 30.6	102.6 ± 16.2	NS
Insulin (mU/L)	12.7 ± 6.2	13.9 ± 8.3	NS	15.4 ± 8.9	11.4 ± 6.5	0.001
HOMA-IR	2.9 ± 1.3	3.3 ± 2.1	NS	4.6 ± 4.7	3.0 ± 2.2	0.001
T-C (mg/dL)	198.3 ± 36.3	203.7 ± 35.6	NS	212.5 ± 52.1	207.2 ± 40.2	NS
LDL-C (mg/dL)	128.6 ± 30.9	129.3 ± 29.7	NS	133.9 ± 45.0	132.6 ± 30.0	NS
HDL-C (mg/dL)	42.7 ± 7.8	42.8 ± 8.1	NS	45.6 ± 7.1	46.5 ± 6.1	NS
TG (mg/dL)	134.8 ± 43.6	157.4 ± 75.3	NS	164.3 ± 69.7	140.4 ± 64.0	NS
Adiponectin (ng/dL)	17.8 ± 9.4	18.9 ± 14.5	NS	17.0 ± 6.3	19.1 ± 5.1	NS
TNF-α (pg/mL)	1.3 ± 0.4	1.3 ± 0.6	NS	0.8 ± 0.5	0.7 ± 0.5	NS

Data are expressed as mean ± standard deviation.

BMI, body mass index; FG, fasting plasma glucose; DBP, diastolic blood pressure; HDL-C, high density lipoprotein cholesterol; HOMA-IR index, homeostasis model assessment-insulin resistance index; LDL-C, low density lipoprotein cholesterol; SBP, systolic blood pressure; T-C, total cholesterol; TG, triglycerides; TNF-α, tumor necrosis factor-alpha; NS, not significant; Waist C, waist circumference.

Table 2.

Percentage Changes in Clinical and Biochemical Parameters After 8-Week Intervention

Δ change	Control group	Telmisartan group	P
BMI	−3.6 ± 4.2	−2.0 ± 2.8	NS
Fat percentage	−4.1 ± 6.9	−2.5 ± 3.7	NS
Waist circumference	−3.2 ± 4.9	−2.2 ± 7.2	NS
SBP	−5.9 ± 11.8	−19.3 ± 6.9	0.0001
DBP	−4.8 ± 11.5	−10.1 ± 9.2	NS
FG	1.4 ± 17.5	−4.5 ± 13.8	NS
Insulin	19.4 ± 83.4	−23.9 ± 21.5	0.040
HOMA-IR	25.8 ± 98.8	−27.5 ± 22.5	0.034
T-C	4.3 ± 19.3	−0.7 ± 13.9	NS
LDL-C	4.0 ± 29.6	3.5 ± 21.8	NS
HDL-C	0.6 ± 9.1	2.6 ± 11.0	NS
TG	21.1 ± 60.8	−9.7 ± 32.2	NS
Adiponectin	7.8 ± 54.3	19.1 ± 41.7	NS
TNF-α	3.3 ± 38.8	7.1 ± 86.9	NS

Data are expressed as mean ± standard deviation.

Anthropometric variables

After the 8-week intervention, there were statistically significant decrements in BMI, fat percentage, and waist circumference in the patients in both groups compared with baseline measurements. When the two patient groups were compared, there were no statistically significant differences in percentage change in BMI, fat percentage, and waist circumference.

Blood pressure

Systolic BP (SBP) was statistically significantly decreased in both control and telmisartan groups (P = 0.033, P = 0.0001, respectively), while diastolic BP (DBP) was decreased only in the telmisartan group (P = 0.0001) compared with baseline values. Percentage changes in SBP were more pronounced in the telmisartan group compared with controls (−19.3% ± 6.9% vs. −5.9% ± 11.8%; P = 0.0001).

Biochemical variables

At the end of the eighth week, serum insulin levels and HOMA-IR were decreased significantly in the telmisartan group (both P = 0.001) compared with baseline values, while they were not changed in the control group. Percentage changes in serum insulin levels and HOMA-IR were also statistically different when the two groups were compared (P = 0.040 and P = 0.034, respectively) (Fig. 1). ANCOVA was performed by taking percentage changes of adiponectin, TNF-α, LDL-C, HDL-C, TG, BMI, fat percentage, and waist circumference as covariates for HOMA-IR percentage change. There was still a statistically significant difference between the two groups after controlling for the effects of the covariates (P = 0.002). There was no covariate in the model that was significantly related to HOMA-IR percentage change (P > 0.05). There was a positive correlation between serum insulin levels and BMI (r = 337, P = 0.04). No significant change was found in LDL-C, HDL-C, TG, and FG in intra- and intergroup comparisons.

FIG. 1.

Mean percentage change of HOMA-IR and serum insulin, adiponectin, and TNF-α levels in control and telmisartan groups. HOMA-IR, homeostasis model assessment-insulin resistance; TNF-α, tumor necrosis factor-alpha.

Serum cytokine levels

Serum adiponectin level was increased by 19.1% ± 41.7% in the telmisartan group, but the difference was not statistically significant compared with the control group. There was also no significant change in serum TNF-α levels in either group. ANCOVA was also performed by taking TNF-α and adiponectin as dependent variables. Nevertheless, there was still no statistically significant difference between the two groups after controlling for the effects of the covariates (both P > 0.05).

Discussion

In the present study, we found that even short-term treatment with telmisartan significantly improved insulin sensitivity in hypertensive patients with MetS, while it did not influence their lipid parameters and serum adiponectin and TNF-α levels.

Insulin resistance is thought to be the underlying pathogenic mechanism of both MetS and essential hypertension.^1
–3 PPAR-γ is a proven therapeutic target in the treatment of insulin resistance, diabetes, and MetS.^5,10 The effect of the telmisartan on PPAR-γ receptors is partial, and the strength of PPAR-gamma activation is about one-third of that of glitazones. This partial PPAR-γ agonistic behavior of telmisartan carries importance in the treatment of hypertensive patients with MetS.¹² Although the results of previous studies examining the effect of telmisartan on insulin resistance are contradictory, a meta-analysis done by Takagi et al. reported its beneficial effects on insulin resistance.¹⁶ Their detailed analyses determined that the treatment duration, patients' age, gender, and baseline BP did not modulate the effects of telmisartan.

Derosa et al.¹⁷ reported no changes in serum insulin, glucose, and HOMA-IR levels and BMI of patients with hypertension and type 2 diabetes mellitus, while an improvement was observed in lipid parameters following 12 months treatment with 40 mg/day telmisartan. Similarly, Bahadir et al.¹⁸ reported that neither telmisartan nor losartan provided amelioration in HOMA-IR, serum lipid levels, or BMI in hypertensive patients with MetS. However, the dosage of telmisartan used in Derosa et al.'s study and the baseline HOMA-IR levels of patients in Bahadir et al.'s study were lower compared with values in the present study. In line with our results, Vitale et al.¹⁹ reported that insulin sensitivity measured by HOMA-IR was improved after telmisartan treatment in hypertensive patients with MetS. A relationship between insulin resistance, BMI, and adiposity has been recognized.

In the present study, there were significant decreases in BMI, percentage of body fat, and waist circumference with respect to baseline measurements after the treatment in both the control and telmisartan groups. Thus, the improvements in insulin sensitivity observed in this study cannot be attributed to the weight loss. The observed effect of short-term telmisartan usage on insulin resistance in our study supports Takagi et al.'s results reporting that telmisartan therapy significantly improved metabolic parameters in patients with MetS.

But contrary to expectations, in TRANSCEND [Telmisartan Randomised Assessment Study in ACE intolerant subjects with cardiovascular Disease] study, addition of the telmisartan to usual care did not prevent development of diabetes or lead to regression of impaired fasting glucose or impaired glucose tolerance in patients at high risk for cardiovascular disease.²⁰ The TRANSCEND study results suggest that the positive effect of telmisartan treatment on insulin resistance obtained in our study may not sustain in the long term.

Adipocyte-derived proteins and cytokines such as adiponectin and TNF-α have been implicated in energy homeostasis, insulin resistance, and atherothrombosis. TNF-α impairs insulin signaling by inhibition of PPAR-γ activity at pretranslational and post-translational levels and some anti-inflammatory and antiatherogenic effects of adiponectin come through by inhibition of TNF-α expression.^9,21
–23 Recent studies have implicated an involvement of TNF-α in the development of salt-sensitive hypertension induced by Ang II.^24,25

Derosa et al.²⁶ reported that telmisartan treatment in addition to rosiglitazone decreased serum TNF-α levels in type 2 diabetic patients with MetS, but we did not find any significant change in serum TNF-α levels with telmisartan in our study group. Their patients had type 2 diabetes mellitus in addition to MetS and higher basal TNF-α levels compared with our patients. Furthermore, their patients were using a known PPAR agonist, rosiglitazone, which can affect serum TNF-α levels.

Unlike TNF-α, plasma concentrations of adiponectin are reduced in obese and insulin-resistant states such as MetS and hypertension.^27
–29 It was reported that telmisartan caused a dose-dependent increase in adiponectin mRNA levels through PPAR-γ-dependent target genes in differentiated adipocytes,³⁰ but the clinical effect of telmisartan on serum adiponectin level is not conclusive and there are contradictory reports.^31

–34 We were unable to determine any significant change in serum adiponectin levels or lipid parameters in this study. Duration of telmisartan usage and/or genetic variations may be the responsible underlying factors for the different results since the telmisartan usage was longer in studies that reported a significant change in serum adiponectin levels and lipid parameters.^35,36

Moreover, genetic variations in the adiponectin gene as reported by Kang et al.³⁷ can affect the treatment response of the circulating adiponectin levels. Although telmisartan is considered a partial PPAR-γ agonist, Kamari et al.³⁸ reported that its beneficial effect in a fructose-induced hypertension, hypertriglyceridemia, and hyperinsulinemia rat model is apparently not mediated by adiponectin elevation but rather by direct inhibition of AT-1 receptor. The renin-angiotensin-aldosterone system is activated in patients with MetS, and AT-1 receptor blockade may affect the expression of genes involved in glucose metabolism and improve insulin sensitivity.^39,40

Amelioration of insulin resistance with telmisartan treatment may be caused by other mechanisms, including inhibition of AT-1 receptors, rather than by PPAR-γ activation. Furthermore, it is possible that serum levels might not reflect the exact change in locally produced adiponectin and TNF-α with telmisartan treatment.

In conclusion, it has been observed that even short-term telmisartan treatment (with lifestyle changes) had favorable effects on insulin resistance compared with lifestyle changes alone. The fundamental effect of short-term (such as the presented 8-week) telmisartan treatment on insulin resistance renders it a good therapeutic option in hypertensive patients with MetS.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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